Amivantamab in combination with carboplatin and pemetrexed for the treatment of non-small cell lung cancer (NSCLC)

Abstract

Disclosed herein are methods of using amivantamab in combination with carboplatin and pemetrexed for the treatment of non-small cell lung cancer (NSCLC).

Description

103693.007525 / JBI6936 AMIVANTAMAB IN COMBINATION WITH CARBOPLATIN AND PEMETREXED FOR THE TREATMENT OF NON-SMALL CELL LUNG CANCER (NSCLC) CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of United States Provisional Patent Application No.63 / 676,192, filed on July 26, 2024, United States Provisional Patent Application No.63 / 687,630, filed on August 27, 2024, and United States Provisional Patent Application No.63 / 696,826, filed on September 19, 2024, the disclosures of each of which are incorporated herein by reference in their entireties. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which is being submitted herewith electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on July 21, 2025, is named 103693_007525_SL.xml and is 19,936 bytes in size. FIELD

[0003] The present disclosure provides methods of using amivantamab in combination with carboplatin and pemetrexed for the treatment of non-small cell lung cancer (NSCLC). BACKGROUND

[0004] Stratification of advanced non-small cell lung cancer (NSCLC) based on oncogenic driver mutations has improved the overall survival and quality of life for patients with actionable driver mutations and effectiveness of solid tumor targeted therapy. In NSCLC, specific mutations in the EGFR gene are associated with high response rates to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Although the majority of NSCLC patients with EGFR mutations initially respond to EGFR TKI therapy, virtually all acquire resistance that prevents a durable response. Nearly 60% of all tumors that become resistant to EGFR tyrosine kinase inhibitors increase Hepatocyte Growth Factor Receptor (c-Met) expression, amplify the c-Met gene, or increase its only known ligand, Hepatocyte Growth Factor (Turke et al., Cancer Cell, 17:77-88, 2010).

[0005] Progression of acquired resistance to EGFR-TKI such as osimertinib in epidermal growth factor receptor mutant (EGFRm) NSCLC likely arises from complex and103693.007525 / JBI6936 heterogenous patterns of resistance together with co-occurrence of multiple resistance mechanisms, and as such the details of such mechanisms remain elusive. Thus, duration and durability of response with targeted therapies pose unique challenges, and there remains a need for new treatment paradigms for patients with NSCLC that had disease progression on or after treatment with at least one prior tyrosine kinase inhibitor (TKI). SUMMARY

[0006] Disclosed herein are methods of reducing an adverse reaction associated with the use of amivantamab in combination with carboplatin and pemetrexed for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the methods comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, and who experiences a grade 1 or grade 2 infusion-related adverse reaction: interrupting the intravenous amivantamab infusion, monitoring the subject until the grade 1 or grade 2 infusion-related adverse reaction resolves, resuming the intravenous amivantamab infusion at 50% of the infusion rate at which the grade 1 or grade 2 infusion-related adverse reaction occurred, and, if there are no additional infusion-related adverse reactions after 30 minutes, increasing the infusion rate; who experiences a grade 3 infusion-related adverse reaction: interrupting the intravenous amivantamab infusion, monitoring the subject until the grade 3 infusion- related adverse reaction resolves, resuming the intravenous amivantamab infusion at 50% of the infusion rate at which the grade 3 infusion-related adverse reaction occurred, and, if there are no additional infusion-related adverse reactions after 30 minutes, increasing the infusion rate; or who experiences a grade 4 infusion-related adverse reaction: permanently discontinuing administration of the amivantamab. 2103693.007525 / JBI6936

[0007] Disclosed herein are methods of reducing an adverse reaction associated with the use of amivantamab in combination with carboplatin and pemetrexed for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the methods comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who is suspected of experiencing interstitial lung disease / pneumonitis of any grade: withholding administration of the amivantamab; or who experiences interstitial lung disease / pneumonitis of any grade: permanently discontinuing administration of the amivantamab.

[0008] Disclosed herein are methods of reducing an adverse reaction associated with the use of amivantamab in combination with carboplatin and pemetrexed for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the methods comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences a grade 1 dermatologic adverse reaction: reassessing after two weeks; who experiences a grade 2 dermatologic adverse reaction: reassessing after two weeks, and if the grade 2 dermatologic adverse reaction does not improve, administering a reduced dose of the amivantamab to the subject; who experiences a grade 3 dermatologic adverse reaction: withholding the amivantamab and resuming administration of the amivantamab at a reduced dose if the grade 3 dermatologic adverse reaction becomes a grade 2 or lower dermatologic adverse reaction, or permanently discontinuing the treatment if 3103693.007525 / JBI6936 no improvement in the grade 3 dermatologic adverse reaction occurs within 2 weeks; or who experiences a grade 4 dermatologic adverse reaction or severe bullous, blistering, or exfoliating skin: permanently discontinuing administration of the amivantamab.

[0009] Disclosed herein are methods of reducing an adverse reaction associated with the use of amivantamab in combination with carboplatin and pemetrexed for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the methods comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences at least one other grade 3 adverse reaction: withholding amivantamab until the at least one other grade 3 adverse reaction reduces to less than or equal to grade 1 or baseline and resuming the amivantamab at the same dose if the subject recovers from the grade 3 adverse reaction within 1 week; resuming the amivantamab at a reduced dose if the subject recovers from the grade 3 adverse reaction after 1 week but within 4 weeks; or permanently discontinuing the amivantamab if the subject does not recover from the grade 3 adverse reaction within 4 weeks; or who experiences at least one other grade 4 adverse reaction: withholding amivantamab until the at least one other grade 4 adverse reaction reduces to less than or equal to grade 1 or baseline and resuming the amivantamab at a reduced dose if the subject recovers from the grade 4 adverse reaction within 4 weeks; or permanently discontinuing the amivantamab if the subject does not recover from the grade 4 adverse reaction within 4 weeks or if the grade 4 infusion-related adverse reaction is a recurrent grade 4 infusion-related adverse reaction. 4103693.007525 / JBI6936

[0010] Disclosed herein are methods of treating locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations in a subject whose NSCLC has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the methods comprising administering to the subject an approved drug product comprising amivantamab, in combination with carboplatin and pemetrexed.

[0011] Disclosed herein are methods of improving median progression free survival (PFS) in a population of subjects having locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations whose NSCLC has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the methods comprising administering to the population of subjects an approved drug product comprising amivantamab, in combination with carboplatin and pemetrexed.

[0012] Disclosed herein are methods of improving overall response rate (ORR) in a population of subjects having locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations whose NSCLC has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the methods comprising administering to the population of subjects an approved drug product comprising amivantamab, in combination with carboplatin and pemetrexed.

[0013] Disclosed herein are methods of improving median duration of response (DOR) in a population of subjects having locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations whose NSCLC has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the methods comprising administering to the population of subjects an approved drug product comprising amivantamab, in combination with carboplatin and pemetrexed. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The summary, as well as the following detailed description, is further understood when read in conjunction with the appended drawings. For the purpose of illustrating the disclosed methods, there are shown in the drawings exemplary embodiments of the methods; however, the methods are not limited to the specific embodiments disclosed. In the drawings:

[0015] FIG.1 shows an exemplary schematic overview of the study.

[0016] FIG.2 is a Kaplan-Meier curve of progression-free survival (PFS) in previously treated NSCLC patients by blinded independent central review (BICR) 5103693.007525 / JBI6936 assessment. The PFS benefit of Rybrevant in combination with carboplatin and pemetrexed (Rybrevant CP) compared to carboplatin and pemetrexed (CP) was consistent across all the predefined subgroups analysed, including ethnicity, age, gender, smoking history, and CNS metastases status at study entry.

[0017] FIG.3 is a Kaplan-Meier curve of overall survival (OS) in previously treated NSCLC patients.

[0018] FIG.4 is a Kaplan-Meier curve of PFS in previously untreated NSCLC patients by BICR assessment. The PFS benefit of Rybrevant in combination with carboplatin and pemetrexed (R-CP) compared to carboplatin and pemetrexed (CP) was consistent across all the predefined subgroups of brain metastases at study entry (yes or no), age (< 65 or ≥ 65), sex (male or female), race (Asian or non Asian), weight (< 80 kg or ≥ 80 kg), ECOG performance status (0 or 1), and smoking history (yes or no).

[0019] FIG.5 is a Kaplan-Meier curve of OS in previously untreated NSCLC patients by BICR assessment.

[0020] FIG.6 is a Kaplan-Meier curve of PFS in previously untreated NSCLC patients by BICR assessment.

[0021] FIG.7 is a Kaplan-Meier curve of PFS in previously treated NSCLC patients by BICR assessment - MARIPOSA-2.

[0022] FIG.8 is a Kaplan-Meier Curve of PFS in previously untreated NSCLC patients by BICR assessment – Papillon Study. DETAILED DESCRIPTION

[0023] The disclosed methods may be understood more readily by reference to the following detailed description taken in connection with the accompanying figures, which form a part of this disclosure. It is to be understood that the disclosed methods are not limited to the specific methods described and / or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed methods.

[0024] It is to be understood that the terminology used herein is for describing particular embodiments only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. 6103693.007525 / JBI6936

[0025] Although any methods and materials similar or equivalent to those described herein may be used in the practice for testing of the present invention, exemplary materials and methods are described herein. In describing and claiming the present invention, the following terminology will be used.

[0026] When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list, and every combination of that list, is a separate embodiment. For example, a list of embodiments presented as “A, B, or C” is to be interpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.”

[0027] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a cell” includes a combination of two or more cells, and the like.

[0028] The conjunctive term “and / or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and / or,” a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or.”

[0029] The transitional terms “comprising,” “consisting essentially of,” and “consisting of” are intended to connote their generally accepted meanings in the patent vernacular; that is, (i) “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; (ii) “consisting of” excludes any element, step, or ingredient not specified in the claim; and (iii) “consisting essentially of” limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention. Embodiments described in terms of the phrase “comprising” (or its equivalents) also provide as embodiments those independently described in terms of “consisting of” and “consisting essentially of.”

[0030] “Co-administration,” “administration with,” “administration in combination with,” “in combination with” or the like, encompass administration of the 7103693.007525 / JBI6936 selected therapeutics or drugs to a single patient, and are intended to include treatment regimens in which the therapeutics or drugs are administered by the same or different route of administration or at the same or different time. “In combination with,” as it relates to amivantamab in combination with carboplatin and pemetrexed, is synonymous with a combination therapy comprising amivantamab, carboplatin, and pemetrexed, wherein the amivantamab, carboplatin, and pemetrexed are administered on the same or different days as separate infusions.

[0031] “Isolated” refers to a homogenous population of molecules (such as synthetic polynucleotides, polypeptides vectors or viruses) which have been substantially separated and / or purified away from other components of the system the molecules are produced in, such as a recombinant cell, as well as a protein that has been subjected to at least one purification or isolation step. “Isolated” refers to a molecule that is substantially free of other cellular material and / or chemicals and encompasses molecules that are isolated to a higher purity, such as to 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% purity.

[0032] “Treat,” “treating” or “treatment” of a disease or disorder such as cancer refers to accomplishing one or more of the following: reducing the severity and / or duration of the disorder, inhibiting worsening of symptoms characteristic of the disorder being treated, limiting or preventing recurrence of the disorder in subjects that have previously had the disorder, or limiting or preventing recurrence of symptoms in subjects that were previously symptomatic for the disorder.

[0033] “Prevent,” “preventing,” “prevention,” or “prophylaxis” of a disease or disorder means preventing that a disorder occurs in subject.

[0034] “Diagnosing” or “diagnosis” refers to methods to determine if a subject is suffering from a given disease or condition or may develop a given disease or condition in the future or is likely to respond to treatment for a prior diagnosed disease or condition, i.e., stratifying a patient population on likelihood to respond to treatment. Diagnosis is typically performed by a physician based on the general guidelines for the disease to be diagnosed or other criteria that indicate a subject is likely to respond to a particular treatment.

[0035] “Responsive,” “responsiveness” or “likely to respond” refers to any kind of improvement or positive response, such as alleviation or amelioration of one or more symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or 8103693.007525 / JBI6936 palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.

[0036] “Therapeutically effective amount” refers to an amount effective, at doses and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount may vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of a therapeutic or a combination of therapeutics to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic or combination of therapeutics that include, for example, improved well-being of the patient.

[0037] “Subject” includes any human or nonhuman animal. “Nonhuman animal” includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. The terms “subject” and “patient” are used interchangeably herein. In some embodiments, the subject is an adult patient.

[0038] “About” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. Unless explicitly stated otherwise within the Examples or elsewhere in the Specification in the context of a particular assay, result or embodiment, “about” means within one standard deviation per the practice in the art, or a range of up to 5%, whichever is larger.

[0039] “Cancer” refers to an abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread) to other areas of a patient’s body.

[0040] “EGFR or c-Met expressing cancer” refers to cancer that has detectable expression of EGFR or c-Met or has EGFR or c-Met mutation or amplification. EGFR or c- Met expression, amplification and mutation status can be detected using know methods, such as sequencing, fluorescent in situ hybridization, immunohistochemistry, flow cytometry or western blotting.

[0041] “Epidermal growth factor receptor” or “EGFR” refers to the human EGFR (also known as HER1 or ErbB1 (Ullrich et al., Nature 309:418-425, 1984)) having the amino acid sequence shown in GenBank accession number NP_005219, as well as naturally- occurring variants thereof.

[0042] “Hepatocyte growth factor receptor” or “c-Met” as used herein refers to the human c-Met having the amino acid sequence shown in GenBank Accession No: NP_001120972 and natural variants thereof. 9103693.007525 / JBI6936

[0043] “Bispecific anti-EGFR / c-Met antibody” or “bispecific EGFR / c-Met antibody” refers to a bispecific antibody having a first domain that specifically binds EGFR and a second domain that specifically binds c-Met. The domains specifically binding EGFR and c-Met are typically VH / VL pairs, and the bispecific anti-EGFR / c-Met antibody is monovalent in terms of binding to EGFR and c-Met.

[0044] “Specific binding” or “specifically binds” or “specifically binding” or “binds” refer to an antibody binding to an antigen or an epitope within the antigen with greater affinity than for other antigens. Typically, the antibody binds to the antigen or the epitope within the antigen with an equilibrium dissociation constant (KD) of about 5x10-8M or less, for example about 1x10-9M or less, about 1x10-10M or less, about 1x10-11M or less, or about 1x10-12M or less, typically with the KDthat is at least one hundred-fold less than its KD for binding to a non-specific antigen (e.g., BSA, casein). The dissociation constant may be measured using known protocols. Antibodies that bind to the antigen or the epitope within the antigen may, however, have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca fascicularis (cynomolgus, cyno) or Pan troglodytes (chimpanzee, chimp). While a monospecific antibody binds one antigen or one epitope, a bispecific antibody binds two distinct antigens or two distinct epitopes.

[0045] “Antibodies” is meant in a broad sense and includes immunoglobulin molecules including monoclonal antibodies including murine, human, humanized and chimeric monoclonal antibodies, antigen binding fragments, multispecific antibodies, such as bispecific, trispecific, tetraspecific etc., dimeric, tetrameric or multimeric antibodies, single chain antibodies, domain antibodies and any other modified configuration of the immunoglobulin molecule that comprises an antigen binding site of the required specificity. “Full length antibodies” are comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds as well as multimers thereof (e.g., IgM). Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (comprised of domains CH1, hinge, CH2 and CH3). Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). The VH and the VL regions may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR). Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-to-carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. 10103693.007525 / JBI6936

[0046] “Biosimilar” (of an approved reference product / biological drug, i.e., reference listed drug) refers to a biological drug that is highly similar to the reference drug with no clinically meaningful differences between the biosimilar and the reference drug in terms of safety, purity and potency, based upon data derived from (a) analytical studies that demonstrate that the biological product is highly similar to the reference drug; (b) animal studies (including the assessment of toxicity); and / or (c) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biosimilar. The biosimilar may be an interchangeable product that may be substituted for the reference product at the pharmacy without the intervention of the prescribing healthcare professional. To meet the additional standard of “interchangeability,” the biosimilar is to be expected to produce the same clinical result as the reference product in any given patient and, if the biosimilar is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biosimilar and the reference product is not greater than the risk of using the reference product without such alternation or switch. The biosimilar utilizes the same mechanisms of action for the proposed conditions of use to the extend the mechanisms are known for the reference product. The condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biosimilar have been previously approved for the reference product. The route of administration, the dosage form, and / or the strength of the biosimilar are the same as those of the reference product and the biosimilar is manufactured, processed, packed or held in a facility that meets standards designed to assure that the biosimilar continues to be safe, pure and potent. The biosimilar may include minor modifications in the amino acid sequence when compared to the reference product, such as N- or C-terminal truncations that are not expected to change the biosimilar performance.

[0047] “Complementarity determining regions” (CDR) are antibody regions that bind an antigen. CDRs may be defined using various delineations such as Kabat (Wu et al. (1970) J Exp Med 132: 211-50) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al. (1987) J Mol Biol 196: 901-17), IMGT (Lefranc et al. (2003) Dev Comp Immunol 27: 55-77) and AbM (Martin and Thornton (1996) J Bmol Biol 263: 800-15). The correspondence between the various delineations and variable region numbering are described (see e.g., Lefranc et al. (2003) Dev Comp Immunol 27: 55-77; Honegger and 11103693.007525 / JBI6936 Pluckthun, (2001) J Mol Biol 309:657-70; International ImMunoGeneTics (IMGT) database; Web resources, http: / / imgt_org). Available programs such as abYsis by UCL Business PLC may be used to delineate CDRs. The term “CDR,” “HCDR1”, “HCDR2”, “HCDR3”, “LCDR1”, “LCDR2” and “LCDR3” as used herein includes CDRs defined by any of the methods described supra, Kabat, Chothia, IMGT or AbM, unless otherwise explicitly stated in the specification.

[0048] Immunoglobulins may be assigned to five major classes, IgA, IgD, IgE, IgG and IgM, depending on the heavy chain constant domain amino acid sequence. IgA and IgG are further sub-classified as the isotypes IgA1, IgA2, IgG1, IgG2, IgG3 and IgG4. Antibody light chains of any vertebrate species may be assigned to one of two clearly distinct types, namely kappa (κ) and lambda (λ), based on the amino acid sequences of their constant domains.

[0049] “Antigen binding fragment” refers to a portion of an immunoglobulin molecule that binds an antigen. Antigen binding fragments may be synthetic, enzymatically obtainable or genetically engineered polypeptides and include the VH, the VL, the VH and the VL, Fab, F(ab')2, Fd and Fv fragments, domain antibodies (dAb) consisting of one VH domain or one VL domain, shark variable IgNAR domains, camelized VH domains, minimal recognition units consisting of the amino acid residues that mimic the CDRs of an antibody, such as FR3-CDR3-FR4 portions, the HCDR1, the HCDR2 and / or the HCDR3 and the LCDR1, the LCDR2 and / or the LCDR3. VH and VL domains may be linked together via a synthetic linker to form various types of single chain antibody designs where the VH / VL domains may pair intramolecularly, or intermolecularly in those cases when the VH and VL domains are expressed by separate single chain antibody constructs, to form a monovalent antigen binding site, such as single chain Fv (scFv) or diabody; described for example in Int. Patent Publ. Nos. WO1998 / 44001, WO1988 / 01649, WO1994 / 13804 and WO1992 / 01047.

[0050] “Monoclonal antibody” refers to an antibody obtained from a substantially homogenous population of antibody molecules, i.e., the individual antibodies comprising the population are identical except for possible well-known alterations such as removal of C- terminal lysine from the antibody heavy chain or post-translational modifications such as amino acid isomerization or deamidation, methionine oxidation or asparagine or glutamine deamidation. Monoclonal antibodies typically bind one antigenic epitope. A bispecific monoclonal antibody binds two distinct antigenic epitopes. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Monoclonal antibody may be monospecific or multispecific such as bispecific, monovalent, bivalent or multivalent. 12103693.007525 / JBI6936

[0051] “Recombinant” refers to DNA, antibodies and other proteins that are prepared, expressed, created or isolated by recombinant means when segments from different sources are joined to produce recombinant DNA, antibodies or proteins.

[0052] “Bispecific” refers to an antibody that specifically binds two distinct antigens or two distinct epitopes within the same antigen. The bispecific antibody may have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca cynomolgus (cynomolgus, cyno) or Pan troglodytes, or may bind an epitope that is shared between two or more distinct antigens.

[0053] "Antagonist" or “inhibitor” refers to a molecule that, when bound to a cellular protein, suppresses at least one reaction or activity that is induced by a natural ligand of the protein. A molecule is an antagonist when the at least one reaction or activity is suppressed by at least about 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% more than the at least one reaction or activity suppressed in the absence of the antagonist (e.g., negative control), or when the suppression is statistically significant when compared to the suppression in the absence of the antagonist.

[0054] “Biological sample” refers to a collection of similar fluids, cells, or tissues isolated from a subject, as well as fluids, cells, or tissues present within a subject. Exemplary samples are biological fluids such as blood, serum and serosal fluids, plasma, lymph, urine, saliva, cystic fluid, tear drops, feces, sputum, mucosal secretions of the secretory tissues and organs, vaginal secretions, ascites fluids, fluids of the pleural, pericardial, peritoneal, abdominal and other body cavities, fluids collected by bronchial lavage, synovial fluid, liquid solutions contacted with a subject or biological source, for example, cell and organ culture medium including cell or organ conditioned medium, lavage fluids and the like, tissue biopsies, tumor tissue biopsies, tumor tissue samples, fine needle aspirations, surgically resected tissue, organ cultures or cell cultures. As a non-limiting example, the biological sample is a blood sample. As another non-limiting example, the biological sample is a plasma sample. As yet another non-limiting example, the biological sample is a tumor sample. In some embodiments, the biological sample is circulating tumor DNA (ctDNA) that may be isolated from various other biological samples disclosed herein such as, but not limited to, a blood or plasma sample. In some embodiments, the biological sample is tumor DNA that may be isolated from, e.g., a tumor sample.

[0055] “Low fucose” or “low fucose content” as used in the application refers to antibodies with fucose content of about between 1%-15%. 13103693.007525 / JBI6936

[0056] “Normal fucose” or “normal fucose content” as used herein refers to antibodies with fucose content of about over 50%, typically about over 80% or over 85%.

[0057] As used herein, “treatment naïve” refers to a subject that has been diagnosed with locally advanced or metastatic NSCLC and has not yet received anti-cancer treatment for the NSCLC; the subject is therefore chemotherapy naïve and TKI naive, e.g., has not received chemotherapy, or a tyrosine kinase inhibitor (including 1st generation TKI, 2nd generation TKI or 3rd generation TKI), or other anti-NSCLC treatment. A method of treating a treatment naïve subject may also be referred to as first-line or front line treatment.

[0058] As used herein, RECIST v1.1 criteria refer to publicly available guidelines for response evaluation criteria in solid tumors as described by Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer.2009;45(2):228-247, which is incorporated by reference herein. Eisenhauer et al., provide the following definitions of criteria used to determine objective tumor response for target lesions: - Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. - Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. - Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). - Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

[0059] As used herein, a partial response or better refers to a partial response (PR) or complete response (CR).

[0060] As used herein, progression-free survival (PFS) refers to the time from randomization in a clinical trial until the date of objective disease progression or death, whichever comes first, based on blinded independent central review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

[0061] As used herein, overall response (OR) is defined as those participants in a clinical trial who achieve either a PR or CR as their best response, as defined by BICR using RECIST v1.1. 14103693.007525 / JBI6936

[0062] As used herein, overall survival (OS) is defined as the time from the date of randomization in a clinical trial until the date of death due to any cause.

[0063] As used herein, the duration of response (DoR) is defined as the time from the date of first documented response (PR or CR) in a clinical trial until the date of documented progression or death, whichever comes first, for participants who have PR or CR.

[0064] As used herein, the Time to Subsequent Therapy (TTST) is defined as the time from the date of randomization in a clinical trial to the start date of the subsequent anticancer therapy following study treatment discontinuation or death, whichever comes first.

[0065] As used herein, the Progression-free Survival After the First Subsequent Therapy (PFS2) is defined as the time from randomization in a clinical trial until the date of second objective disease progression, after initiation of subsequent anticancer therapy, based on investigator assessment (after that used for PFS) or death, whichever comes first.

[0066] As used herein, the Time to Symptomatic Progression (TTSP) is defined as the time from randomization in a clinical trial to documentation of any of the following (whichever occurs earlier): onset of new symptoms or symptom worsening that is considered by the investigator to be related to lung cancer and requires either a change in anticancer treatment and / or clinical intervention to manage symptoms.

[0067] As used herein, Intracranial Progression-Free Survival (Intracranial PFS) is defined as the time from randomization in a clinical trial until the date of objective intracranial disease progression or death, whichever comes first, based on BICR using RECIST v1.1. Specifically, intracranial disease progression is defined as having progression of brain metastasis or occurrence of new brain lesion.

[0068] “Approved drug product” as used herein refers to a product that contains an active pharmaceutical ingredient that has been approved for marketing by a governmental authority, e.g., the Food and Drug Administration (FDA) or the similar authority in other countries.

[0069] Resistance to osimertinib is diverse, polyclonal, and difficult to treat. There are currently no targeted therapies approved in the post-osimertinib setting. Two studies of immunotherapy-chemotherapy regimens have recently failed to show efficacy in the TKI- resistant setting. Currently, there are 6 other phase 3 studies (NCT05261399, NCT04765059, NCT05089734, NCT05338970, NCT04656652, NCT05184712) investigating targeted therapy combinations versus chemotherapy as second-line (or later) treatment in EGFR- mutated advanced NSCLC, highlighting the unmet need in this patient population. 15103693.007525 / JBI6936

[0070] The present disclosure is directed to novel regimens for the treatment of patients with EGFR-mutated advanced NSCLC whose disease had progressed on or after a TKI therapy, such as osimertinib. Embodiments of the present disclosure provide methods of significantly improving progression-free survival with amivantamab- chemotherapy and amivantamab-lazertinib-chemotherapy compared with chemotherapy in patients with EGFR- mutated advanced NSCLC whose disease had progressed on or after osimertinib monotherapy.

[0071] Disclosed herein are methods of reducing an adverse reaction associated with the use of amivantamab in combination with carboplatin and pemetrexed for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the methods comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, and who experiences a grade 1 or grade 2 infusion-related adverse reaction: interrupting the intravenous amivantamab infusion, monitoring the subject until the grade 1 or grade 2 infusion-related adverse reaction resolves, resuming the intravenous amivantamab infusion at 50% of the infusion rate at which the grade 1 or grade 2 infusion-related adverse reaction occurred, and, if there are no additional infusion-related adverse reactions after 30 minutes, increasing the infusion rate; who experiences a grade 3 infusion-related adverse reaction: interrupting the intravenous amivantamab infusion, monitoring the subject until the grade 3 infusion- related adverse reaction resolves, resuming the intravenous amivantamab infusion at 50% of the infusion rate at which the grade 3 infusion-related adverse reaction occurred, and, if there are no additional infusion-related adverse reactions after 30 minutes, increasing the infusion rate; or who experiences a grade 4 infusion-related adverse reaction: permanently discontinuing administration of the amivantamab.

[0072] Amivantamab comprises a first domain that specifically binds EGFR and a second domain that specifically binds c-Met, wherein the first domain comprises the heavy 16103693.007525 / JBI6936 chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5 and the LCDR3 of SEQ ID NO: 6, and wherein the second domain that binds c-Met comprises the CDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, the LCDR1 of SEQ ID NO: 10, the LCDR2 of SEQ ID NO: 11 and the LCDR3 of SEQ ID NO: 12. The first domain that specifically binds EGFR comprises the heavy chain variable region (VH) of SEQ ID NO: 13 and the light chain variable region (VL) of SEQ ID NO: 14, and the second domain that specifically binds c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16. Amivantamab is an IgG1 isotype that comprises the first heavy chain (HC1) of SEQ ID NO: 17, the first light chain (LC1) of SEQ ID NO: 18, the second heavy chain (HC2) of SEQ ID NO: 19, and the second light chain (LC2) of SEQ ID NO: 20. In some embodiments, amivantamab comprises a biantennary glycan structure with a fucose content of about between 1% to about 15%.

[0073] In some embodiments the methods comprise to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, and who experiences a grade 1 or grade 2 infusion-related adverse reaction: interrupting the intravenous amivantamab infusion, monitoring the subject until the grade 1 or grade 2 infusion-related adverse reaction resolves, resuming the intravenous amivantamab infusion at 50% of the infusion rate at which the grade 1 or grade 2 infusion-related adverse reaction occurred, and, if there are no additional infusion-related adverse reactions after 30 minutes, increasing the infusion rate.

[0074] In some embodiments the methods comprise to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, and who experiences a grade 3 infusion-related adverse reaction: interrupting the intravenous amivantamab infusion, monitoring the subject until the grade 3 infusion-related adverse reaction resolves, resuming the intravenous amivantamab infusion at 50% of the infusion rate at which the grade 3 infusion-related adverse reaction 17103693.007525 / JBI6936 occurred, and, if there are no additional infusion-related adverse reactions after 30 minutes, increasing the infusion rate.

[0075] In some embodiments the methods comprise, for grade 1, grade 2, or grade 3 infusion-related reactions, administering an antihistamine, an antipyretic, and a glucocorticoid prior to resuming the intravenous amivantamab infusion. Below is a list of “premedications” that can be administered prior to resuming the intravenous amivantamab infusion. Table 1. PremedicationsRequired at initial dose (Week 1 Day 1) + Required at second dose (Week 1 Day 2); optional for subsequent doses.

[0076] The antihistamine can comprise diphenhydramine. The antipyretic can comprise acetaminophen. The glucocorticoid can comprise dexamethasone.

[0077] In some embodiments the methods comprise permanently discontinuing administration of the amivantamab if the grade 3 infusion-related adverse reaction is a recurrent grade 3 infusion-related adverse reaction.

[0078] Infusion Rates of amivantamab in combination with carboplatin and pemetrexed for treatment of NSCLC are provided below: Table 2. Infusion Rates of amivantamab in combination with carboplatin and pemetrexed for treatment of NSCLC18103693.007525 / JBI6936† In the absence of infusion-related reactions, increase the initial infusion rate to the subsequent infusion rate after 2 hours based on patient tolerance. Total infusion time approximately 4-6 hours for day 1 and 6-8 hours for day 2. Subsequent infusion time is approximately 2 hours.

[0079] In some embodiments the methods comprise to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, and who experiences a grade 4 infusion-related adverse reaction: permanently discontinuing administration of the amivantamab.

[0080] The recommended dosage and dosing schedule for amivantamab to be administered in combination with carboplatin and pemetrexed are provided below: Table 3. The recommended dosage and dosing schedule for amivantamab to be administered in combination with carboplatin and pemetrexed.19103693.007525 / JBI6936aDose adjustments not required for subsequent body weight changes.

[0081] The therapeutically effective amount of amivantamab comprises: for subjects who weigh less than 80 kg, 1400 mg weekly from week 1 to week 4 and 1750 mg every three weeks starting at week 7; or for subjects who weigh greater than or equal to 80 kg, 1750 mg weekly from week 1 to week 4 and 2100 mg every three weeks starting at week 7. The therapeutically effective amount of pemetrexed comprises 500 mg / m2every three weeks. The therapeutically effective amount of carboplatin comprises AUC 5 every three weeks for up to 12 weeks.

[0082] Disclosed herein are methods of reducing an adverse reaction associated with the use of amivantamab in combination with carboplatin and pemetrexed for the treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the methods comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who is suspected of experiencing interstitial lung disease / pneumonitis of any grade: withholding administration of the amivantamab; or who experiences interstitial lung disease / pneumonitis of any grade: permanently discontinuing administration of the amivantamab.

[0083] In some embodiments the methods comprise to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who is suspected of experiencing interstitial lung disease / pneumonitis of any grade: withholding administration of the amivantamab. 20103693.007525 / JBI6936

[0084] In some embodiments the methods comprise to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences interstitial lung disease / pneumonitis of any grade: permanently discontinuing administration of the amivantamab.

[0085] The therapeutically effective amount of amivantamab comprises: for subjects who weigh less than 80 kg, 1400 mg weekly from week 1 to week 4 and 1750 mg every three weeks starting at week 7; or for subjects who weigh greater than or equal to 80 kg, 1750 mg weekly from week 1 to week 4 and 2100 mg every three weeks starting at week 7. The therapeutically effective amount of pemetrexed comprises 500 mg / m2every three weeks. The therapeutically effective amount of carboplatin comprises AUC 5 every three weeks for up to 12 weeks.

[0086] Disclosed herein are methods of reducing an adverse reaction associated with the use of amivantamab in combination with carboplatin and pemetrexed for the treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the method comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences a grade 1 dermatologic adverse reaction: reassessing after two weeks; who experiences a grade 2 dermatologic adverse reaction: reassessing after two weeks, and if the grade 2 dermatologic adverse reaction does not improve, administering a reduced dose of the amivantamab to the subject; who experiences a grade 3 dermatologic adverse reaction: withholding the amivantamab and resuming administration of the amivantamab at a reduced dose if the grade 3 dermatologic adverse reaction becomes a grade 2 or lower dermatologic adverse reaction, or permanently discontinuing the treatment if 21103693.007525 / JBI6936 no improvement in the grade 3 dermatologic adverse reaction occurs within 2 weeks; or who experiences a grade 4 dermatologic adverse reaction or severe bullous, blistering, or exfoliating skin: permanently discontinuing administration of the amivantamab.

[0087] In some embodiments the methods comprise to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences a grade 1 dermatologic adverse reaction: reassessing after two weeks. In some embodiments, the methods comprise initiating supportive care management prior to the reassessing after two weeks.

[0088] In some embodiments the methods comprise to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences a grade 2 dermatologic adverse reaction: reassessing after two weeks, and if the grade 2 dermatologic adverse reaction does not improve, administering a reduced dose of the amivantamab to the subject. In some embodiments, the methods comprise initiating supportive care management prior to the reassessing after two weeks.

[0089] In some embodiments the methods comprise to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences a grade 3 dermatologic adverse reaction: withholding the amivantamab and resuming administration of the amivantamab at a reduced dose if the grade 3 dermatologic adverse reaction becomes a grade 2 or lower dermatologic adverse reaction, or permanently discontinuing the treatment if no improvement in the grade 3 dermatologic adverse reaction occurs within 2 weeks. In some embodiments, 22103693.007525 / JBI6936 the methods comprise initiating supportive care management prior to resuming administration of the amivantamab.

[0090] The reduced dose of amivantamab comprises 1050 mg or 700 mg if the adverse reactions occurred at an amivantamab dose of 1400 mg, 1400 mg or 1050 mg if the adverse reactions occurred at an amivantamab dose of 1750 mg, or 1750 mg or 1400 mg if the adverse reactions occurred at an amivantamab dose of 2100 mg.

[0091] The methods can further comprise administering an antihistamine and an antipyretic prior to resuming the intravenous amivantamab infusion. The antihistamine can comprise diphenhydramine and the antipyretic can comprise acetaminophen.

[0092] In some embodiments the methods comprise to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences a grade 4 dermatologic adverse reaction or severe bullous, blistering, or exfoliating skin: permanently discontinuing administration of the amivantamab.

[0093] The therapeutically effective amount of amivantamab comprises: for subjects who weigh less than 80 kg, 1400 mg weekly from week 1 to week 4 and 1750 mg every three weeks starting at week 7; or for subjects who weigh greater than or equal to 80 kg, 1750 mg weekly from week 1 to week 4 and 2100 mg every three weeks starting at week 7. The therapeutically effective amount of pemetrexed comprises 500 mg / m2every three weeks. The therapeutically effective amount of carboplatin comprises AUC 5 every three weeks for up to 12 weeks.

[0094] Disclosed herein are methods of reducing an adverse reaction associated with the use of amivantamab in combination with carboplatin and pemetrexed for the treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the method comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and 23103693.007525 / JBI6936 who experiences at least one other grade 3 adverse reaction: withholding amivantamab until the at least one other grade 3 adverse reaction reduces to less than or equal to grade 1 or baseline and resuming the amivantamab at the same dose if the subject recovers from the grade 3 adverse reaction within 1 week; resuming the amivantamab at a reduced dose if the subject recovers from the grade 3 adverse reaction after 1 week but within 4 weeks; or permanently discontinuing the amivantamab if the subject does not recover from the grade 3 adverse reaction within 4 weeks; or who experiences at least one other grade 4 adverse reaction: withholding amivantamab until the at least one other grade 4 adverse reaction reduces to less than or equal to grade 1 or baseline and resuming the amivantamab at a reduced dose if the subject recovers from the grade 4 adverse reaction within 4 weeks; or permanently discontinuing the amivantamab if the subject does not recover from the grade 4 adverse reaction within 4 weeks or if the grade 4 infusion-related adverse reaction is a recurrent grade 4 infusion-related adverse reaction.

[0095] In some embodiments the methods comprise to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences at least one other grade 3 adverse reaction: withholding amivantamab until the at least one other grade 3 adverse reaction reduces to less than or equal to grade 1 or baseline and resuming the amivantamab at the same dose if the subject recovers from the grade 3 adverse reaction within 1 week; resuming the amivantamab at a reduced dose if the subject recovers from the grade 3 adverse reaction after 1 week but within 4 weeks; or permanently discontinuing the amivantamab if the subject does not recover from the grade 3 adverse reaction within 4 weeks.

[0096] In some embodiments the methods comprise to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with 24103693.007525 / JBI6936 a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences at least one other grade 4 adverse reaction: withholding amivantamab until the at least one other grade 4 adverse reaction reduces to less than or equal to grade 1 or baseline and resuming the amivantamab at a reduced dose if the subject recovers from the grade 4 adverse reaction within 4 weeks; or permanently discontinuing the amivantamab if the subject does not recover from the grade 4 adverse reaction within 4 weeks or if the grade 4 infusion-related adverse reaction is a recurrent grade 4 infusion-related adverse reaction.

[0097] The therapeutically effective amount of amivantamab comprises: for subjects who weigh less than 80 kg, 1400 mg weekly from week 1 to week 4 and 1750 mg every three weeks starting at week 7; or for subjects who weigh greater than or equal to 80 kg, 1750 mg weekly from week 1 to week 4 and 2100 mg every three weeks starting at week 7. The therapeutically effective amount of pemetrexed comprises 500 mg / m2every three weeks. The therapeutically effective amount of carboplatin comprises AUC 5 every three weeks for up to 12 weeks.

[0098] Amivantamab dose reductions for adverse reactions are provided below: Table 4. Amivantamab dose reductions for adverse reactions.

[0099] The reduced dose of amivantamab comprises 1050 mg or 700 mg if the adverse reactions occurred at an amivantamab dose of 1400 mg, 1400 mg or 1050 mg if the adverse reactions occurred at an amivantamab dose of 1750 mg, or 1750 mg or 1400 mg if the adverse reactions occurred at an amivantamab dose of 2100 mg.

[0100] The methods can further comprise administering an antihistamine and an antipyretic prior to resuming the intravenous amivantamab infusion. The antihistamine can comprise diphenhydramine and the antipyretic can comprise acetaminophen. 25103693.007525 / JBI6936

[0101] Disclosed herein are methods of reducing an adverse reaction associated with the use of amivantamab in combination with carboplatin and pemetrexed for the treatment of adult patients with advanced NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations after failure of prior therapy including an EGFR tyrosine kinase inhibitor (TKI), the methods comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the advanced NSCLC after failure of prior therapy including an EGFR TKI and who experiences a grade 1, grade 2, or grade 3 infusion-related adverse reaction: interrupting the intravenous amivantamab infusion, monitoring the subject until the grade 1, grade 2, or grade 3 infusion-related adverse reaction resolves, resuming the intravenous amivantamab infusion at 50% of the infusion rate at which the grade 1, grade 2, or grade 3 infusion-related adverse reaction occurred, and, if there are no additional infusion- related adverse reactions, increasing the infusion rate.

[0102] If there are no additional symptoms, the rate may be increased per the recommended infusion rates below. Table 5. Infusion rates for amivantamab* Starting at Week 7, patients are dosed every 3 weeks. † Increase the initial infusion rate to the subsequent infusion rate after 2 hours in the absence of infusion-related reactions. 26103693.007525 / JBI6936

[0103] Prior to infusion (Week 1, Days 1 and 2), antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of IRRs (see below). For subsequent doses, antihistamines and antipyretics are required to be administered. Glucocorticoids should also be re initiated after prolonged dose interruptions. Antiemetics should be administered as needed. Concomitant medicinal products should be administered at the next dose (including dexamethasone (20 mg) or equivalent) as provided below. Table 6. Dosing schedule of premedications* Required at all doses. Required at initial dose (Week 1, Day 1) or at the next subsequent dose in the event of an IRR. + Required at second dose (Week 1, Day 2); optional for subsequent doses.

[0104] Disclosed herein are methods of reducing an adverse reaction associated with the use of amivantamab in combination with carboplatin and pemetrexed for the treatment of adult patients with advanced NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations after failure of prior therapy including an EGFR TKI, the methods comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the advanced NSCLC after failure of prior therapy including an EGFR TKI and who experiences a recurrent grade 3 or grade 4 infusion-related adverse reaction: permanently discontinuing administration of the amivantamab.

[0105] Disclosed herein are methods of reducing an adverse reaction associated with the use of amivantamab in combination with carboplatin and pemetrexed for the 27103693.007525 / JBI6936 treatment of adult patients with advanced NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations after failure of prior therapy including an EGFR TKI, the methods comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the advanced NSCLC after failure of prior therapy including an EGFR TKI and who experiences a Grade 1-2 skin or nail reaction: reduce the dose of amivantamab if there is no improvement after 2 weeks; a Grade 3 skin or nail reaction: interrupt the amivantamab until the adverse reaction improves, and upon recovery of the skin or nail reaction to ≤ Grade 2, administer amivantamab at a reduced dose; or a Grade 4 skin reactions: permanently discontinue the amivantamab.

[0106] Amivantamab dose reductions for adverse reactions are provided below. Table 7. Amivantamab dose reductions for adverse reactions

[0107] Disclosed herein are methods of reducing an adverse reaction associated with the use of amivantamab in combination with carboplatin and pemetrexed for the treatment of adult patients with advanced NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations after failure of prior therapy including an EGFR TKI, the methods comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the advanced NSCLC after failure of prior therapy including an EGFR TKI and who 28103693.007525 / JBI6936 is suspected of having interstitial lung disease (ILD) or ILD-like adverse reactions (pneumonitis): withhold the amivantamab; or is confirmed to have ILD or ILD-like adverse reactions (e.g., pneumonitis): permanently discontinuing the amivantamab.

[0108] Dosing should be interrupted for Grade 3 or 4 adverse reactions until the adverse reaction resolves to ≤ Grade 1 or baseline. If an interruption is 7 days or less, restart at the current dose. If an interruption is longer than 7 days, it is recommended restarting at a reduced dose.

[0109] Disclosed herein are methods of treating locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations in a subject whose NSCLC has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the method comprising administering to the subject an approved drug product comprising amivantamab, in combination with carboplatin and pemetrexed.

[0110] The approved drug product comprising amivantamab is described in the approved drug product labels provided in Example 3 and Example 4 herein.

[0111] Disclosed herein are methods of improving median progression free survival (PFS) in a population of subjects having locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations whose NSCLC has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the methods comprising administering to the population of subjects an approved drug product comprising amivantamab, in combination with carboplatin and pemetrexed. The median PFS can be 5.6 months to 8.4 months. The median PFS can be 6.3 months.

[0112] Disclosed herein are methods of improving overall response rate (ORR) in a population of subjects having locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations whose NSCLC has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the methods comprising administering to the population of subjects an approved drug product comprising amivantamab, in combination with carboplatin and pemetrexed. The ORR can be 44% to 62%. The ORR can be 53%.

[0113] Disclosed herein are methods of improving median duration of response (DOR) in a population of subjects having locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations whose NSCLC has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the methods comprising 29103693.007525 / JBI6936 administering to the population of subjects an approved drug product comprising amivantamab, in combination with carboplatin and pemetrexed. The DOR can be greater than or equal to 5.5 months. The DOR can be 6.9 months.

[0114] Disclosed herein are methods of improving median PFS in a population of adult patients with advanced NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations after failure of prior therapy including an EGFR tyrosine kinase inhibitor (TKI), the methods comprising administering to the population of patients an approved drug product comprising amivantamab, in combination with carboplatin and pemetrexed. The median PFS can be 5.6 months to 8.4 months. The median PFS can be 6.3 months.

[0115] Disclosed herein are methods of improving overall survival (OS) in a population of adult patients with advanced NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations after failure of prior therapy including an EGFR TKI, the methods comprising administering to the population of patients an approved drug product comprising amivantamab, in combination with carboplatin and pemetrexed. The OS can be 16 months to 22.4 months. The OS can be 17.7 months.

[0116] Disclosed herein are methods of improving objective response rate (ORR) in a population of adult patients with advanced NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations after failure of prior therapy including an EGFR TKI, the methods comprising administering to the population of patients an approved drug product comprising amivantamab, in combination with carboplatin and pemetrexed. The ORR can be 55% to 72%. The ORR can be 64%.

[0117] Disclosed herein are methods of improving median DOR in a population of adult patients with advanced NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations after failure of prior therapy including an EGFR TKI, the methods comprising administering to the population of patients an approved drug product comprising amivantamab, in combination with carboplatin and pemetrexed. The median DOR can be greater than or equal to 5.52 months. The median DOR can be 6.9 months.

[0118] The methods can comprise administering amivantamab intravenously at 1,400 mg for patients who weigh less than 80 kg or 1,750 mg for patients who weigh greater than or equal to 80 kg once weekly through 4 weeks, then every 3 weeks with a dose of 1,750 mg for patients who weigh less than 80 kg or 2,100 mg for patients who weigh great than or equal to 80 kg starting at Week 7 until disease progression or unacceptable toxicity. The methods can further comprise administering 500 mg / m2of pemetrexed every three weeks 30103693.007525 / JBI6936 until disease progression or unacceptable toxicity and administering AUC 5 of carboplatin every three weeks for up to 12 weeks.

[0119] Disclosed herein are methods of improving median PFS in a population of subjects with locally advanced or metastatic (NSCLC harboring one or more (EGFR mutations whose NSCLC progressed on or after treatment with at least one prior TKI (i.e., the subjects are not treatment naïve but have previously received TKI therapy), comprises administering to the population of subjects a combination therapy comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, (ii) a therapeutically effective amount of carboplatin, and (iii) a therapeutically effective amount of pemetrexed wherein the improvement in median PFS is relative to median PFS of a reference population of subjects with NSCLC harboring one or more EGFR mutations whose NSCLC progressed on or after treatment with the prior TKI, said reference population having been administered carboplatin and pemetrexed but not said bispecific anti-EGFR / c-Met antibody.

[0120] Disclosed herein are methods of improving median PFS in a population of subjects with locally advanced or metastatic NSCLC harboring one or more epidermal growth factor receptor (EGFR) mutations whose NSCLC progressed on or after treatment with a prior TKI (i.e., the subjects are not treatment naïve but have previously received TKI therapy), comprises administering to the population of subjects a combination therapy comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, (ii) a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, (iii) a therapeutically effective amount of carboplatin, and (iv) a therapeutically effective amount of pemetrexed, wherein the improvement in median PFS is relative to median PFS of a reference population of subjects with NSCLC harboring one or more EGFR mutations whose NSCLC progressed on or after treatment with a third- generation TKI , said reference population having been administered carboplatin and pemetrexed but not said bispecific anti-EGFR / c-Met antibody nor said lazertinib or pharmaceutically acceptable salt or hydrate thereof.

[0121] Disclosed herein are methods of improving median intracranial PFS in a population of subjects with locally advanced or metastatic NSCLC harboring one or more EGFR mutations whose NSCLC progressed on or after treatment with at least one prior TKI (i.e., the subjects are not treatment naïve but have previously received TKI therapy), comprises administering to the population of subjects a combination therapy comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, (ii) a therapeutically effective amount of carboplatin, and (iii) a therapeutically effective amount of 31103693.007525 / JBI6936 pemetrexed wherein the improvement in median PFS is relative to median PFS of a reference population of subjects with NSCLC harboring one or more EGFR mutations whose NSCLC progressed on or after treatment with the prior TKI, said reference population having been administered carboplatin and pemetrexed but not said bispecific anti-EGFR / c-Met antibody.

[0122] Disclosed herein are methods of improving median intracranial PFS in a population of subjects with locally advanced or metastatic NSCLC harboring one or more EGFR mutations whose NSCLC progressed on or after treatment with a prior TKI (i.e., the subjects are not treatment naïve but have previously received TKI therapy), comprises administering to the population of subjects a combination therapy comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, (ii) a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, (iii) a therapeutically effective amount of carboplatin, and (iv) a therapeutically effective amount of pemetrexed, wherein the improvement in median PFS is relative to median PFS of a reference population of subjects with NSCLC harboring one or more EGFR mutations whose NSCLC progressed on or after treatment with a third- generation TKI , said reference population having been administered carboplatin and pemetrexed but not said bispecific anti-EGFR / c-Met antibody nor said lazertinib or pharmaceutically acceptable salt or hydrate thereof.

[0123] According to another embodiment of the present invention, a method of treating a subject with locally advanced or metastatic NSCLC harboring one or more EGFR mutations whose NSCLC progressed on or after treatment with a prior TKI (i.e., the subjects are not treatment naïve but have previously received TKI therapy), comprises administering to the subject a combination therapy comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, (ii) a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, (iii) a therapeutically effective amount of carboplatin, and (iv) a therapeutically effective amount of pemetrexed, wherein administration of the combination therapy begins on Cycle 1 Day 1 of a first 21-day cycle, and continues in subsequent 21-day cycles, and wherein the method comprises administering the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, after administration of the carboplatin is completed (e.g., wherein the method comprises: (a) administering the carboplatin at a dose of AUC 5 on Day 1 of each 21-day cycle, for up to 4 cycles, and (b) administering the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, at a dose of about 240 mg orally, once daily starting Cycle 5 Day 1 or sooner if said carboplatin is discontinued earlier). 32103693.007525 / JBI6936

[0124] In some embodiments, the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, is lazertinib mesylate. In some embodiments, the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, is lazertinib mesylate monohydrate.

[0125] In some embodiments, the method comprises administering the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, at a dose of about 240 mg orally, once daily.

[0126] In some embodiments, the method comprises administering the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, at a dose of about 240 mg orally, once daily starting Cycle 5 Day 1 or sooner if said carboplatin is discontinued earlier.

[0127] In some embodiments, the one or more EGFR mutations comprise one or more exon 19 deletions, or exon 21 L858R substitution, or any combination thereof. In some embodiments, the one or more EGFR mutations comprise one or more exon 19 deletions. In some embodiments, the one or more EGFR mutations comprise exon 21 L858R substitution.

[0128] In some embodiments, the at least one prior TKI comprises a 1st generation EGFR TKI. In some embodiments, the at least one prior TKI comprises a 2ndgeneration EGFR TKI. In some embodiments, the at least one prior TKI comprises a 2ndgeneration EGFR TKI. In some embodiments, the at least one prior TKI comprises osimertinib. EGFR- TKIs are EGFR-targeted agents that interfere with EGFR signaling. To date, three different generations of EGFR-TKIs are available, though all remain subject to development of resistance mechanisms. The mechanism of action of first-generation TKIs (e.g., Erlotinib, Gefinitib, and Icotinib) causes a reversible ATP-binding sites blockade, stopping downstream signaling. Second-generation TKIs (e.g., Afatinib and Dacominitib) provide an alternative for patients with acquired resistance to first-generation TKIs. Third generation TKIs (e.g., Osimertinib, Rociletinib, Olmutinib, Lazertinib) offer a treatment for patients with acquired resistance to first and second-generation TKIs. See, e.g., Caponnetto et al., J. Mol. Pathol.2021, 2(1), 1-10.

[0129] In some embodiments, the method comprises administering the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, in an amount of about 80 mg to about 320 mg orally once daily. In some embodiments, the method comprises administering the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, in an amount of about 240 mg orally once daily. In some embodiments, the method comprises administering the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, at a dose in an amount of about 240 mg orally, once daily starting Cycle 5 Day 1 or sooner if said carboplatin is discontinued earlier. 33103693.007525 / JBI6936

[0130] In some embodiments, administration of the combination therapy begins on Cycle 1 Day 1 of the first 21-day cycle, and continues in subsequent 21-day cycles.

[0131] In some embodiments, the method elicits a clinical response in the subject according to RECIST v1.1 criteria. In some embodiments, the method achieves a partial response or better in the subject according to RECIST v1.1 criteria. In some embodiments, the combination therapy achieves an improvement in the median PFS of at least two weeks. In some embodiments, the combination therapy achieves an improvement in the median PFS of at least 1 month. In some embodiments, the combination therapy achieves an improvement in the median PFS of at least 1.5 months. In some embodiments, the combination therapy achieves an improvement in the median PFS of at least 2 months. In some embodiments, the subject exhibits PFSfor at least 4.5 months. In some embodiments, the subject exhibits PFSfor at least 5 months. In some embodiments, the subject exhibits PFS for at least 5.5 months. In some embodiments, the subject exhibits PFSfor at least 6 months, or at least 10 months, or at least 12 months, or at least 14 months. In some embodiments, the combination therapy further achieves an improvement in objective response relative to said reference population. In some embodiments, the combination therapy further achieves an improvement in (OS relative to said reference population. In some embodiments, the combination therapy further achieves an improvement in duration of response (DoR) relative to said reference population. In some embodiments, the combination therapy further achieves an improvement in time to subsequent therapy relative to said reference population. In some embodiments, the combination therapy further achieves an improvement in PFS after first subsequent therapy (PFS2) relative to said reference population. In some embodiments, the combination therapy further achieves an improvement in intracranial median PFS relative to said reference population.

[0132] In some embodiments, the subject is progression-free after at least 20 months. In some embodiments, the subject is progression-free after at least 30 months. In some embodiments, the method achieves a PFS rate of 85% at 12 months, 65% at 24 months, and / or 51% at 36 months in a population of the treatment naïve subjects diagnosed with locally advanced or metastatic NSCLC harboring one or more EGFR mutations.

[0133] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds EGFR and a second domain that specifically binds c-Met, wherein the first domain comprises the heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, the 34103693.007525 / JBI6936 LCDR2 of SEQ ID NO: 5 and the LCDR3 of SEQ ID NO: 6, and wherein the second domain that binds c-Met comprises the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, the LCDR1 of SEQ ID NO: 10, the LCDR2 of SEQ ID NO: 11 and the LCDR3 of SEQ ID NO: 12. In some embodiments, the first domain that specifically binds EGFR comprises the heavy chain variable region (VH) of SEQ ID NO: 13 and the light chain variable region (VL) of SEQ ID NO: 14, and the second domain that specifically binds c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16. In some embodiments, the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises the first heavy chain (HC1) of SEQ ID NO: 17, the first light chain (LC1) of SEQ ID NO: 18, the second heavy chain (HC2) of SEQ ID NO: 19, and the second light chain (LC2) of SEQ ID NO: 20. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about between 1% to about 15%.

[0134] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered intravenously to the subject. In some embodiments, the bispecific anti-EGFR / c- Met antibody is administered at a dose of between about 140 mg to about 2240 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 700 mg, about 750 mg, about 800 mg, about 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1575 mg, 1600 mg, 1750 mg, 2100 mg, or 2240 mg. According to certain embodiments, the method comprises administering the dose weekly for 4 weeks, then administering the dose every 2 weeks starting at Week 5, wherein, for body weight at baseline that is less than 80 kg, the dose is 1050 mg; and for body weight at baseline that is greater than or equal to 80 kg, the dose is 1400 mg. In some embodiments, the initial dose is administered as a split infusion in Week 1 on Day 1 and Day 2. In some embodiments, the initial dose is administered in Week 1 on Day 1.

[0135] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1400 mg on Cycle 1 Days 1, 8, and 15, and Cycle 2 Day 1 if the subject has a body weight of less than 80 kg. In some embodiments, the initial dose is administered as a split infusion in Week 1 on Day 1 and Day 2. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1750 mg on Day 1 of each 21-day cycle, starting with Cycle 3 if the subject has a body weight of less than 80 kg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1750 mg on Cycle 1 Days 1, 8, and 15, and Cycle 2 Day 1 if the subject has a body 35103693.007525 / JBI6936 weight of greater than or equal to 80 kg. In some embodiments, the initial dose is administered as a split infusion in Week 1 on Day 1 and Day 2. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 2100 mg on Day 1 of each 21-day cycle, starting with Cycle 3 if the subject has a body weight of greater than or equal to 80 kg.

[0136] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered twice a week, once a week, once in two weeks, once in three weeks or once in four weeks.

[0137] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds EGFR and a second domain that specifically binds c-Met, wherein the first domain comprises the heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6, and wherein the second domain that binds c-Met comprises the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, the LCDR1 of SEQ ID NO: 10, the LCDR2 of SEQ ID NO: 11, and the LCDR3 of SEQ ID NO: 12. In some embodiments, the first domain that specifically binds EGFR comprises the heavy chain variable region (VH) of SEQ ID NO: 13 and the light chain variable region (VL) of SEQ ID NO: 14, and the second domain that specifically binds c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.

[0138] In some embodiments, the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype.

[0139] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises the first heavy chain (HC1) of SEQ ID NO: 17, the first light chain (LC1) of SEQ ID NO: 18, the second heavy chain (HC2) of SEQ ID NO: 19, and the second light chain (LC2) of SEQ ID NO: 20.

[0140] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about between 1% to about 15%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about between 2% to about 14%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about between 3% to about 13%. In some embodiments, the bispecific anti- EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of 36103693.007525 / JBI6936 about between 4% to about 12%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about between 5% to about 11%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 1%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 2%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 3%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 4%. In some embodiments, the bispecific anti- EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 5%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 6%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 7%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 8%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 9%. In some embodiments, the bispecific anti- EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 10%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 11%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 12%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 13%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 14%. In some embodiments, the bispecific anti- EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 15%.

[0141] In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with a tyrosine kinase inhibitor (TKI) such as, but not limited to an epidermal growth factor receptor (EGFR TKI). Non-limiting examples of TKI are erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib or sunitinib. In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with lazertinib. 37103693.007525 / JBI6936

[0142] Lazertinib is an oral, third-generation, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in development for the treatment of non-small cell lung cancer (NSCLC).

[0143] Lazertinib is described in WO 2016 / 060443 as N-(5-(4-(4- ((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2- morpholinophenyl)acrylamide, depicted below as a compound of Formula I.Formula I

[0144] In addition, WO2018 / 194356 describes salts, hydrates and crystalline forms thereof; and WO2019 / 022485, WO2019 / 022486 and WO2019 / 022487 disclose processes for the production of lazertinib.

[0145] Lazertinib mesylate monohydrate is depicted below as a compound of Formula Ia,Formula Ia, which may be referred to as N-[5-[[4-[4-[(dimethylamino)methyl]-3-phenyl-1H-pyrazol-1- yl]pyrimidin-2-yl]amino]-4-methoxy-2-(morpholin-4-yl)phenyl]acrylamide methanesulfonate hydrate.

[0146] In some embodiments, the method comprises administering the carboplatin at a dose of AUC 5 on Day 1 of each 21-day cycle, for up to 4 cycles. Carboplatin may be administered at a dose of AUC 5 in accordance with commercially available methods that are approved by health authorities. 38103693.007525 / JBI6936

[0147] In some embodiments, the method comprises administering the pemetrexed at a dose of about 500 mg / m2on Day 1 of each 21-day cycle, with the carboplatin for up to 4 cycles, and then as maintenance until disease progression.

[0148] The bispecific anti-EGFR / c-Met antibody may be administered in a pharmaceutically acceptable carrier. "Carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the antibody of the invention is administered. Such vehicles may be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. For example, 0.4% saline and 0.3% glycine may be used to formulate the bispecific anti-EGFR / c-Met antibody. These solutions are sterile and generally free of particulate matter. They may be sterilized by conventional, well-known sterilization techniques (e.g., filtration). For parenteral administration, the carrier may comprise sterile water and other excipients may be added to increase solubility or preservation. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives. Suitable vehicles and formulations, inclusive of other human proteins, e.g., human serum albumin, are described, for example, in e.g., Remington: The Science and Practice of Pharmacy, 21st Edition, Troy, D.B. ed., Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing pp 691-1092, See especially pp.958-989.

[0149] The mode of administration may be any suitable route that delivers the bispecific anti-EGFR-c-Met antibody to the host, such as parenteral administration, e.g., intradermal, intramuscular, intraperitoneal, intravenous or subcutaneous, pulmonary, transmucosal (oral, intranasal, intravaginal, rectal), using a formulation in a tablet, capsule, solution, powder, gel, particle; and contained in a syringe, an implanted device, osmotic pump, cartridge, micropump; or other means appreciated by the skilled artisan, as well known in the art. Site specific administration may be achieved by for example intratumoral, intra- articular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intracardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravascular, intravesical, intralesional, vaginal, rectal, buccal, sublingual, intranasal, or transdermal delivery.

[0150] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered intravenously. 39103693.007525 / JBI6936

[0151] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally to the subject. The bispecific anti-EGFR / c-Met antibody may be administered subcutaneously or intradermally at a dose sufficient to achieve a therapeutic effect in the subject.

[0152] In some embodiments, the bispecific anti-EGFR / c-Met antibody is formulated as a subcutaneous formulation as disclosed in PCT International Publication No. WO 2022 / 224187A1.

[0153] In some embodiments, the method comprises administering the dose weekly for 4 weeks, then administering the dose every 2 weeks starting at Week 5, wherein, for body weight at baseline that is less than 80 kg, the dose is 1050 mg; and for body weight at baseline that is greater than or equal to 80 kg, the dose is 1400 mg. In some embodiments, the initial dose is administered as a split infusion in Week 1 on Day 1 and Day 2.

[0154] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of between about 140 mg and about 2240 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of between about 1400 mg to about 3360 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of between about 1400 mg to about 1750 mg.

[0155] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about 1040 mg, about 1050 mg, about 1060 mg, about 1070 mg, about 1080 mg, about 1090 mg, about 1100 mg, about 1110 mg, about 1120 mg, about 1130 mg, about 40103693.007525 / JBI6936 1140 mg, about 1150 mg, about 1160 mg, about 1170 mg, about 1180 mg, about 1190 mg, about 1200 mg, about 1210 mg, about 1220 mg, about 1230 mg, about 1240 mg, about 1250 mg, about 1260 mg, about 1270 mg, about 1280 mg, about 1290 mg, about 1300 mg, about 1310 mg, about 1320 mg, about 1330 mg, about 1340 mg, about 1350 mg, about 1360 mg, about 1370 mg, about 1380 mg, about 1390 mg, about 1400 mg, about 1410 mg, about 1420 mg, about 1430 mg, about 1440 mg, about 1450 mg, about 1460 mg, about 1470 mg, about 1480 mg, about 1490 mg, about 1500 mg, about 1510 mg, about 1520 mg, about 1530 mg, about 1540 mg, about 1550 mg, about 1560 mg, about 1570 mg, 1575 mg, about 1580 mg, about 1590 mg, about 1600 mg, about 1610 mg, 1620 mg, about 1630 mg, about 1640 mg, about 1650 mg, about 1660 mg, about 1670 mg, about 1680 mg, about 1690 mg, about 1700 mg, about 1710 mg, about 1720 mg, about 1730 mg, about 1740 mg, about 1750 mg, about 1760 mg, about 1770 mg, about 1780 mg, about 1790 mg, about 1800 mg, about 1810 mg, about 1820 mg, about 1830 mg, about 1840 mg, about 1850 mg, about 1860 mg, about 1870 mg, about 1880 mg, 1890 mg, about 1900 mg, about 1910 mg, about 1920 mg, about 1930 mg, about 1940 mg, about 1950 mg, about 1960 mg, about 1970 mg, about 1980 mg, about 1990 mg, about 2000 mg, 2100 mg, 2110 mg, 2120 mg, 2130 mg, 2140 mg, 2150 mg, 2160 mg, 2170 mg, 2180 mg, 2190 mg, 2200 mg, 2210 mg, 2220 mg, 2230 mg, 2240 mg, 2250 mg, 2260 mg , 2270 mg, 2280 mg, 2290 mg, 2300 mg, 2310 mg, 2320 mg, 2330 mg, 2340 mg, 2350 mg, 2360 mg, 2370 mg, 2380 mg, 2390 mg, 2400 mg or 2410 mg.

[0156] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg, about 700 mg, about 1050 mg, about 1400 mg, about 1750 mg or about 2100mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg. In some embodiments, the bispecific anti- EGFR / c-Met antibody is administered at a dose of about 700 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 750 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 800 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 850 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 900 mg. In some embodiments, the bispecific anti-EGFR / c- Met antibody is administered at a dose of about 950 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1000 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1050 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1100 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is 41103693.007525 / JBI6936 administered at a dose of about 1150 mg. In some embodiments, the bispecific anti-EGFR / c- Met antibody is administered at a dose of about 1200 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1250 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1300 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1350 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1400 mg. In some embodiments, the bispecific anti-EGFR / c- Met antibody is administered at a dose of about 1750 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 2100 mg.

[0157] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered is administered at a dose of about 1400 mg on Cycle 1 Days 1, 8, and 15, and Cycle 2 Day 1 if the subject has a body weight of less than 80 kg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered is administered at a dose of about 1400 mg on Cycle 1 Days 1 / 2 (split dosing), 8, and 15, and Cycle 2 Day 1 if the subject has a body weight of less than 80 kg.

[0158] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1750 mg on Day 1 of each 21-day cycle, starting with Cycle 3 if the subject has a body weight of less than 80 kg.

[0159] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1750 mg on Cycle 1 Days 1, 8, and 15, and Cycle 2 Day 1 if the subject has a body weight of greater than or equal to 80 kg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1750 mg on Cycle 1 Days 1 / 2 (split dosing), 8, and 15, and Cycle 2 Day 1 if the subject has a body weight of greater than or equal to 80 kg.

[0160] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 2100 mg on Day 1 of each 21-day cycle, starting with Cycle 3 if the subject has a body weight of greater than or equal to 80 kg.

[0161] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered twice a week. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once a week. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once in two weeks. In some embodiments, the bispecific anti- EGFR / c-Met antibody is administered once in three weeks. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once in four weeks. 42103693.007525 / JBI6936

[0162] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered twice a week, once a week, once in two weeks, once in three weeks or once in four weeks.

[0163] In some embodiments, the mode of administration that may the suitable route that delivers lazertinib to the subject may be oral administration, such as oral administration of a tablet. Lazertinib tablet formulations suitable for oral administration in accordance with the present invention are described, for example, in WO2021 / 209893 and WO2020 / 079637, which are incorporated by reference herein.

[0164] In some embodiments, lazertinib is administered at a dose of between about 10 mg to about 400 mg. In some embodiments, lazertinib is administered at a dose of between about 20 mg to about 320 mg. In some embodiments, lazertinib is administered at a dose of between about 50 mg to about 300 mg. In some embodiments, lazertinib is administered at a dose of between about 100 mg to about 300 mg. In some embodiments, lazertinib is administered at a dose of between about 150 mg to about 280 mg. In some embodiments, lazertinib is administered at a dose of between about 200 mg to about 250 mg. In some embodiments, lazertinib is administered at a dose of between about 220 mg to about 250 mg.

[0165] In some embodiments, lazertinib is administered at a dose of about 20 mg, about 50 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, or about 400 mg. In some embodiments, lazertinib is administered at a dose of about 240 mg.

[0166] In some embodiments, lazertinib is administered daily. In some embodiments, lazertinib is administered twice a week. In some embodiments, lazertinib is administered once a week. In some embodiments, lazertinib is administered once in two weeks. In some embodiments, lazertinib is administered once in three weeks. In some embodiments, lazertinib is administered once in four weeks.

[0167] In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with lazertinib, which may be administered using any of the doses and dosages disclosed herein. In some embodiments, lazertinib is administered at a dose of between about 10 mg to about 400 mg. In some embodiments, 43103693.007525 / JBI6936 lazertinib is administered at a dose of between about 20 mg to about 320 mg. In some embodiments, lazertinib is administered at a dose of about 20 mg, about 50 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, or about 400 mg. In some embodiments, lazertinib is administered at a dose of about 240 mg.

[0168] In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in any of these doses and dosages disclosed herein in combination with lazertinib, which may be administered in any of these doses and dosages disclosed herein. As a non-limiting example, 1400 mg amivantamab may be administered in combination with 240 mg lazertinib. As a non-limiting example, 1750 mg amivantamab may be administered in combination with 240 mg lazertinib. As a non-limiting example, 2100 mg amivantamab may be administered in combination with 240 mg lazertinib.

[0169] In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with lazertinib, wherein lazertinib is administered daily, every other day, twice a week, or once a week. In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with lazertinib, wherein lazertinib is administered daily. In some embodiments, the bispecific anti- EGFR / c-Met antibody disclosed herein may be administered in combination with lazertinib, wherein lazertinib is administered orally.

[0170] In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with carboplatin.

[0171] In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with pemetrexed.

[0172] In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with Lazertinib, carboplatin and pemetrexed.

[0173] In some embodiments, the combination therapy comprising a bispecific anti- EGFR / c-Met bispecific antibody and an EGFR TKI may further include one or more additional anti-cancer therapies.

[0174] In some embodiments, the methods of the present disclosure comprise administering to a subject a cancer therapy which does not include the combination therapy comprising a bispecific anti- EGFR / c-Met bispecific antibody and an EGFR TKI disclosed 44103693.007525 / JBI6936 herein. In some embodiments, the cancer therapy may include any one of those described herein. As a non-limiting example, the cancer therapy that may be administered in the methods of the disclosure may comprise any number of various platinum-based chemotherapies or combinations thereof. As a non-limiting example, the platinum-based chemotherapy comprises carboplatin, cisplatin, or a combination thereof.

[0175] Additional anti-cancer therapies that may be administered in the methods of the disclosure may include any one or more of the chemotherapeutic drugs or other anti- cancer therapeutics known to those of skill in the art. Chemotherapeutic agents are chemical compounds useful in the treatment of cancer and include growth inhibitory agents or other cytotoxic agents and include alkylating agents, anti-metabolites, anti-microtubule inhibitors, topoisomerase inhibitors, receptor tyrosine kinase inhibitors, angiogenesis inhibitors and the like. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-FU; folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; etoglucid; gallium nitrate; 45103693.007525 / JBI6936 hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″- trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; members of taxoid or taxane family, such as paclitaxel (TAXOL® docetaxel (TAXOTERE®) and analogues thereof; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogues such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine; inhibitors of receptor tyrosine kinases and / or angiogenesis, including sorafenib (NEXAVAR®), sunitinib (SUTENT®), pazopanib (VOTRIENT™), toceranib (PALLADIA™), vandetanib (ZACTIMA™), cediranib (RECENTIN®), regorafenib (BAY 73-4506), axitinib (AG013736), lestaurtinib (CEP-701), erlotinib (TARCEVA®), gefitinib (IRESSA®), afatinib (BIBW 2992), lapatinib (TYKERB®), neratinib (HKI-272), and the like, and pharmaceutically acceptable salts, acids or derivatives of any of the above. Also included in this definition are anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (FARESTON®); and anti- androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Other conventional cytotoxic chemical compounds as those disclosed in Wiemann et al., 1985, in Medical Oncology (Calabresi et aL, eds.), Chapter 10, McMillan Publishing, are also applicable to the methods of the present invention. Generation of bispecific anti-EGFR / c-Met antibodies used in the methods of the disclosure

[0176] An exemplary bispecific anti-EGFR / c-Met antibody that can be used in the methods of the disclosures is amivantamab. Amivantamab is an IgG1 anti-EGFR / c-Met bispecific antibody described in U.S. Pat. No.9,593,164, which is incorporated herein by reference in its entirety. Amivantamab is characterized by following amino acid sequences: EGFR binding arm 46103693.007525 / JBI6936 >SEQ ID NO: 1 (HCDR1, EGFR binding arm) TYGMH >SEQ ID NO: 2 (HCDR2, EGFR binding arm) VIWDDGSYKYYGDSVKG >SEQ ID NO: 3 (HCDR3, EGFR binding arm) DGITMVRGVMKDYFDY >SEQ ID NO: 4 (LCDR1, EGFR binding arm) RASQDISSALV >SEQ ID NO: 5 (LCDR2, EGFR binding arm) DASSLES >SEQ ID NO: 6 (LCDR3, EGFR binding arm) QQFNSYPLT >SEQ ID NO: 7 (HCDR1, c-Met binding arm) SYGIS >SEQ ID NO: 8 (HCDR2, c-Met binding arm) WISAYNGYTNYAQKLQG >SEQ ID NO: 9 (HCDR3, c-Met binding arm) DLRGTNYFDY >SEQ ID NO: 10 (LCDR1, c-Met binding arm) RASQGISNWLA >SEQ ID NO: 11 (LCDR2, c-Met binding arm) AASSLLS >SEQ ID NO: 12 (LCDR3, c-Met binding arm) 47103693.007525 / JBI6936 QQANSFPIT >SEQ ID NO: 13 (VH, EGFR binding arm) QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDG SYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKD YFDYWGQGTLVTVSS >SEQ ID NO: 14 (VL, EGFR binding arm) AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVP SRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK >SEQ ID NO: 15 (VH, c-Met binding arm) QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYN GYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWG QGTLVTVSS >SEQ ID NO: 16 (VL, c-Met binding arm) DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIK >SEQ ID NO: 17 HC1 QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDG SYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKD YFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEP KSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP APIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK >SEQ ID NO: 18 LC1 AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVP SRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKRTVAAPSVFIFP 48103693.007525 / JBI6936 PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC >SEQ ID NO: 19 HC2 QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYN GYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK >SEQ ID NO: 20 LC2 DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0177] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds EGFR and a second domain that specifically binds c-Met, wherein the first domain comprises the heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6; and the second domain comprises the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, the LCDR1 of SEQ ID NO: 10, the LCDR2 of SEQ ID NO: 11, and the LCDR3 of SEQ ID NO: 12.

[0178] In some embodiments, the first domain that specifically binds EGFR comprises the heavy chain variable region (VH) of SEQ ID NO: 13 and the light chain variable region (VL) of SEQ ID NO: 14; and the second domain that specifically binds c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.

[0179] In some embodiments, the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype. 49103693.007525 / JBI6936

[0180] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises the first heavy chain (HC1) of SEQ ID NO: 17, the first light chain (LC1) of SEQ ID NO: 18, the second heavy chain (HC2) of SEQ ID NO: 19, and the second light chain (LC2) of SEQ ID NO: 20.

[0181] In some embodiments, the bispecific anti-EGFR / c-Met antibody is amivantamab.

[0182] In some embodiments, the bispecific anti-EGFR / c-Met antibody is a biosimilar of amivantamab.

[0183] In some embodiments, a non-limiting example of a biosimilar of amivantamab can be found in publicly available Web resource: us.proteogenix_science / product / amivantamab-biosimilar-anti-egfr-me-rccp2-mab-research- grade / .

[0184] In some embodiments, a non-limiting example of a biosimilar of amivantamab can be found in publicly available Web resource: thermofisher_com / antibody / product / Amivantamab-Antibody-Recombinant- Monoclonal / MA5-42260.

[0185] In some embodiments, a non-limiting example of a biosimilar of amivantamab can be found in publicly available Web resource: genemedi.net / i / biologics- biosimilar-GMP-Bios-ab-021.

[0186] In some embodiments, a non-limiting example of a biosimilar of amivantamab can be found in publicly available Web resource: prosci- inc_com / product / amivantamab-egfr-me-rccp2-research-grade-biosimilar-10-966 / .

[0187] In some embodiments, a non-limiting example of a biosimilar of amivantamab can be found in publicly available Web resource: antibodysystem_com / product / 6201.

[0188] In some embodiments, a non-limiting example of a biosimilar of amivantamab can be found in publicly available Web resource: biorbyt_com / amivantamab- biosimilar-antibody-orb1140752.

[0189] In one embodiment, the bispecific anti-EGFR / c-Met antibody comprises one or more Fc silencing mutations.

[0190] In one embodiment, the one or more Fc silencing mutations decrease affinity to Fcγ receptors.

[0191] In one embodiment, the one or more Fc silencing mutations comprise V234A / G237A / P238S / H268A / V309L / A330S / P331S. 50103693.007525 / JBI6936

[0192] In one embodiment, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content between about 1% to about 15%. Antibodies with reduced fucose content can be made using different methods reported to lead to the successful expression of relatively high defucosylated antibodies bearing the biantennary complex-type of Fc oligosaccharides such as control of culture osmolality (Konno et al., Cytotechnology 64(:249-65, 2012), application of a variant CHO line Lec13 as the host cell line (Shields et al., J Biol Chem 277:26733-26740, 2002), application of a variant CHO line EB66 as the host cell line (Olivier et al., MAbs ;2(4), 2010; Epub ahead of print; PMID:20562582), application of a rat hybridoma cell line YB2 / 0 as the host cell line (Shinkawa et al., J Biol Chem 278:3466-3473, 2003), introduction of small interfering RNA specifically against the α 1,6-fucosyltrasferase ( FUT8) gene (Mori et al., Biotechnol Bioeng88:901-908, 2004), or coexpression of β-1,4-N-acetylglucosaminyltransferase III and Golgi α-mannosidase II or a potent alpha-mannosidase I inhibitor, kifunensine (Ferrara et al., J Biol Chem281:5032-5036, 2006, Ferrara et al., Biotechnol Bioeng 93:851-861, 2006; Xhou et al., Biotechnol Bioeng 99:652-65, 2008). In general, lowering fucose content in the glycan of the antibodies potentiates antibody-mediated cellular cytotoxicity (ADCC).

[0193] Other bispecific anti-EGFR / c-Met antibodies publicly available may also be used in the methods of the disclosure as long as they demonstrate similar characteristics when compared to amivantamab as described in U.S. Pat. No.9,593,164. Bispecific anti-EGFR / c- Met antibodies that may be used in the methods of the disclosure may also be generated by combining EGFR binding VH / VL domains and c-Met binding VH / VL domains that are publicly available and testing the resulting bispecific antibodies for their characteristics as described in U.S. Pat. No.9,593,164. In some embodiments, the anti-EGFR / c-Met antibodies are biosimilar of anti-EGFR / c-Met antibodies as described in U.S. Pat. No.9,593,164.

[0194] Bispecific anti-EGFR / c-Met antibodies used in the methods of the disclosure may be generated for example using Fab arm exchange (or half molecule exchange) between two monospecific bivalent antibodies by introducing substitutions at the heavy chain CH3 interface in each half molecule to favor heterodimer formation of two antibody half molecules having distinct specificity either in vitro in cell-free environment or using co- expression. The Fab arm exchange reaction is the result of a disulfide-bond isomerization reaction and dissociation-association of CH3 domains. The heavy chain disulfide bonds in the hinge regions of the parental monospecific antibodies are reduced. The resulting free cysteines of one of the parental monospecific antibodies form an inter heavy-chain disulfide bond with cysteine residues of a second parental monospecific antibody molecule and 51103693.007525 / JBI6936 simultaneously CH3 domains of the parental antibodies release and reform by dissociation- association. The CH3 domains of the Fab arms may be engineered to favor heterodimerization over homodimerization. The resulting product is a bispecific antibody having two Fab arms or half molecules which each bind a distinct epitope, i.e., an epitope on EGFR and an epitope on c-Met. For example, the bispecific antibodies of the invention may be generated using the technology described in Int.Pat. Publ. No. WO2011 / 131746. Mutations F405L in one heavy chain and K409R in the other heavy chain may be used in case of IgG1 antibodies. For IgG2 antibodies, a wild-type IgG2 and a IgG2 antibody with F405L and R409K substitutions may be used. For IgG4 antibodies, a wild-type IgG4 and a IgG4 antibody with F405L and R409K substitutions may be used. To generate bispecific antibodies, first monospecific bivalent antibody and the second monospecific bivalent antibody are engineered to have the aforementioned mutation in the Fc region, the antibodies are incubated together under reducing conditions sufficient to allow the cysteines in the hinge region to undergo disulfide bond isomerization; thereby generating the bispecific antibody by Fab arm exchange. The incubation conditions may optimally be restored to non-reducing. Exemplary reducing agents that may be used are 2- mercaptoethylamine (2-MEA), dithiothreitol (DTT), dithioerythritol (DTE), glutathione, tris(2-carboxyethyl)phosphine (TCEP), L-cysteine and beta- mercaptoethanol. For example, incubation for at least 90 min at a temperature of at least 20°C in the presence of at least 25 mM 2-MEA or in the presence of at least 0.5 mM dithiothreitol at a pH of from 5-8, for example at pH of 7.0 or at pH of 7.4 may be used.

[0195] Bispecific anti-EGFR / c-Met antibodies used in the methods of the disclosure may also be generated using designs such as the Knob-in-Hole (Genentech), CrossMAbs (Roche) and the electrostatically-matched (Chugai, Amgen, NovoNordisk, Oncomed), the LUZ-Y (Genentech), the Strand Exchange Engineered Domain body (SEEDbody)(EMD Serono), and the Biclonic (Merus).

[0196] In the “knob-in-hole” strategy (see, e.g., Intl. Publ. No. WO 2006 / 028936) select amino acids forming the interface of the CH3 domains in human IgG can be mutated at positions affecting CH3 domain interactions to promote heterodimer formation. An amino acid with a small side chain (hole) is introduced into a heavy chain of an antibody specifically binding a first antigen and an amino acid with a large side chain (knob) is introduced into a heavy chain of an antibody specifically binding a second antigen. After co-expression of the two antibodies, a heterodimer is formed as a result of the preferential interaction of the heavy chain with a “hole” with the heavy chain with a “knob.” Exemplary CH3 substitution pairs 52103693.007525 / JBI6936 forming a knob and a hole are (expressed as modified position in the first CH3 domain of the first heavy chain / modified position in the second CH3 domain of the second heavy chain): T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S and T366W / T366S_L368A_Y407V.

[0197] CrossMAb technology, in addition to utilizing the “knob-in-hole” strategy to promoter Fab arm exchange utilizes CH1 / CL domain swaps in one half arm to ensure correct light chain pairing of the resulting bispecific antibody (see e.g., U.S. Patent No.8,242,247).

[0198] Other cross-over strategies may be used to generate full length bispecific antibodies of the invention by exchanging variable or constant, or both domains between the heavy chain and the light chain or within the heavy chain in the bispecific antibodies, either in one or both arms. These exchanges include for example VH-CH1 with VL-CL, VH with VL, CH3 with CL and CH3 with CH1 as described in Int. Patent Publ. Nos. WO2009 / 080254, WO2009 / 080251, WO2009 / 018386 and WO2009 / 080252.

[0199] Other strategies such as promoting heavy chain heterodimerization using electrostatic interactions by substituting positively charged residues at one CH3 surface and negatively charged residues at a second CH3 surface may be used, as described in US Patent Publ. No. US2010 / 0015133; US Patent Publ. No. US2009 / 0182127; US Patent Publ. No. US2010 / 028637 or US Patent Publ. No. US2011 / 0123532. In other strategies, heterodimerization may be promoted by following substitutions (expressed as modified positions in the first CH3 domain of the first heavy chain / modified position in the second CH3 domain of the second heavy chain): L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, or T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W as described in U.S. Patent Publ. No. US2012 / 0149876 or U.S. Patent Publ. No. US2013 / 0195849.

[0200] SEEDbody technology may be utilized to generate bispecific antibodies of the invention. SEEDbodies have, in their constant domains, select IgG residues substituted with IgA residues to promote heterodimerization as described in U.S. Patent No. US20070287170.

[0201] Mutations are typically made at the DNA level to a molecule such as the constant domain of the antibody using standard methods. Exemplary Embodiments

[0202] Provided below is a list of exemplary embodiments: 53103693.007525 / JBI6936 Embodiment 1. A method of reducing an adverse reaction associated with the use of amivantamab in combination with carboplatin and pemetrexed for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the method comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, and who experiences a grade 1 or grade 2 infusion-related adverse reaction: interrupting the intravenous amivantamab infusion, monitoring the subject until the grade 1 or grade 2 infusion-related adverse reaction resolves, resuming the intravenous amivantamab infusion at 50% of the infusion rate at which the grade 1 or grade 2 infusion-related adverse reaction occurred, and, if there are no additional infusion-related adverse reactions after 30 minutes, increasing the infusion rate; who experiences a grade 3 infusion-related adverse reaction: interrupting the intravenous amivantamab infusion, monitoring the subject until the grade 3 infusion-related adverse reaction resolves, resuming the intravenous amivantamab infusion at 50% of the infusion rate at which the grade 3 infusion-related adverse reaction occurred, and, if there are no additional infusion-related adverse reactions after 30 minutes, increasing the infusion rate; or who experiences a grade 4 infusion-related adverse reaction: permanently discontinuing administration of the amivantamab. Embodiment 2. The method of embodiment 1, comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, and who experiences a 54103693.007525 / JBI6936 grade 1 or grade 2 infusion-related adverse reaction: interrupting the intravenous amivantamab infusion, monitoring the subject until the grade 1 or grade 2 infusion- related adverse reaction resolves, resuming the intravenous amivantamab infusion at 50% of the infusion rate at which the grade 1 or grade 2 infusion-related adverse reaction occurred, and, if there are no additional infusion-related adverse reactions after 30 minutes, increasing the infusion rate. Embodiment 3. The method of embodiment 1, comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, and who experiences a grade 3 infusion-related adverse reaction: interrupting the intravenous amivantamab infusion, monitoring the subject until the grade 3 infusion-related adverse reaction resolves, resuming the intravenous amivantamab infusion at 50% of the infusion rate at which the grade 3 infusion-related adverse reaction occurred, and, if there are no additional infusion-related adverse reactions after 30 minutes, increasing the infusion rate. Embodiment 4. The method of any one of the previous embodiments, further comprising, for grade 1, grade 2, or grade 3 infusion-related reactions, administering an antihistamine, an antipyretic, and a glucocorticoid prior to resuming the intravenous amivantamab infusion. Embodiment 5. The method of embodiment 4, wherein the antihistamine comprises diphenhydramine. Embodiment 6. The method of embodiment 4, wherein the antipyretic comprises acetaminophen. Embodiment 7. The method of embodiment 4, wherein the glucocorticoid comprises dexamethasone. Embodiment 8. The method of embodiment 3, further comprising permanently discontinuing administration of the amivantamab if the grade 3 infusion-related adverse reaction is a recurrent grade 3 infusion-related adverse reaction. Embodiment 9. The method of embodiment 1, comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin 55103693.007525 / JBI6936 infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, and who experiences a grade 4 infusion-related adverse reaction: permanently discontinuing administration of the amivantamab. Embodiment 10. The method of any one of the previous embodiments, wherein the therapeutically effective amount of amivantamab comprises for subjects who weigh less than 80 kg, 1400 mg weekly from week 1 to week 4 and 1750 mg every three weeks starting at week 7 for subjects who weigh greater than or equal to 80 kg, 1750 mg weekly from week 1 to week 4 and 2100 mg every three weeks starting at week 7; the therapeutically effective amount of pemetrexed comprises 500 mg / m2every three weeks; and the therapeutically effective amount of carboplatin comprises AUC 5 every three weeks for up to 12 weeks. Embodiment 11. A method of reducing an adverse reaction associated with the use of amivantamab in combination with carboplatin and pemetrexed for the treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the method comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who is suspected of experiencing interstitial lung disease / pneumonitis of any grade: withholding administration of the amivantamab; or who experiences interstitial lung disease / pneumonitis of any grade: permanently discontinuing administration of the amivantamab. Embodiment 12. The method of embodiment 11, comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion 56103693.007525 / JBI6936 to treat the locally advanced or metastatic NSCLC whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who is suspected of experiencing interstitial lung disease / pneumonitis of any grade: withholding administration of the amivantamab. Embodiment 13. The method of embodiment 11, comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences interstitial lung disease / pneumonitis of any grade: permanently discontinuing administration of the amivantamab. Embodiment 14. The method of any one of embodiments 11-13, wherein the therapeutically effective amount of amivantamab comprises for subjects who weigh less than 80 kg, 1400 mg weekly from week 1 to week 4 and 1750 mg every three weeks starting at week 7 for subjects who weigh greater than or equal to 80 kg, 1750 mg weekly from week 1 to week 4 and 2100 mg every three weeks starting at week 7; the therapeutically effective amount of pemetrexed comprises 500 mg / m2every three weeks; and the therapeutically effective amount of carboplatin comprises AUC 5 every three weeks for up to 12 weeks. Embodiment 15. A method of reducing an adverse reaction associated with the use of amivantamab in combination with carboplatin and pemetrexed for the treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the method comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and 57103693.007525 / JBI6936 who experiences a grade 1 dermatologic adverse reaction: reassessing after two weeks; who experiences a grade 2 dermatologic adverse reaction: reassessing after two weeks, and if the grade 2 dermatologic adverse reaction does not improve, administering a reduced dose of the amivantamab to the subject; who experiences a grade 3 dermatologic adverse reaction: withholding the amivantamab and resuming administration of the amivantamab at a reduced dose if the grade 3 dermatologic adverse reaction becomes a grade 2 or lower dermatologic adverse reaction, or permanently discontinuing the treatment if no improvement in the grade 3 dermatologic adverse reaction occurs within 2 weeks; or who experiences a grade 4 dermatologic adverse reaction or severe bullous, blistering, or exfoliating skin: permanently discontinuing administration of the amivantamab. Embodiment 16. The method of embodiment 15, comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences a grade 1 dermatologic adverse reaction: reassessing after two weeks. Embodiment 17. The method of embodiment 15, comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences a grade 2 dermatologic adverse reaction: reassessing after two weeks, and if the grade 2 dermatologic adverse reaction does not improve, administering a reduced dose of the amivantamab to the subject. Embodiment 18. The method of embodiment 15, comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin 58103693.007525 / JBI6936 infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences a grade 3 dermatologic adverse reaction: withholding the amivantamab and resuming administration of the amivantamab at a reduced dose if the grade 3 dermatologic adverse reaction becomes a grade 2 or lower dermatologic adverse reaction, or permanently discontinuing the treatment if no improvement in the grade 3 dermatologic adverse reaction occurs within 2 weeks. Embodiment 19. The method of any one of embodiments 15-18, wherein the reduced dose of amivantamab comprises 1050 mg or 700 mg if the adverse reactions occurred at an amivantamab dose of 1400 mg, 1400 mg or 1050 mg if the adverse reactions occurred at an amivantamab dose of 1750 mg, or 1750 mg or 1400 mg if the adverse reactions occurred at an amivantamab dose of 2100 mg. Embodiment 20. The method of any one of embodiments 15-19, further comprising administering an antihistamine and an antipyretic prior to resuming the intravenous amivantamab infusion. Embodiment 21. The method of embodiment 20, wherein the antihistamine comprises diphenhydramine and the antipyretic comprises acetaminophen. Embodiment 22. The method of embodiment 15, comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences a grade 4 dermatologic adverse reaction or severe bullous, blistering, or exfoliating skin: permanently discontinuing administration of the amivantamab. Embodiment 23. The method of any one of embodiments 15-22, wherein the therapeutically effective amount of amivantamab comprises for subjects who weigh less than 80 kg, 1400 mg weekly from week 1 to week 4 and 1750 mg every three weeks starting at week 7 for subjects who weigh greater than or equal to 80 kg, 1750 mg weekly from week 1 to week 4 and 2100 mg every three weeks starting at week 7; the therapeutically effective amount of pemetrexed comprises 500 mg / m2every three weeks; and 59103693.007525 / JBI6936 the therapeutically effective amount of carboplatin comprises AUC 5 every three weeks for up to 12 weeks. Embodiment 24. A method of reducing an adverse reaction associated with the use of amivantamab in combination with carboplatin and pemetrexed for the treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the method comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences at least one other grade 3 adverse reaction: withholding amivantamab until the at least one other grade 3 adverse reaction reduces to less than or equal to grade 1 or baseline and resuming the amivantamab at the same dose if the subject recovers from the grade 3 adverse reaction within 1 week; resuming the amivantamab at a reduced dose if the subject recovers from the grade 3 adverse reaction after 1 week but within 4 weeks; or permanently discontinuing the amivantamab if the subject does not recover from the grade 3 adverse reaction within 4 weeks; or who experiences at least one other grade 4 adverse reaction: withholding amivantamab until the at least one other grade 4 adverse reaction reduces to less than or equal to grade 1 or baseline and resuming the amivantamab at a reduced dose if the subject recovers from the grade 4 adverse reaction within 4 weeks; or permanently discontinuing the amivantamab if the subject does not recover from the grade 4 adverse reaction within 4 weeks or if the grade 4 infusion-related adverse reaction is a recurrent grade 4 infusion-related adverse reaction. Embodiment 25. The method of embodiment 24, comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin 60103693.007525 / JBI6936 infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences at least one other grade 3 adverse reaction: withholding amivantamab until the at least one other grade 3 adverse reaction reduces to less than or equal to grade 1 or baseline and resuming the amivantamab at the same dose if the subject recovers from the grade 3 adverse reaction within 1 week; resuming the amivantamab at a reduced dose if the subject recovers from the grade 3 adverse reaction after 1 week but within 4 weeks; or permanently discontinuing the amivantamab if the subject does not recover from the grade 3 adverse reaction within 4 weeks. Embodiment 26. The method of embodiment 24, comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences at least one other grade 4 adverse reaction: withholding amivantamab until the at least one other grade 4 adverse reaction reduces to less than or equal to grade 1 or baseline and resuming the amivantamab at a reduced dose if the subject recovers from the grade 4 adverse reaction within 4 weeks; or permanently discontinuing the amivantamab if the subject does not recover from the grade 4 adverse reaction within 4 weeks or if the grade 4 infusion-related adverse reaction is a recurrent grade 4 infusion-related adverse reaction. Embodiment 27. The method of any one of embodiments 24-26, wherein the therapeutically effective amount of amivantamab comprises for subjects who weigh less than 80 kg, 1400 mg weekly from week 1 to week 4 and 1750 mg every three weeks starting at week 7 for subjects who weigh greater than or equal to 80 kg, 1750 mg weekly from week 1 to week 4 and 2100 mg every three weeks starting at week 7; the therapeutically effective amount of pemetrexed comprises 500 mg / m2every three weeks; and 61103693.007525 / JBI6936 the therapeutically effective amount of carboplatin comprises AUC 5 every three weeks for up to 12 weeks. Embodiment 28. The method of any one of embodiments 24-27, wherein the reduced dose of amivantamab comprises 1050 mg or 700 mg if the adverse reactions occurred at an amivantamab dose of 1400 mg, 1400 mg or 1050 mg if the adverse reactions occurred at an amivantamab dose of 1750 mg, or 1750 mg or 1400 mg if the adverse reactions occurred at an amivantamab dose of 2100 mg. Embodiment 29. The method of any one of embodiments 24-28, further comprising administering an antihistamine and an antipyretic prior to resuming the intravenous amivantamab infusion. Embodiment 30. The method of embodiment 29, wherein the antihistamine comprises diphenhydramine and the antipyretic comprises acetaminophen. Embodiment 31. A method of treating locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations in a subject whose NSCLC has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the method comprising administering to the subject an approved drug product comprising amivantamab, in combination with carboplatin and pemetrexed. Embodiment 32. A method of improving median progression free survival (PFS) in a population of subjects having locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations whose NSCLC has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the method comprising administering to the population of subjects an approved drug product comprising amivantamab, in combination with carboplatin and pemetrexed. Embodiment 33. The method of embodiment 32, wherein the median PFS is 5.6 months to 8.4 months. Embodiment 34. The method of embodiment 32 or 33, wherein the median PFS is 6.3 months. Embodiment 35. A method of improving overall response rate (ORR) in a population of subjects having locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations whose NSCLC has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the method comprising administering to the population of subjects an approved drug product comprising amivantamab, in combination with carboplatin and pemetrexed. Embodiment 36. The method of embodiment 35, wherein the ORR is 44% to 62%. 62103693.007525 / JBI6936 Embodiment 37. The method of embodiment 35 or 36, wherein the ORR is 53%. Embodiment 38. A method of improving median duration of response (DOR) in a population of subjects having locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations whose NSCLC has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the method comprising administering to the population of subjects an approved drug product comprising amivantamab, in combination with carboplatin and pemetrexed. Embodiment 39. The method of embodiment 36, wherein the DOR is greater than or equal to 5.5 months. Embodiment 40. The method of embodiment 38 or 39, wherein the DOR is 6.9 months. Embodiment 41. The method of any one of embodiments 31-40, comprising administering amivantamab intravenously at 1,400 mg for patients who weigh less than 80 kg or 1,750 mg for patients who weigh greater than or equal to 80 kg once weekly through 4 weeks, then every 3 weeks with a dose of 1,750 mg for patients who weigh less than 80 kg or 2,100 mg for patients who weigh great than or equal to 80 kg starting at Week 7 until disease progression or unacceptable toxicity. Embodiment 42. The method of embodiment 41, comprising administering 500 mg / m2of pemetrexed every three weeks until disease progression or unacceptable toxicity and administering AUC 5 of carboplatin every three weeks for up to 12 weeks. EXAMPLES

[0203] The following examples are provided to further describe some of the embodiments disclosed herein. The examples are intended to illustrate, not to limit, the disclosed embodiments. Example 1. CHRYSALIS-2 Clinical Trial

[0204] CHRYSALIS-2 (NCT04077463) is an open-label Phase 1 / 1b study to evaluate the safety and pharmacokinetics of Lazertinib as monotherapy or in combinations with amivantamab in participants with advanced non-small cell lung cancer. The study includes multiple cohorts. Provided below are results for the LACP (lazertinib, amivantamab, carboplatin, pemetrexed) cohort of 20 patients. Methods:

[0205] The LACP cohort of the CHRYSALIS-2 study enrolled patients with relapsed / refractory EGFR-mutated advanced NSCLC whose disease progressed on or after 63103693.007525 / JBI6936 treatment with an EGFR TKI as last line of therapy (maximum of 3 prior lines). Patients received intravenous amivantamab 1400 mg (1750 mg, ≥80 kg) weekly for the first 4 weeks and 1750 mg (2100 mg, ≥80 kg) every 3 weeks starting at cycle 3 plus 240 mg oral lazertinib daily, and pemetrexed (500 mg / m2) with carboplatin (AUC5 for the first 4 cycles) on a 21- day cycle. Response was assessed by the investigator per RECIST v1.1. Results:

[0206] Of the 20 patients enrolled, median age was 61 years (range, 38-76), 55% female, 55% Asian and 40% White, and a median of 2 prior lines (70% prior osimertinib, 45% prior 1st / 2nd-generation EGFR TKIs). The objective response rate was 50%, with median duration of response not estimable (median follow-up was 13.1 [range, 2.4-17.5] months). Eight of 10 responders have a response duration ≥6 months. Eleven (55%) patients are ongoing treatment; median progression-free survival (PFS) was 14.0 (95% CI, 4.3-not estimable) months. A total of 5 patients were treated beyond progression, with an incremental median treatment duration of 4.2 (range, 3.1-7.1) months. Of the 12 patients with history of brain metastases, median PFS was 6.7 (95% CI, 1.4-not estimable) months. The most frequent treatment-emergent adverse events (TEAEs) were rash (100%), neutropenia (90%), and infusion-related reactions (65%). Most common grade ≥3 TEAEs were neutropenia (70%), thrombocytopenia (25%), and fatigue (25%). For grade ≥3 neutropenia, febrile neutropenia, and thrombocytopenia TEAEs, all but two cases of neutropenia had fully resolved by Day 1 of the subsequent cycle. Fifteen of 20 patients (75%) experienced cytopenia events during the first 4 cycles versus 2 of 17 patients (12%) during cycle 5 or onwards. Five of 7 patients who were given colony stimulating factors for neutropenia had no recurrent episodes of neutropenia. Treatment-related dose interruptions, reductions, and discontinuations of any study agent occurred in 18 (90%), 14 (70%), and 8 (40%) patients, respectively; no patient discontinued all study agents due to TEAEs.

[0207] Conclusions: Among patients with EGFR-mutated advanced NSCLC who experienced disease progression on EGFR TKIs, amivantamab, lazertinib plus chemotherapy demonstrated meaningful and durable response rates. Example 2. MARIPOSA-2 Clinical Study

[0208] MARIPOSA-2 is a randomized, open-label, active-controlled, parallel, multicenter, Phase 3 study to compare the efficacy and safety of Arm A (lazertinib, amivantamab, carboplatin, and pemetrexed “LACP / ACP-L”) versus Arm B (carboplatin and pemetrexed, “CP”) and Arm C (amivantamab, carboplatin, and pemetrexed, “ACP”) versus 64103693.007525 / JBI6936 Arm B (CP) in participants with EGFR-mutated locally advanced or metastatic nonsquamous NSCLC who have progressed on or after treatment with osimertinib. Study ID numbers include: NCT04988295, CR109061, 2021-001825-33 (EudraCT) and 61186372NSC3002.

[0209] The purpose of this study is to assess the efficacy of adding lazertinib to amivantamab, carboplatin, and pemetrexed (LACP / ACP-L dosing strategies) and amivantamab, carboplatin and pemetrexed (ACP) compared with carboplatin and pemetrexed (CP) in participants with locally advanced or metastatic epidermal growth factor receptor (EGFR) Exon 19del or Exon 21 L858R substitution non-small cell lung cancer (NSCLC) after osimertinib failure. The purpose of the extension cohort is to further describe the safety and efficacy for the ACP-L dosing schedule versus ACP with additional data. Study Design

[0210] The original study design of MARIPOSA-2 had 3 arms with a randomization ratio of 2:2:1 for LACP, CP and ACP respectively, for the primary objective of comparing LACP and CP, with an ACP arm in the study to demonstrate the contribution of lazertinib. A decision was made to amend MARIPOSA-2 to implement the dual primary hypotheses of comparing ACP versus CP and LACP versus CP.

[0211] Arm A was eventually modified to withhold lazertinib during administration of carboplatin. The modified dosing schedule whereby lazertinib was started after treatment with carboplatin was completed is referred to as ACP-L; the prior dosing schedule before modification (i.e., participants started lazertinib from the beginning of treatment) is referred to as LACP. The primary statistical analyses compared all participants randomized between Arm A and Arm B, regardless of dosing schedule, and between Arm C and Arm B on an intent to treat basis.

[0212] To further characterize the safety and efficacy of the modified ACP-L dosing schedule versus ACP, a separate open-label, randomized extension cohort was added to the study. Enrollment of participants into the extension cohort began after enrollment into the main study was complete. The extension cohort had the same eligibility criteria and study procedures, and operated within the same investigational sites as the main study. Participants were planned to be randomly assigned to study treatment arms in 2:1 ratio (Arms A2 and C2 respectively) in the extension cohort.

[0213] Data from the extension cohort were not included in the primary analysis. The primary analysis for Arm A as pre-specified in statistical analysis plan (SAP) pools data from participants treated with LACP and ACP-L. As a result of the limited follow-up of participants receiving ACP-L in the main study and extension cohort, the full comparison of 65103693.007525 / JBI6936 ACP-L with CP is not in scope of this analysis. A diagram of the study design is provided in Figure 1. Inclusion / Exclusion Criteria.

[0214] Eligible patients were 18 years of age or older, had locally advanced or metastatic NSCLC with disease progression on or after osimertinib monotherapy (as the most recent line of treatment), and had EGFR Ex19del or L858R mutations. Patients with brain metastases were eligible provided intracranial disease was stable, asymptomatic, and on unchanged doses of steroids. Additional information about the criteria is provided below. Inclusion Criteria: • Participant must have at least 1 measurable lesion, according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, that has not been previously irradiated; • Participant must have histologically or cytologically confirmed, locally advanced or metastatic, non-squamous non-small cell lung cancer (NSCLC), characterized at or after the time of locally advanced or metastatic disease diagnosis by either epidermal growth factor receptor (EGFR) Exon 19del or Exon 21 L858R mutation; • A participant with a history of brain metastases must have had all lesions treated as clinically indicated (that is, no current indication for further definitive local therapy). Any definitive local therapy to brain metastases must have been completed at least 14 days prior to randomization and the participant can be receiving no greater than10 milligrams (mg) prednisone or equivalent daily for the treatment of intracranial disease; • Participant must have Eastern Cooperative Oncology Group (ECOG) status of 0 or 1; • Any toxicities from prior systemic anticancer therapy must have resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 Grade 1 or baseline level (except for alopecia [any grade], Grade <= 2 peripheral neuropathy, or Grade <= 2 hypothyroidism stable on hormone replacement); • A woman of childbearing potential must have a negative serum pregnancy test at screening and within 72 hours of the first dose of study treatment and must agree to further serum or urine pregnancy tests during the study; 66103693.007525 / JBI6936 • Participant must have progressed on or after osimertinib monotherapy as the most recent line of treatment. Osimertinib must have been administered as either the first- line treatment for locally advanced or metastatic disease or in the second- line setting after prior treatment with first- or second-generation EGFR tyrosine kinase inhibitor (TKI) as a monotherapy. Participants who received either neoadjuvant and / or adjuvant treatment of any type are eligible if progression to locally advanced or metastatic disease occurred at least 12 months after the last dose of such therapy and then the participant progressed on or after osimertinib in the locally advanced or metastatic setting. Treatment with osimertinib must be discontinued at least 8 days (4 half-lives) prior to randomization (that is last dose no later than Day -8). Exclusion Criteria: • Participant received radiotherapy for palliative treatment of NSCLC less than 14 days prior to randomization; • Participant with symptomatic or progressive brain metastases; • Participant has history of or current evidence of leptomeningeal disease, or participant has spinal cord compression not definitively treated with surgery or radiation; • Participant has known small cell transformation; • Participant has a medical history of interstitial lung disease (ILD), including drug- induced ILD or radiation pneumonitis; • Participant has a history of clinically significant cardiovascular disease including, but not limited to diagnosis of deep vein thrombosis or pulmonary embolism within 4 weeks prior to randomization; myocardial infarction; unstable angina; stroke; transient ischemic attack; coronary / peripheral artery bypass graft; or acute coronary syndrome. Participant has a significant genetic predisposition to venous thromboembolic events. Participant has a prior history of venous thromboembolic events and is not on appropriate therapeutic anticoagulation as per National Comprehensive Cancer Network or local guidelines. Treatment duration / Trial duration:

[0215] The study included a Screening Phase, a Treatment Phase, and a Follow-up Phase. Participants were to complete screening procedures within 28 days before randomization. The Treatment Phase began on Cycle 1 Day 1 and continued in 21-day cycles 67103693.007525 / JBI6936 until the End of Treatment visit, that was to occur within 30 days after discontinuation of study treatment or prior to starting subsequent systemic therapy, whichever occurred first. Participants who discontinued study treatment for any reason were to be followed for survival and symptomatic progression in the Follow-up Phase. The Follow-up Phase starts after the End of Treatment Visit and continues until death, lost to follow-up, or withdrawal of consent, whichever comes first. Main Study Arms: Arm A Dosing Schedule 1 (LACP): • Lazertinib 240 mg orally, once daily • Amivantamab by intravenous (IV) infusion in 21-day cycles: • 1,400 mg (1,750 mg if body weight ≥80 kg) on Cycle 1 Days 1 / 2(split dosing), 8, and 15, and Cycle 2 Day 1 • 1,750 mg (2,100 mg if body weight ≥80 kg) on Day 1 of each 21-day cycle, starting with Cycle 3 • Carboplatin and pemetrexed as in Arm B. Dosing Schedule 2 (ACP-L): • Lazertinib 240 mg orally, once daily starting Cycle 5 Day 1 or sooner if carboplatin is discontinued earlier • Amivantamab by IV infusion in 21-day cycles: • 1,400 mg (1,750 mg if body weight ≥80 kg) on Cycle 1 Days 1 / 2(split dosing), 8, and 15, and Cycle 2 Day 1 • 1,750 mg (2,100 mg if body weight ≥80 kg) on Day 1 of each 21-day cycle, starting with Cycle 3 • Carboplatin and pemetrexed as in Arm B. Arm B (CP): • Carboplatin AUC 5 on Day 1 of each 21-day cycle, for up to 4 cycles • Pemetrexed 500 mg / m2on Day 1 of each 21-day cycle, with carboplatin for up to 4 cycles, and then as maintenance until disease progression Arm C (ACP): • Amivantamab administered as per schedule in Arm A • Carboplatin and pemetrexed as in Arm B 68103693.007525 / JBI6936 Table 8. Primary and Secondary Endpoints:69103693.007525 / JBI6936 Results:

[0216] As noted above, MARIPOSA-2 (NCT04988295) is a randomized, open- label Phase 3 study evaluating the efficacy and safety of two dosing regimens of RYBREVANT® (amivantamab) and chemotherapy. Patients with locally advanced or metastatic EGFR ex19del or L858R substitution NSCLC who had disease progression on or after osimertinib were randomized to treatment with RYBREVANT® plus chemotherapy, RYBREVANT® plus chemotherapy with lazertinib or chemotherapy alone. Dual primary endpoints were used to compare the PFS (using RECIST v1.1 guidelines) as assessed by blinded independent central review (BICR) for each experimental arm to chemotherapy alone. Secondary endpoints included objective response as assessed by BICR, overall survival (OS), duration of response (DoR), time to subsequent therapy, PFS after first subsequent therapy (PFS2) and intracranial PFS. All study participants underwent serial brain imaging to allow for the robust assessment of intracranial endpoints, and to assess the central nervous system (CNS) activity of RYBREVANT® with and without lazertinib. As brain metastases can lead to significant burden and poor outcomes for patients, this aspect of the study design provides critical information in an area of high unmet need. The study enrolled 657 participants with locally advanced or metastatic EGFR exon 19 deletions (ex19del) or L858R substitution non-small cell lung cancer (NSCLC) after disease progression on or after osimertinib.

[0217] Summarized below are positive topline results from the Phase 3 MARIPOSA-2 study evaluating RYBREVANT® (amivantamab) given with and without lazertinib, combined with chemotherapy (carboplatin and pemetrexed). The study met its dual primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in PFS versus chemotherapy alone in both experimental treatment arms. No new safety signals were found for the addition of RYBREVANT® to chemotherapy.

[0218] A total of 657 participants (ACP: 131; LACP / ACP-L: 263; CP: 263) were randomized in the main study and included in this primary analysis. The key efficacy results are summarized in the Table 9. At the clinical cut-off (CCO), with a median study follow-up of 8.74 months, there were 371 PFS events by BICR observed. 70103693.007525 / JBI6936 Table 9: Key Efficacy ResultsEfficacy Results: 71103693.007525 / JBI6936

[0219] The median progression-free survival by blinded independent central review was 6.3 months (95% CI, 5.55 to 8.4) with amivantamab-chemotherapy, 8.3 months (95% CI, 6.8 to 9.1) with amivantamab-lazertinib-chemotherapy, and 4.2 months (95% CI, 4.0 to 4.4) with chemotherapy. The hazard ratio for disease progression or death was 0.48 (95% CI,0.36 to 0.64; P<0.001) for amivantamab-chemotherapy versus chemotherapy and similar in magnitude to amivantamab-lazertinib-chemotherapy versus chemotherapy (0.44; 95% CI, 0.35 to 0.56; P<0.001).

[0220] The median investigator-assessed progression-free survival was 8.2 months (95% CI, 6.8 to 10.9) for amivantamab-chemotherapy and 8.3 months (95% CI, 7.1 to 9.9) for amivantamab-lazertinib-chemotherapy versus 4.2 months (95% CI, 4.0 to 4.5) for chemotherapy, corresponding to similar hazard ratios for disease progression or death of 0.41 and 0.38, respectively (P<0.001 for both versus chemotherapy).

[0221] The progression-free survival benefit was consistent across predefined subgroups for amivantamab-chemotherapy and similar in magnitude to amivantamab- lazertinib-chemotherapy, including subgroups based on history of brain metastases, osimertinib line of therapy, and EGFR mutation type.

[0222] The objective response rate was 64% (95% CI, 55 to 72) for amivantamab- chemotherapy, 63% (95% CI, 57 to 69) for amivantamab-lazertinib-chemotherapy, and 36% (95% CI, 30 to 42) for chemotherapy, with similar significant improvements versus chemotherapy for amivantamab-chemotherapy (odds ratio, 3.10; 95% CI, 2.00 to 4.80; P<0.001) and amivantamab-lazertinib-chemotherapy (odds ratio, 2.97; 95% CI, 2.08 to 4.24; P<0.001). Among patients with a confirmed response, median duration of response was 6.9 months (95% CI, 5.5 to not estimable) for amivantamab-chemotherapy, 9.4 months (95% CI, 6.9 to not estimable) for amivantamab-lazertinib-chemotherapy, and 5.55 months (95% CI, 4.2 to 9.6) for chemotherapy.

[0223] With 161 deaths observed in the study, there was a trend favoring improved overall survival for amivantamab-chemotherapy versus chemotherapy (hazard ratio for death, 0.77; 95% CI, 0.49 to 1.21). A non-detrimental effect was seen for amivantamab-lazertinib- chemotherapy versus chemotherapy (hazard ratio for death, 0.96; 95% CI, 0.67 to 1.35).

[0224] Median intracranial progression-free survival was 12.45 months (95% CI, 10.8 to not estimable) for amivantamab-chemotherapy, 12.8 months (95% CI, 11.1 to 14.3) for amivantamab-lazertinib-chemotherapy, and 8.3 months (95% CI, 7.3 to 11.3) for chemotherapy. The improvement versus chemotherapy was significant for amivantamab- chemotherapy (hazard ratio for disease progression or death, 0.55; 95% CI, 0.38 to 0.79; 72103693.007525 / JBI6936 P=0.001) and similar in magnitude to amivantamab-lazertinib-chemotherapy versus chemotherapy (hazard ratio for disease progression or death, 0.58; 95% CI, 0.44 to 0.78; P<0.001).

[0225] As a result of the limited follow-up of participants receiving ACP-L in the main study and extension cohort to date, the comparison of ACP-L with CP is not in scope for this analysis and will be further evaluated when additional data is available. Discussion

[0226] Amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy significantly prolonged progression-free survival versus chemotherapy, with a 52% and 56% reduction in the risk of disease progression or death, respectively. Early separation of curves was observed between both amivantamab-chemotherapy and amivantamab-lazertinib- chemotherapy versus chemotherapy. The progression-free survival benefit was consistent across predefined subgroups. The magnitude of improvement over chemotherapy was similar for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy.

[0227] Amivantamab is a large molecule and was not expected to readily cross the blood-brain barrier. This was one of the key drivers for including lazertinib, a known CNS- active TKI, in the amivantamab-lazertinib-chemotherapy arm. It is thus notable that amivantamab-chemotherapy demonstrated similar intracranial progression-free survival advantages over chemotherapy as amivantamab-lazertinib-chemotherapy. These findings suggest that amivantamab exerts an antitumor effect intracranially, whether this occurs through direct engagement with intracranial metastases or indirectly through an immune- based mechanism is unclear. Despite the frequent utilization of TKI continuation out of concern for CNS progression, no prior prospective trial has shown improved clinical outcomes with this approach.

[0228] Resistance to osimertinib is diverse, polyclonal, and difficult to treat. There are currently no targeted therapies approved in the post-osimertinib setting. Two studies of immunotherapy-chemotherapy regimens have recently failed to show efficacy in the TKI- resistant setting. Currently, there are 6 other phase 3 studies (NCT05261399, NCT04765059, NCT05089734, NCT05338970, NCT04656652, NCT05184712) investigating targeted therapy combinations versus chemotherapy as second-line (or later) treatment in EGFR- mutated advanced NSCLC, highlighting the unmet need in this patient population. 73103693.007525 / JBI6936

[0229] In summary, progression-free survival was significantly longer with amivantamab- chemotherapy and amivantamab-lazertinib-chemotherapy compared with chemotherapy in patients with EGFR-mutated advanced NSCLC whose disease had progressed on or after osimertinib monotherapy. Example 3: Approved Drug Product Label 74103693.007525 / JBI6936 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 75103693.007525 / JBI6936

[0230] This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT

[0231] Rybrevant 350 mg concentrate for solution for infusion. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION

[0232] One mL of concentrate for solution for infusion contains 50 mg amivantamab.

[0233] One 7 mL vial contains 350 mg of amivantamab.

[0234] Amivantamab is a fully-human Immunoglobulin G1 (IgG1)-based bispecific antibody directed against the epidermal growth factor (EGF) and mesenchymal-epidermal transition (MET) receptors, produced by a mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology.

[0235] For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM

[0236] Concentrate for solution for infusion.

[0237] The solution is colourless to pale yellow, with a pH of 5.7 and an osmolality of approximately 310 mOsm / kg. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications

[0238] Rybrevant is indicated: • in combination with carboplatin and pemetrexed for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations after failure of prior therapy including an EGFR tyrosine kinase inhibitor (TKI). • in combination with carboplatin and pemetrexed for the first-line treatment of adult patients with advanced NSCLC with activating EGFR Exon 20 insertion mutations. 76103693.007525 / JBI6936 • as monotherapy for treatment of adult patients with advanced NSCLC with activating EGFR Exon 20 insertion mutations, after failure of platinum-based therapy. 4.2 Posology and method of administration

[0239] Treatment with Rybrevant should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

[0240] Rybrevant should be administered by a healthcare professional with access to appropriate medical support to manage infusion-related reactions (IRRs) if they occur.

[0241] Before initiation of Rybrevant therapy, EGFR mutation status in tumour tissue or plasma specimens must be established using a validated test method. If no mutation is detected in a plasma specimen, tumour tissue should be tested if available in sufficient amount and quality due to the potential for false negative results using a plasma-test. Testing may be performed at any time from initial diagnosis until the initiation of therapy; testing does not need to be repeated once EGFR mutation status has been established (see section 5.1). Posology

[0242] Premedications should be administered to reduce the risk of IRRs with Rybrevant (see below “Dose modifications” and “Recommended concomitant medicinal products”). Every 3 weeks

[0243] The recommended dosages of Rybrevant, when used in combination with carboplatin and pemetrexed, is provided in Table 10 (see below “Infusion rates” and Table 14). Table 10: Recommended dosage of Rybrevant every 3 weeks77103693.007525 / JBI6936a Dose adjustments not required for subsequent body weight changes.

[0244] When used in combination with carboplatin and pemetrexed, Rybrevant should be administered after carboplatin and pemetrexed in the following order: pemetrexed, carboplatin and then Rybrevant. See section 5.1 and the manufacturer’s prescribing information for dosing instructions for carboplatin and pemetrexed. Every 2 weeks

[0245] The recommended dosages of Rybrevant monotherapy is provided in Table 11 (see below “Infusion rates” and Table 15). Table 11: Recommended dosage of Rybrevant every 2 weeksa Dose adjustments not required for subsequent body weight changes. Duration of treatment

[0246] It is recommended that patients are treated with Rybrevant until disease progression or unacceptable toxicity. Missed dose

[0247] If a planned dose is missed, the dose should be administered as soon as possible and the dosing schedule should be adjusted accordingly, maintaining the treatment interval. Dose modifications

[0248] Dosing should be interrupted for Grade 3 or 4 adverse reactions until the adverse reaction resolves to ≤ Grade 1 or baseline. If an interruption is 7 days or less, restart at the current dose. If an interruption is longer than 7 days, it is recommended restarting at a 78103693.007525 / JBI6936 reduced dose as presented in Table 12. See also specific dose modifications for specific adverse reactions below Table 12. Table 12: Recommended dose modifications for adverse reactionsInfusion-related reactions

[0249] Infusion should be interrupted at the first sign of IRRs. Additional supportive medicinal products (e.g., additional glucocorticoids, antihistamine, antipyretics and antiemetics) should be administered as clinically indicated (see section 4.4). • Grade 1-3 (mild-severe): Upon recovery of symptoms, resume infusion at 50% of the previous rate. If there are no additional symptoms, the rate may be increased per the recommended infusion rate (see Tables 14 and 15). Concomitant medicinal products should be administered at the next dose (including dexamethasone (20 mg) or equivalent (see Table 13). • Recurrent Grade 3 or Grade 4 (life-threatening): Permanently discontinue Rybrevant. Skin and nail reactions

[0250] If the patient develops a Grade 1-2 skin or nail reaction, supportive care should be initiated; if there is no improvement after 2 weeks, dose reduction should be considered for persistent Grade 2 rash (see Table 12). If the patient develops a Grade 3 skin or nail reaction, supportive care should be initiated, and interruption of Rybrevant should be considered until the adverse reaction improves. Upon recovery of the skin or nail reaction to ≤ Grade 2, Rybrevant should be resumed at a reduced dose. If the patient develops Grade 4 skin reactions, permanently discontinue Rybrevant (see section 4.4). Interstitial lung disease

[0251] Rybrevant should be withheld if interstitial lung disease (ILD) or ILD-like adverse reactions (pneumonitis) is suspected. If the patient is confirmed to have ILD or ILD-like adverse reactions (e.g., pneumonitis), permanently discontinue Rybrevant (see section 4.4). Recommended concomitant medicinal products

[0252] Prior to infusion (Week 1, Days 1 and 2), antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of IRRs (see Table 13). For subsequent doses, antihistamines and antipyretics are required to be administered. 79103693.007525 / JBI6936 Glucocorticoids should also be re-initiated after prolonged dose interruptions. Antiemetics should be administered as needed. Table 13: Dosing schedule of premedications* Required at all doses. Required at initial dose (Week 1, Day 1) or at the next subsequent dose in the event of an IRR. + Required at second dose (Week 1, Day 2); optional for subsequent doses. Special populations Paediatric population

[0253] There is no relevant use of amivantamab in the paediatric population in the treatment of non-small cell lung cancer. Elderly

[0254] No dose adjustments are necessary (see section 4.8, section 5.1, and section 5.2). Renal impairment

[0255] No formal studies of amivantamab in patients with renal impairment have been conducted. Based on population pharmacokinetic (PK) analyses, no dose adjustment is necessary for patients with mild or moderate renal impairment. Caution is required in patients with severe renal impairment as amivantamab has not been studied in this patient population (see section 5.2). If treatment is started, patients should be monitored for adverse reactions with dose modifications per the recommendations above. Hepatic impairment

[0256] No formal studies of amivantamab in patients with hepatic impairment have been conducted. Based on population PK analyses, no dose adjustment is necessary for patients with mild hepatic impairment. Caution is required in patients with moderate or severe hepatic impairment as amivantamab has not been studied in this patient population 80103693.007525 / JBI6936 (see section 5.2). If treatment is started, patients should be monitored for adverse reactions with dose modifications per the recommendations above. Method of administration

[0257] Rybrevant is for intravenous use. It is administered as an intravenous infusion following dilution with sterile 5% glucose solution or sodium chloride 9 mg / mL (0.9%) solution for injection. Rybrevant must be administered with in-line filtration.

[0258] For instructions on dilution of the medicinal product before administration, see section 6.6. Infusion rates

[0259] Following dilution, the infusion should be administered intravenously at the infusion rates presented in Table 14 or 6 below. Due to the frequency of IRRs at the first dose, amivantamab should be infused via a peripheral vein at Week 1 and Week 2; infusion via a central line may be administered for subsequent weeks when the risk of IRR is lower (see section 6.6). It is recommended for the first dose to be prepared as close to administration as possible to maximise the likelihood of completing the infusion in the event of an IRR. Table 14: Infusion rates for Rybrevant every 3 weeks* Starting at Week 7, patients are dosed every 3 weeks. † Increase the initial infusion rate to the subsequent infusion rate after 2 hours in the absence of infusion-related reactions. 81103693.007525 / JBI6936 Table 15: Infusion rates for Rybrevant every 2 weeks* After Week 5, patients are dosed every 2 weeks. Increase the initial infusion rate to the subsequent infusion rate after 2 hours in the absence of IRRs. 4.3 Contraindications

[0260] Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use Traceability

[0261] In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Infusion-related reactions

[0262] Infusion-related reactions commonly occurred in patients treated with amivantamab (see section 4.8).

[0263] Prior to initial infusion (Week 1), antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of IRRs. For subsequent doses, antihistamines and antipyretics should be administered. The initial infusion should be administered in split doses on Week 1, Day 1 and 2.

[0264] Patients should be treated in a setting with appropriate medical support to treat IRRs. Infusions should be interrupted at the first sign of IRRs of any severity and post-infusion medicinal products should be administered as clinically indicated. Upon resolution of symptoms, the infusion should be resumed at 50% of the previous rate. For 82103693.007525 / JBI6936 recurrent Grade 3 or Grade 4 IRRs, Rybrevant should be permanently discontinued (see section 4.2). Interstitial lung disease

[0265] Interstitial lung disease (ILD) or ILD-like adverse reactions (e.g., pneumonitis) have been reported in patients treated with amivantamab (see section 4.8). Patients should be monitored for symptoms indicative of ILD / pneumonitis (e.g., dyspnoea, cough, fever). If symptoms develop, treatment with Rybrevant should be interrupted pending investigation of these symptoms. Suspected ILD or ILD-like adverse reactions should be evaluated and appropriate treatment should be initiated as necessary. Rybrevant should be permanently discontinued in patients with confirmed ILD or ILD-like adverse reactions (see section 4.2). Skin and nail reactions

[0266] Rash (including dermatitis acneiform), pruritus and dry skin occurred in patients treated with amivantamab (see section 4.8). Patients should be instructed to limit sun exposure during and for 2 months after Rybrevant therapy. Protective clothing and use of broad-spectrum UVA / UVB sunscreen are advisable. Alcohol-free emollient cream is recommended for dry areas. A prophylactic approach to rash prevention should be considered. If skin reactions develop, topical corticosteroids and topical and / or oral antibiotics should be administered. For Grade 3 or poorly-tolerated Grade 2 events, systemic antibiotics and oral steroids should also be administered. Patients presenting with severe rash that has an atypical appearance or distribution or lack improvement within 2 weeks should be referred promptly to a dermatologist. Rybrevant should be dose reduced, interrupted, or permanently discontinued based on severity (see section 4.2).

[0267] Toxic epidermal necrolysis (TEN) has been reported. Treatment with this medicinal product should be discontinued if TEN is confirmed. Eye disorders

[0268] Eye disorders, including keratitis, occurred in patients treated with amivantamab (see section 4.8). Patients presenting with worsening eye symptoms should promptly be referred to an ophthalmologist and should discontinue use of contact lenses until symptoms are evaluated. For dose modifications for Grade 3 or 4 eye disorders, see section 4.2. Sodium content

[0269] This medicinal product contains less than 1 mmol (23 mg) sodium per dose, that is to say essentially “sodium-free”. This medicinal product may be diluted in sodium 83103693.007525 / JBI6936 chloride 9 mg / mL (0.9%) solution for infusion. This should be taken into consideration for patients on a controlled sodium diet (see section 6.6). 4.5 Interaction with other medicinal products and other forms of interaction

[0270] No drug interaction studies have been performed. As an IgG1 monoclonal antibody, renal excretion and hepatic enzyme-mediated metabolism of intact amivantamab are unlikely to be major elimination routes. As such, variations in drug-metabolising enzymes are not expected to affect the elimination of amivantamab. Due to the high affinity to a unique epitope on EGFR and MET, amivantamab is not anticipated to alter drug-metabolising enzymes. Vaccines

[0271] No clinical data are available on the efficacy and safety of vaccinations in patients taking amivantamab. Avoid the use of live or live-attenuated vaccines while patients are taking amivantamab. 4.6 Fertility, pregnancy and lactation Women of child-bearing potential / Contraception

[0272] Women of child-bearing potential should use effective contraception during and for 3 months after cessation of amivantamab treatment. Pregnancy

[0273] There are no human data to assess the risk of amivantamab use during pregnancy. No animal reproductive studies were conducted to inform a drug-associated risk. Administration of EGFR and MET inhibitor molecules in pregnant animals resulted in an increased incidence of impairment of embryo-foetal development, embryo lethality, and abortion. Therefore, based on its mechanism of action and findings in animal models, amivantamab could cause foetal harm when administered to a pregnant woman. Amivantamab should not be given during pregnancy unless the benefit of treatment of the woman is considered to outweigh potential risks to the foetus. If the patient becomes pregnant while taking this medicinal product the patient should be informed of the potential risk to the foetus (see section 5.3). Breast-feeding

[0274] It is unknown whether amivantamab is excreted in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which is decreasing to low concentrations soon afterwards. A risk to the breast-fed child cannot be excluded during this short period just after birth, although IgGs are likely to be degraded in 84103693.007525 / JBI6936 the gastrointestinal tract of the breast-fed child and not absorbed. A decision must be made whether to discontinue breast-feeding or to discontinue / abstain from amivantamab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility

[0275] There are no data on the effect of amivantamab on human fertility. Effects on male and female fertility have not been evaluated in animal studies. 4.7 Effects on ability to drive and use machines

[0276] Rybrevant may have moderate influence on the ability to drive and use machines. Please see section 4.8 (e.g., dizziness, fatigue, visual impairment). If patients experience treatment-related symptoms, including vision-related adverse reactions, affecting their ability to concentrate and react, it is recommended that they do not drive or use machines until the effect subsides. 4.8 Undesirable effects Summary of the safety profile

[0277] In the dataset of amivantamab as monotherapy (N=380), the most frequent adverse reactions in all grades were rash (76%), infusion-related reactions (67%), nail toxicity (47%), hypoalbuminaemia (31%), oedema (26%), fatigue (26%), stomatitis (24%), nausea (23%), and constipation (23%). Serious adverse reactions included ILD (1.3%), IRR (1.1%), and rash (1.1%). Three percent of patients discontinued Rybrevant due to adverse reactions. The most frequent adverse reactions leading to treatment discontinuation were IRR (1.1%), ILD (0.5%), and nail toxicity (0.5%). Tabulated list of adverse reactions

[0278] Table 16 summarises the adverse drug reactions that occurred in patients receiving amivantamab as monotherapy.

[0279] The data reflects exposure to amivantamab in 380 patients with locally advanced or metastatic non-small cell lung cancer after failure of platinum-based chemotherapy. Patients received amivantamab 1050 mg (for patients < 80 kg) or 1400 mg (for patients ≥ 80 kg). The median exposure to amivantamab was 4.1 months (range: 0.0 to 39.7 months).

[0280] Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories are defined as follows: very common (≥ 1 / 10); 85103693.007525 / JBI6936 common (≥ 1 / 100 to < 1 / 10); uncommon (≥ 1 / 1000 to < 1 / 100); rare (≥ 1 / 10000 to < 1 / 1000); very rare (< 1 / 10000); and not known (frequency cannot be estimated from the available data).

[0281] Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Table 16: Adverse reactions in patients receiving amivantamab as monotherapy86103693.007525 / JBI6936 * Grouped terms † Grade 3 events only Summary of the safety profile

[0282] In the dataset of amivantamab in combination with carboplatin and pemetrexed (N=301), the most frequent adverse reactions in all grades were rash (83%), neutropenia (57%), nail toxicity (53%), infusion related reactions (51%), fatigue (43%), stomatitis (39%), nausea (43%), thrombocytopenia (40%), constipation (40%), oedema (40%), decreased appetite (33%), hypoalbuminaemia (32%), alanine aminotransferase increased (26%), aspartate aminotransferase increased (23%), vomiting (22%), and hypokalaemia (20%). Serious adverse reactions included rash (2.7%), venous thromboembolism (2.3%), thrombocytopenia (2.3%) and ILD (2.0%). Eight percent of patients discontinued Rybrevant due to adverse reactions. The most frequent adverse reactions leading to treatment discontinuation were IRR (2.7%), rash (2.3%), ILD (2.3%), and nail toxicity (1.0%).

[0283] Table 17 summarises the adverse drug reactions that occurred in patients receiving amivantamab in combination with chemotherapy.

[0284] The data reflects exposure to amivantamab in combination with carboplatin and pemetrexed in 301 patients with locally advanced or metastatic non-small cell lung cancer. Patients received amivantamab 1400 mg (for patients < 80 kg) or 1750 mg (for patients ≥ 80 kg) weekly for 4 weeks. Starting at Week 7, patients received amivantamab 1750 mg (for patients < 80 kg) or 2100 mg (for patients ≥ 80 kg) every 3 weeks. The median exposure to amivantamab in combination with carboplatin and pemetrexed was 7.7 months (range: 0.0 to 28.1 months).

[0285] Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories are defined as follows: very common (≥ 1 / 10); common (≥ 1 / 100 to < 1 / 10); uncommon (≥ 1 / 1000 to < 1 / 100); rare (≥ 1 / 10000 to < 1 / 1000); very rare (< 1 / 10000); and not known (frequency cannot be estimated from the available data).

[0286] Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. 87103693.007525 / JBI6936 Table 17: Adverse reactions in patients receiving amivantamab in combination with carboplatin and pemetrexed* Grouped terms 88103693.007525 / JBI6936 Description of selected adverse reactions Infusion-related reactions

[0287] In patients treated with amivantamab monotherapy, infusion-related reactions occurred in 67% of patients. Ninety-eight percent of IRRs were Grade 1-2. Ninety-nine percent of IRRs occurred at the first infusion with a median time to onset of 60 minutes, and the majority occurring within 2 hours of infusion start. The most frequent signs and symptoms include chills, dyspnoea, nausea, flushing, chest discomfort, and vomiting (see section 4.4).

[0288] In patients treated with amivantamab in combination with carboplatin and pemetrexed, infusion-related reactions occurred in 50% of patients. Greater than 94% of IRRs were Grade 1-2. A majority of IRRs occurred at the first infusion with a median time to onset of 60 minutes (range 0-7 hours), and the majority occurring within 2 hours of infusion start. Occasionally an IRR can occur at re-initiation of amivantamab after prolonged dose interruptions of more than 6 weeks. Interstitial lung disease

[0289] Interstitial lung disease or ILD-like adverse reactions have been reported with the use of amivantamab as well as with other EGFR inhibitors. Interstitial lung disease or pneumonitis was reported in 2.6% of patients treated with amivantamab monotherapy and 2.3 % of patients treated with amivantamab in combination with carboplatin and pemetrexed. Patients with a medical history of ILD, drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD were excluded from the clinical study (see section 4.4). Skin and nail reactions

[0290] Rash (including dermatitis acneiform), pruritus, and dry skin occurred in 86% of patients treated with amivantamab alone. Most cases were Grade 1 or 2, with Grade 3 rash events occurring in 3% of patients. Rash leading to amivantamab discontinuation occurred in 0.3% of patients. Rash usually developed within the first 4 weeks of therapy, with a median time to onset of 14 days. Nail toxicity occurred in patients treated with amivantamab. Most events were Grade 1 or 2, with Grade 3 nail toxicity occurring in 1.8% of patients.

[0291] Rash (including dermatitis acneiform), occurred in 83% of patients treated with amivantamab in combination with carboplatin and pemetrexed. Most cases were Grade 1 or 2, with Grade 3 rash events occurring in 14% of patients. Rash leading to 89103693.007525 / JBI6936 amivantamab discontinuation occurred in 2.3% of patients. Rash usually developed within the first 4 weeks of therapy, with a median time to onset of 14 days. Nail toxicity occurred in patients treated with amivantamab in combination with carboplatin and pemetrexed. Most events were Grade 1 or 2, with Grade 3 nail toxicity occurring in 4.3% of patients (see section 4.4). Eye disorders

[0292] Eye disorders, including keratitis (0.5%), occurred in 9% of patients treated with amivantamab alone. Other reported adverse reactions included growth of eyelashes, visual impairment, and other eye disorders. All events were Grade 1-2.

[0293] Eye disorders, including keratitis (0.3%), occurred in 11% of patients treated with amivantamab in combination with carboplatin and pemetrexed. Other reported adverse reactions included growth of eyelashes, visual impairment, uveitis, and other eye disorders. All events were Grade 1-2 (see section 4.4). Other special populations Elderly

[0294] There are limited clinical data with amivantamab in patients 75 years of age or over (see section 5.1). No overall differences in safety were observed between patients ≥ 65 years of age and patients < 65 years of age. Immunogenicity

[0295] As with all therapeutic proteins, there is the potential for immunogenicity. In clinical studies of patients with locally advanced or metastatic NSCLC treated with amivantamab, 4 of the 865 (0.5%) participants who were treated with Rybrevant and evaluable for the presence of anti-drug antibodies (ADA), tested positive for treatment-emergent anti-amivantamab antibodies. There was no evidence of an altered pharmacokinetic, efficacy, or safety profile due to anti-amivantamab antibodies. Reporting of suspected adverse reactions

[0296] Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions. 90103693.007525 / JBI6936 4.9 Overdose

[0297] No maximum tolerated dose has been determined in a clinical study in which patients received up to 2100 mg administered intravenously. There is no known specific antidote for amivantamab overdose. In the event of an overdose, treatment with Rybrevant should be stopped, the patient should be monitored for any signs or symptoms of adverse events and appropriate general supportive measures should be instituted immediately until clinical toxicity has diminished or resolved. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Monoclonal antibodies and antibody drug conjugates, ATC code: L01FX18. Mechanism of action

[0298] Amivantamab is a low-fucose, fully-human IgG1-based EGFR-MET bispecific antibody with immune cell-directing activity that targets tumours with activating EGFR mutations such as Exon 19 deletions, L858R substitution, and Exon 20 insertion mutations. Amivantamab binds to the extracellular domains of EGFR and MET.

[0299] Amivantamab disrupts EGFR and MET signalling functions through blocking ligand binding and enhancing degradation of EGFR and MET, thereby preventing tumour growth and progression. The presence of EGFR and MET on the surface of tumour cells also allows for targeting of these cells for destruction by immune effector cells, such as natural killer cells and macrophages, through antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms, respectively. Pharmacodynamic effects Albumin

[0300] Amivantamab decreased serum albumin concentration, a pharmacodynamic effect of MET inhibition, typically during the first 8 weeks (see section 4.8); thereafter, albumin concentration stabilised for the remainder of amivantamab treatment. Clinical efficacy and safety Previously treated NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations (MARIPOSA-2)

[0301] MARIPOSA-2 is a randomised (2:2:1) open-label, multicentre Phase 3 study in patients with locally advanced or metastatic NSCLC with EGFR Exon 19 deletions or 91103693.007525 / JBI6936 Exon 21 L858R substitution mutations (mutation testing could have been performed at or after the time of locally advanced or metastatic disease diagnosis. Testing did not need to be repeated at the time of study entry once EGFR mutation status was previously established) after failure of prior therapy including a third-generation EGFR tyrosine kinase inhibitor (TKI). A total of 657 patients were randomised in the study, of which 263 received carboplatin and pemetrexed (CP); and 131 which received Rybrevant in combination with carboplatin and pemetrexed (Rybrevant-CP). Additionally, 236 patients were randomised to receive Rybrevant in combination with lazertinib, carboplatin, and pemetrexed in a separate arm of the study. Rybrevant was administered intravenously at 1400 mg (for patients < 80 kg) or 1750 mg (for patients ≥ 80 kg) once weekly through 4 weeks, then every 3 weeks with a dose of 1750 mg (for patients < 80 kg) or 2100 mg (for patients ≥ 80 kg) starting at Week 7 until disease progression or unacceptable toxicity. Carboplatin was administered intravenously at area under the concentration-time curve 5 mg / mL per minute (AUC 5) once every 3 weeks, for up to 12 weeks. Pemetrexed was administered intravenously at 500 mg / m2on once every 3 weeks until disease progression or unacceptable toxicity.

[0302] Patients were stratified by osimertinib line of therapy (first-line or second-line), prior brain metastases (yes or no), and Asian race (yes or no).

[0303] Of the 394 patients randomised to the Rybrevant-CP arm or CP arm, the median age was 62 (range: 31-85) years, with 38% of the patients ≥ 65 years of age; 60% were female; and 48% were Asian and 46% were White. Baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 (40%) or 1 (60%); 66% never smoked; 45% had history of brain metastasis, and 92% had Stage IV cancer at initial diagnosis.

[0304] Rybrevant in combination with carboplatin and pemetrexed demonstrated a statistically significant improvement in progression-free survival (PFS) compared to carboplatin and pemetrexed, with a HR of 0.48 (95% CI: 0.36, 0.64; p<0.0001). At the time of the second interim analysis for OS, with a median follow-up of approximately 18.6 months for Rybrevant-CP and approximately 17.8 months for CP, the OS HR was 0.73 (95%CI: 0.54, 0.99; p=0.0386). This was not statistically significant (tested at a prespecified significance level of 0.0142).

[0305] Efficacy results are summarised in Table 18. 92103693.007525 / JBI6936 Table 18: Efficacy results in MARIPOSA-2CI = Confidence Interval PFS and ORR results are from data cut-off 10 July-2023 when hypothesis testing and final analysis for these endpoints was performed. OS results are from data cut-off 26 April 2024 from the second interim OS analysis. a BICR-assessed b The p-value is compared to a 2-sided significance level of 0.0142. Thus the OS results are not significant as of the second interim analysis.

[0306] Figure 2 shows a Kaplan-Meier curve of PFS in previously treated NSCLC patients by BICR assessment.

[0307] The PFS benefit of Rybrevant-CP compared to CP was consistent across all the predefined subgroups analysed, including ethnicity, age, gender, smoking history, and CNS metastases status at study entry.

[0308] Figure 3 shows a Kaplan-Meier curve of OS in previously treated NSCLC patients. Intracranial metastases efficacy data

[0309] Patients with asymptomatic or previously treated and stable intracranial metastases were eligible to be randomised in MARIPOSA-2. Treatment with Rybrevant-CP was associated with a numeric increase in intracranial ORR (23.3% for Rybrevant-CP versus 16.7% for CP, odds ratio of 1.52; 95% CI (0.51, 4.50), and intracranial DOR (13.3 months; 95% CI (1.4, NE) in the Rybrevant-CP arm compared with 2.2 months; 95% CI (1.4, NE) in the CP arm). The median follow-up for Rybrevant-CP was approximately 18.6 months. 93103693.007525 / JBI6936 Previously-untreated non-small cell lung cancer (NSCLC) with Exon 20 insertion mutations (PAPILLON)

[0310] PAPILLON is a randomised, open-label, multicentre Phase 3 study comparing treatment with Rybrevant in combination with carboplatin and pemetrexed to chemotherapy alone (carboplatin and pemetrexed) in patients with treatment-naïve, locally advanced or metastatic NSCLC with activating EGFR Exon 20 insertion mutations. Tumour tissue (92.2%) and / or plasma (7.8%) samples for all 308 patients were tested locally to determine EGFR Exon 20 insertion mutation status using next generation sequencing (NGS) in 55.5% of patients and / or polymerase chain reaction (PCR) in 44.5% of patients. Central testing was also performed using the AmoyDx® LC10 tissue test, Thermo Fisher Oncomine Dx Target Test, and the Guardant 360® CDx plasma test.

[0311] Patients with brain metastases at screening were eligible for participation once they were definitively treated, clinically stable, asymptomatic, and off corticosteroid treatment for at least 2 weeks prior to randomisation.

[0312] Rybrevant was administered intravenously at 1400 mg (for patients < 80 kg) or 1750 mg (for patients ≥ 80 kg) once weekly through 4 weeks, then every 3 weeks with a dose of 1750 mg (for patients < 80 kg) or 2100 mg (for patients ≥ 80 kg) starting at Week 7 until disease progression or unacceptable toxicity. Carboplatin was administered intravenously at area under the concentration-time curve 5 mg / mL per minute (AUC 5) once every 3 weeks, for up to 12 weeks. Pemetrexed was administered intravenously at 500 mg / m2on once every 3 weeks until disease progression or unacceptable toxicity. Randomisation was stratified by ECOG performance status (0 or 1), and prior brain metastases (yes or no). Patients randomised to the carboplatin and pemetrexed arm who had confirmed disease progression were permitted to cross over to receive Rybrevant monotherapy.

[0313] A total of 308 subjects were randomised (1:1) to Rybrevant in combination with carboplatin and pemetrexed (N=153) or carboplatin and pemetrexed (N=155). The median age was 62 (range: 27 to 92) years, with 39% of the subjects ≥ 65 years of age; 58% were female; and 61% were Asian and 36% were White. Baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 (35%) or 1 (64%); 58% never smoked; 23% had history of brain metastasis and 84% had Stage IV cancer at initial diagnosis.

[0314] The primary endpoint for PAPILLON was PFS, as assessed by BICR. The median follow-up was14.9 months (range: 0.3 to 27.0).

[0315] Efficacy results are summarised in Table 19. 94103693.007525 / JBI6936 Table 19: Efficacy results in PAPILLONCI = confidence interval NE = not estimable a Blinded Independent Central Review by RECIST v1.1 b Based on Kaplan-Meier estimate. c Based on the results of an updated OS with median follow-up of 20.9 months. The OS analysis was not adjusted for the potentially confounding effects of crossover (78 [50.3%] patients on the carboplatin + pemetrexed arm who received subsequent Rybrevant monotherapy treatment).

[0316] Figure 4 shows Kaplan-Meier curve of PFS in previously untreated NSCLC patients by BICR assessment.

[0317] The PFS benefit of Rybrevant in combination with carboplatin and pemetrexed compared to carboplatin and pemetrexed was consistent across all the predefined subgroups of brain metastases at study entry (yes or no), age (< 65 or ≥ 65), sex (male or female), race (Asian or non-Asian), weight (< 80 kg or ≥ 80 kg), ECOG performance status (0 or 1), and smoking history (yes or no).

[0318] Figure 5 shows a Kaplan-Meier curve of OS in previously untreated NSCLC patients by BICR assessment. Previously-treated non-small cell lung cancer(NSCLC) with Exon 20 insertion mutations (CHRYSALIS)

[0319] CHRYSALIS is a multicentre, open-label, multi-cohort study conducted to assess the safety and efficacy of Rybrevant in patients with locally advanced or metastatic NSCLC. Efficacy was evaluated in 114 patients with locally advanced or metastatic NSCLC who had EGFR Exon 20 insertion mutations, whose disease had progressed on or after platinum-based chemotherapy, and who had a median follow-up of 12.5 months. Tumour tissue (93%) and / or plasma (10%) samples for all patients were tested locally to determine EGFR Exon 20 insertion mutation status using next generation sequencing (NGS) in 46% of 95103693.007525 / JBI6936 patients and / or polymerase chain reaction (PCR) in 41% of patients; for 4% of patients, the testing methods were not specified. Patients with untreated brain metastases or a history of ILD requiring treatment with prolonged steroids or other immunosuppressive agents within the last 2 years were not eligible for the study. Rybrevant was administered intravenously at 1050 mg for patients < 80 kg or 1400 mg for patients ≥ 80 kg once weekly for 4 weeks, then every 2 weeks starting at Week 5 until loss of clinical benefit or unacceptable toxicity. The primary efficacy endpoint was investigator-assessed overall response rate (ORR), defined as confirmed complete response (CR) or partial response (PR) based on RECIST v1.1. In addition, the primary endpoint was assessed by a blinded independent central review (BICR). Secondary efficacy endpoints included duration of response (DOR). The median age was 62 (range: 36–84) years, with 41% of the patients ≥ 65 years of age; 61% were female; and 52% were Asian and 37% were White. The median number of prior therapies was 2 (range: 1 to 7 therapies). At baseline, 29% had Eastern Cooperative Oncology Group (ECOG) performance status of 0 and 70% had ECOG performance status of 1; 57% never smoked; 100% had Stage IV cancer; and 25% had previous treatment for brain metastases. Insertions in Exon 20 were observed at 8 different residues; the most common residues were A767 (22%), S768 (16%), D770 (12%), and N771 (11%).

[0320] Efficacy results are summarised in Table 20. Table 20: Efficacy results in CHRYSALISCI = Confidence Interval a Confirmed response b ORR and DOR results by investigator assessment were consistent with those reported by BICR assessment; ORR by BICR assessment was 43% (34%, 53%), with a 3% CR rate and a 40% PR rate, median DOR by BICR assessment was 10.8 months (95% CI: 6.9, 15.0), and patients with DOR ≥ 6 months by BICR assessment was 55%. c Based on Kaplan-Meier estimate.

[0321] Anti-tumour activity was observed across studied mutation subtypes. Elderly

[0322] No overall differences in effectiveness were observed between patients ≥ 65 years of age and patients < 65 years of age. 96103693.007525 / JBI6936 Paediatric population

[0323] The European Medicines Agency has waived the obligation to submit the results of studies with Rybrevant in all subsets of the paediatric population in non-small cell lung cancer (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties

[0324] Based on Rybrevant monotherapy data, amivantamab area under the concentration-time curve (AUC1 week) increases proportionally over a dose range from 350 to 1750 mg.

[0325] Based on simulations from the population pharmacokinetic model, AUC1week was approximately 2.8-fold higher after the fifth dose for the 2-week dosing regimen and 2.6-fold higher after the fourth dose for the 3-week dosing regimen. Steady-state concentrations of amivantamab were reached by Week 13 for both the 3-week and 2-week dosing regimen and the systemic accumulation was 1.9-fold. Distribution

[0326] Based on the individual amivantamab PK parameter estimates in population PK analysis, the geometric mean (CV%) total volume of distribution, is 5.12 (27.8%) L, following administration of the recommended dose of Rybrevant. Elimination

[0327] Based on the individual amivantamab PK parameter estimates in population PK analysis, the geometric mean (CV%) linear clearance (CL) and terminal half-life associated with linear clearance is 0.266 (30.4%) L / day and 13.7 (31.9%) days respectively. Special populations Elderly

[0328] No clinically meaningful differences in the pharmacokinetics of amivantamab were observed based on age (27-87 years). Renal impairment

[0329] No clinically meaningful effect on the pharmacokinetics of amivantamab was observed in patients with mild (60 ≤ creatinine clearance [CrCl] < 90 mL / min) and moderate (29 ≤ CrCl < 60 mL / min) renal impairment. The effect of severe renal impairment (15 ≤ CrCl < 29 mL / min) on amivantamab pharmacokinetics is unknown. 97103693.007525 / JBI6936 Hepatic impairment

[0330] Changes in hepatic function are unlikely to have any effect on the elimination of amivantamab since IgG1-based molecules such as amivantamab are not metabolised through hepatic pathways.

[0331] No clinically meaningful effect in the pharmacokinetics of amivantamab was observed based on mild hepatic impairment [(total bilirubin ≤ ULN and AST > ULN) or (ULN < total bilirubin ≤ 1.5 x ULN)]. The effect of moderate (total bilirubin 1.5 to 3 times ULN) and severe (total bilirubin > 3 times ULN) hepatic impairment on amivantamab pharmacokinetics is unknown. Paediatric population

[0332] The pharmacokinetics of Rybrevant in paediatric patients have not been investigated. 5.3 Preclinical safety data

[0333] Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity. Carcinogenicity and mutagenicity

[0334] No animal studies have been performed to establish the carcinogenic potential of amivantamab. Routine genotoxicity and carcinogenicity studies are generally not applicable to biologic pharmaceuticals as large proteins cannot diffuse into cells and cannot interact with DNA or chromosomal material. Reproductive toxicology

[0335] No animal studies have been conducted to evaluate the effects on reproduction and foetal development; however, based on its mechanism of action, amivantamab can cause foetal harm or developmental anomalies. As reported in the literature, reduction, elimination, or disruption of embryo foetal or maternal EGFR signaling can prevent implantation, cause embryo foetal loss during various stages of gestation (through effects on placental development), cause developmental anomalies in multiple organs or early death in surviving foetuses. Similarly, knock out of MET or its ligand hepatocyte growth factor (HGF) was embryonic lethal due to severe defects in placental development, and foetuses displayed defects in muscle development in multiple organs. Human IgG1 is known to cross the placenta; therefore, amivantamab has the potential to be transmitted from the mother to the developing foetus. 98103693.007525 / JBI6936 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Ethylenediaminetetraacetic acid (EDTA) disodium salt dihydrate L-Histidine L-Histidine hydrochloride monohydrate L-Methionine Polysorbate 80 (E433) Sucrose Water for injections 6.2 Incompatibilities

[0336] This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. 6.3 Shelf life Unopened vial

[0337] 3 years After dilution

[0338] Chemical and physical in-use stability has been demonstrated for 10 hours at 15°C to 25°C in room light. From a microbiological point of view, unless the method of dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user. 6.4 Special precautions for storage

[0339] Store in a refrigerator (2°C to 8°C).

[0340] Do not freeze.

[0341] Store in the original package in order to protect from light.

[0342] For storage conditions after dilution of the medicinal product, see section 6.3. 99103693.007525 / JBI6936 6.5 Nature and contents of container

[0343] 7 mL concentrate in a Type 1 glass vial with an elastomeric closure and aluminium seal with a flip-off cap containing 350 mg amivantamab. Pack size of 1 vial. 6.6 Special precautions for disposal and other handling

[0344] Prepare the solution for intravenous infusion using aseptic technique as follows: Preparation • Determine the dose required and the number of Rybrevant vials needed based on patient’s baseline weight (see section 4.2). Each vial contains 350 mg of amivantamab. • For every 2-week dosing, patients < 80 kg receive 1050 mg and for patients ≥ 80 kg, 1400 mg once weekly for a total of 4 doses, then every 2 weeks starting at Week 5. • For every 3-week dosing, patients < 80 kg receive 1400 mg once weekly for a total of 4 doses, then 1750 mg every 3 weeks starting at Week 7, and for patients ≥ 80 kg, 1750 mg once weekly for a total of 4 doses, then 2100 mg every 3 weeks starting at Week 7. • Check that the Rybrevant solution is colourless to pale yellow. Do not use if discolouration or visible particles are present. • Withdraw and then discard a volume of either 5% glucose solution or sodium chloride 9 mg / mL (0.9%) solution for injection from the 250 mL infusion bag that is equal to the required volume of Rybrevant solution to be added (discard 7 mL diluent from the infusion bag for each vial). Infusion bags must be made of polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE), or polyolefin blend (PP+PE). • Withdraw 7 mL of Rybrevant from each vial needed then add it to the infusion bag. Each vial contains a 0.5 mL overfill to ensure sufficient extractable volume. The final volume in the infusion bag should be 250 mL. Discard any unused portion left in the vial. • Gently invert the bag to mix the solution. Do not shake. • Visually inspect for particulate matter and discolouration prior to administration. Do not use if discolouration or visible particles are observed. Administration • Administer the diluted solution by intravenous infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.22 or 0.2 micrometer). Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP, or PE. • The administration set with filter must be primed with either 5% glucose solution or 0.9% sodium chloride solution prior to the initiation of each Rybrevant infusion. 100103693.007525 / JBI6936 • Do not infuse Rybrevant concomitantly in the same intravenous line with other agents. • The diluted solution should be administered within 10 hours (including infusion time) at room temperature (15°C to 25°C) and in room light. • Due to the frequency of IRRs at the first dose, amivantamab should be infused via a peripheral vein at Week 1 and Week 2; infusion via a central line may be administered for subsequent weeks when the risk of IRR is lower. See infusion rates in section 4.2. Disposal

[0345] This medicinal product is for single use only and any unused medicinal product that is not administered within 10 hours should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium 8. MARKETING AUTHORISATION NUMBER(S) EU / 1 / 21 / 1594 / 001 9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

[0346] Date of first authorisation: 09 December 2021

[0347] Date of latest renewal: 11 September 2023 10. DATE OF REVISION OF THE TEXT

[0348] Detailed information on this medicinal product is available on the website of the European Medicines Agency https: / / www.ema.europa.eu. 101103693.007525 / JBI6936 ANNEX II A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 102103693.007525 / JBI6936 A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer of the biological active substance Janssen Sciences Ireland UC Barnahely Ringaskiddy, Co. Cork Ireland Name and address of the manufacturer responsible for batch release Janssen Biologics B.V. Einsteinweg 101 2333 CB Leiden The Netherlands B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

[0349] Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports (PSURs)

[0350] The requirements for submission of PSURs for this medicinal product are set out in Article 9 of Regulation (EC) No 507 / 2006 and, accordingly, the marketing authorisation holder (MAH) shall submit PSURs every 6 months.

[0351] The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001 / 83 / EC and any subsequent updates published on the European medicines web-portal.

[0352] The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 6 months following authorisation. 103103693.007525 / JBI6936 D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk management plan (RMP)

[0353] The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP.

[0354] An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit / risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 104103693.007525 / JBI6936 ANNEX III LABELLING AND PACKAGE LEAFLET 105A. LABELLING103693.007525 / JBI6936Rybrevant 350 mg concentrate for solution for infusion amivantamabOne vial of 7 mL contains 350 mg of amivantamab (50 mg / mL). 3. LIST OF EXCIPIENTSExcipients: ethylenediaminetetraacetic acid (EDTA), L-histidine, L-histidine hydrochloride monohydrate, L-methionine, polysorbate 80, sucrose, and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTSConcentrate for solution for infusion 1 vial 5. METHOD AND ROUTE(S) OF ADMINISTRATIONFor intravenous use after dilution. Read the package leaflet before use.Keep out of the sight and reach of children.EXP 107103693.007525 / JBI6936 9. SPECIAL STORAGE CONDITIONSStore in a refrigerator. Do not freeze. Store in the original package in order to protect from light.11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDERJanssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium 12. MARKETING AUTHORISATION NUMBER(S)EU / 1 / 21 / 1594 / 001 13. BATCH NUMBERLot 14. GENERAL CLASSIFICATION FOR SUPPLY15. INSTRUCTIONS ON USE16. INFORMATION IN BRAILLEJustification for not including Braille accepted. 17. UNIQUE IDENTIFIER – 2D BARCODE2D barcode carrying the unique identifier included. 108103693.007525 / JBI6936 18. UNIQUE IDENTIFIER - HUMAN READABLE DATAPC SN NN 109103693.007525 / JBI6936110B. PACKAGE LEAFLET103693.007525 / JBI6936 Package leaflet: Information for the patient Rybrevant 350 mg concentrate for solution for infusion amivantamab

[0355] This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you are given this medicine because it contains important information for you. • Keep this leaflet. You may need to read it again. • If you have any further questions, ask your doctor or nurse. • If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Rybrevant is and what it is used for 2. What you need to know before you are given Rybrevant 3. How Rybrevant is given 4. Possible side effects 5. How to store Rybrevant 6. Contents of the pack and other information 1. What Rybrevant is and what it is used for What Rybrevant is

[0356] Rybrevant is a cancer medicine. It contains the active substance ‘amivantamab’, which is an antibody (type of protein) designed to recognise and attach to specific targets in the body. What Rybrevant is used for

[0357] Rybrevant is used in adults with a type of lung cancer called ‘non-small cell lung cancer’. It is used when the cancer has spread to other parts of your body and has gone through certain changes in a gene called ‘EGFR’. Rybrevant can be prescribed for you: • in combination with chemotherapy after failure of prior therapy including an EGFR tyrosine kinase inhibitor (TKI). • as the first medicine you receive for your cancer in combination with chemotherapy, or • when chemotherapy is no longer working against your cancer. 112103693.007525 / JBI6936 How Rybrevant works

[0358] The active substance in Rybrevant, amivantamab, targets two proteins found on cancer cells: • epidermal growth factor receptor (EGFR), and • mesenchymal-epithelial transition factor (MET).

[0359] This medicine works by attaching to these proteins. This may help to slow or stop your lung cancer from growing. It may also help to reduce the size of the tumour.

[0360] Rybrevant may be given in combination with other anti-cancer medicines. It is important that you also read the package leaflets for these other medicines. If you have any questions about these medicines, ask your doctor. 2. What you need to know before you are given Rybrevant Do not use Rybrevant if • you are allergic to amivantamab or any of the other ingredients of this medicine (listed in section 6).

[0361] Do not use this medicine if the above applies to you. If you are not sure, talk to your doctor or nurse before you are given this medicine. Warnings and precautions

[0362] Tell your doctor or nurse before you are given Rybrevant if: • you have suffered from inflammation of your lungs (a condition called ‘interstitial lung disease’ or ‘pneumonitis’). Tell your doctor or nurse straight away while taking this medicine if you get any of the following side effects (see section 4 for more information): • Any side effect while the medicine is being given into your vein. • Sudden difficulty in breathing, cough, or fever that may suggest inflammation of the lungs. • Skin problems. To reduce the risk of skin problems, keep out of the sun, wear protective clothing, apply sunscreen, and use moisturisers regularly on your skin and nails while taking this medicine. You will need to continue doing this for 2 months after you stop treatment. • Eye problems. If you have vision problems or eye pain contact your doctor or nurse straight away. If you use contact lenses and have any new eye symptoms, stop using contact lenses and tell your doctor straight away. Children and adolescents

[0363] Do not give this medicine to children or young people below 18 years of age. This is because it is not known whether the medicine is safe and effective in this age group. 113103693.007525 / JBI6936 Other medicines and Rybrevant

[0364] Tell your doctor or nurse if you are taking, have recently taken or might take any other medicines. Contraception • If you could become pregnant, you must use effective contraception during Rybrevant treatment and for 3 months after stopping treatment. Pregnancy • Tell your doctor or nurse before you are given this medicine if you are pregnant, think you might be pregnant, or are planning to have a baby. • It is possible that this medicine may harm an unborn baby. If you become pregnant while being treated with this medicine, tell your doctor or nurse straight away. You and your doctor will decide if the benefit of having the medicine is greater than the risk to your unborn baby. Breast-feeding

[0365] It is not known if Rybrevant passes into breast milk. Ask your doctor for advice before being given this medicine. You and your doctor will decide if the benefit of breast-feeding is greater than the risk to your baby. Driving and using machines

[0366] If you feel tired, feel dizzy, or if your eyes are irritated or vision is affected after taking Rybrevant, do not drive or use machinery. Rybrevant contains sodium

[0367] This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’. However, before Rybrevant is given to you, it may be mixed with a solution that contains sodium. Talk to your doctor if you are on a low salt diet. Rybrevant contains polysorbate

[0368] This medicine contains 0.6 mg of polysorbate 80 in each mL, which is equivalent to 4.2 mg per 7 mL vial. Polysorbates may cause allergic reactions. Tell your doctor if you have any known allergies. 3. How Rybrevant is given How much is given

[0369] Your doctor will work out the correct dose of Rybrevant for you. The dose of this medicine will depend on your body weight at the start of your therapy. You will be 114103693.007525 / JBI6936 treated with Rybrevant once every 2 or 3 weeks according to the treatment your doctor decides for you.

[0370] The recommended dose of Rybrevant every 2 weeks is: • 1050 mg if you weigh less than 80 kg. • 1400 mg if you weigh more than or equal to 80 kg.

[0371] The recommended dose of Rybrevant every 3 weeks is: • 1400 mg for the first 4 doses and 1750 mg for subsequent doses if you weigh less than 80 kg. • 1750 mg for the first 4 doses and 2100 mg for subsequent doses if you weigh more than or equal to 80 kg. How the medicine is given

[0372] This medicine will be given to you by a doctor or nurse. It is given as a drip into a vein (‘intravenous infusion’) over several hours.

[0373] Rybrevant is given as follows: • once a week for the first 4 weeks • then once every 2 weeks starting at week 5 or once every 3 weeks starting at week 7, for as long as you keep getting benefit from the treatment.

[0374] In the first week, your doctor will give you the Rybrevant dose split over two days. Medicines given during treatment with Rybrevant

[0375] Before each infusion of Rybrevant, you will be given medicines which help lower the chance of infusion-related reactions. These may include: • medicines for an allergic reaction (antihistamines) • medicines for inflammation (corticosteroids) • medicines for fever (such as paracetamol).

[0376] You may also be given additional medicines based on any symptoms you may experience. If you are given more Rybrevant than you should

[0377] This medicine will be given by your doctor or nurse. In the unlikely event that you are given too much (an overdose), your doctor will check you for side effects. 115103693.007525 / JBI6936 If you forget your appointment to have Rybrevant

[0378] It is very important to go to all your appointments. If you miss an appointment, make another one as soon as possible.

[0379] If you have any further questions on the use of this medicine, ask your doctor or nurse. 4. Possible side effects

[0380] Like all medicines, this medicine can cause side effects, although not everybody gets them. Serious side effects

[0381] Tell your doctor or nurse straight away if you notice the following serious side effects: Very common (may affect more than 1 in 10 people): • Signs of a reaction to the infusion - such as chills, feeling short of breath, feeling sick (nausea), flushing, chest discomfort, and vomiting while the medicine is being given. This can happen especially with the first dose. Your doctor may give you other medicines, or the infusion may need to be slowed down or stopped. • Skin problems - such as rash (including acne), infected skin around the nails, dry skin, itching, pain, and redness. Tell your doctor if your skin or nail problems get worse. Common (may affect up to 1 in 10 people): • Eye problems - such as dry eye, swollen eyelid, itchy eyes, problems with vision, growth of eyelashes. • Signs of an inflammation in the lungs - such as sudden difficulty in breathing, cough, or fever. This could lead to permanent damage (‘interstitial lung disease’). Your doctor may wish to stop Rybrevant if you get this side effect. Uncommon (may affect up to 1 in 100 people): • inflamed cornea (front part of the eye) • inflammation inside the eye that may affect vision • life-threatening rash with blisters and peeling skin over much of the body (toxic epidermal necrolysis).

[0382] The following side effects have been reported in clinical studies with Rybrevant when given alone: 116103693.007525 / JBI6936 Other side effects

[0383] Tell your doctor if you notice any of the following side effects: Very common (may affect more than 1 in 10 people): • low level of the protein ‘albumin’ in the blood • swelling caused by fluid build up in the body • feeling very tired • sores in the mouth • constipation or diarrhoea • decreased appetite • increased level of the liver enzyme ‘alanine aminotransferase’ in the blood, a possible sign of liver problems • increased level of the enzyme ‘aspartate aminotransferase’ in the blood, a possible sign of liver problems • feeling dizzy • increased level of the enzyme ‘alkaline phosphatase’ in the blood • muscle aches • fever • low level of calcium in the blood Common (may affect up to 1 in 10 people) • stomach pain • low level of potassium in the blood • low level of magnesium in the blood • haemorrhoids

[0384] The following side effects have been reported in clinical studies with Rybrevant in combination with chemotherapy: Other side effects

[0385] Tell your doctor if you notice any of the following side effects: Very common (may affect more than 1 in 10 people): • low number of a type of white blood cell (neutropenia) • low number of ‘platelets’(cells that help blood to clot) • blood clot in the veins • feeling very tired • nausea • sores in the mouth 117103693.007525 / JBI6936 • constipation • swelling caused by fluid build up in the body • decreased appetite • low level of the protein ‘albumin’ in the blood • increased level of the liver enzyme ‘alanine aminotransferase’ in the blood, a possible sign of liver problems • increased level of the enzyme ‘aspartate aminotransferase’ in the blood, a possible sign of liver problems • vomiting • low level of potassium in the blood • diarrhoea • fever • low level of magnesium in the blood • low level of calcium in the blood Common (may affect up to 1 in 10 people) • increased level of the enzyme ‘alkaline phosphatase’ in the blood • stomach pain • feeling dizzy • haemorrhoids • muscle aches Reporting of side effects

[0386] If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. By reporting side effects, you can help provide more information on the safety of this medicine. 5. How to store Rybrevant

[0387] Rybrevant will be stored at the hospital or clinic.

[0388] Keep this medicine out of the sight and reach of children.

[0389] Do not use this medicine after the expiry date which is stated on the carton and the vial label after “EXP”. The expiry date refers to the last day of that month.

[0390] Chemical and physical in-use stability has been demonstrated for 10 hours at 15°C to 25°C in room light. From a microbiological point of view, unless the method of dilution precludes the risk of microbial contamination, the product should be used 118103693.007525 / JBI6936 immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

[0391] Store in a refrigerator (2°C to 8°C). Do not freeze.

[0392] Store in the original package in order to protect from light.

[0393] Medicines should not be disposed of via wastewater or household waste. Your healthcare professional will throw away any medicines that are no longer being used. These measures will help protect the environment. 6. Contents of the pack and other information What Rybrevant contains • The active substance is amivantamab. One mL of concentrate for solution for infusion contains 50 mg of amivantamab. One vial of 7 mL concentrate contains 350 mg of amivantamab. • The other ingredients are ethylenediaminetetraacetic acid (EDTA), L-histidine, L-histidine hydrochloride monohydrate, L-methionine, polysorbate 80, sucrose, and water for injections (see section 2). What Rybrevant looks like and contents of the pack

[0394] Rybrevant is a concentrate for solution for infusion and is a colourless to pale yellow liquid. This medicine is available in a carton pack containing 1 glass vial of 7 mL of concentrate. Marketing Authorisation Holder Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium Manufacturer Janssen Biologics B.V. Einsteinweg 101 2333 CB Leiden The Netherlands

[0395] For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: 119103693.007525 / JBI6936120103693.007525 / JBI6936This leaflet was last revised in. Other sources of information

[0396] Detailed information on this medicine is available on the European Medicines Agency web site https: / / www.ema.eueu. 121103693.007525 / JBI6936122103693.007525 / JBI6936 Example 4: Approved Drug Product Label 123103693.007525 / JBI6936 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use RYBREVANT safely and effectively. See full prescribing information for RYBREVANT. RYBREVANT®(amivantamab-vmjw) injection, for intravenous use Initial U.S. Approval: 2021 -----------------------------RECENT MAJOR CHANGES-------------------------

[0397] Indications and Usage (1) 09 / 2024 [osage a s a o

[0399] Warnings and Precautions (5) 09 / 2024 -----------------------------INDICATIONS AND USAGE---------------------------

[0400] RYBREVANT is a bispecific EGF receptor-directed and MET receptor-directed antibody indicated: • in combination with lazertinib for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test. (1, 2.2) • in combination with carboplatin and pemetrexed for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor. (1, 2.2) • in combination with carboplatin and pemetrexed for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test. (1, 2.2) • as a single agent for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. (1, 2.2) ------------------------DOSAGE AND ADMINISTRATION----------------------- • The recommended dosage of RYBREVANT is based on baseline body weight and administered as an intravenous infusion after dilution. (2.3, 2.5, 2.6, 2.7) • Administer premedications as recommended. (2.5) 124103693.007525 / JBI6936 • Administer via a peripheral line on Week 1 and Week 2 to reduce the risk of infusion-related reactions. (2.8) • Administer RYBREVANT in combination with chemotherapy weekly for 4 weeks, with the initial dose as a split infusion in Week 1 on Day 1 and Day 2, then administer every 3 weeks starting at Week 7. (2.3) • Administer RYBREVANT in combination with lazertinib or RYBREVANT as a single agent weekly for 5 weeks, with the initial dose as a split infusion in Week 1 on Day 1 and Day 2, then administer every 2 weeks starting at Week 7. (2.4) • When administering RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis to prevent venous thromboembolic (VTE) events for the first four months of treatment. (2.4) • Administer diluted RYBREVANT intravenously according to the infusion rates in Tables 29 and 30. (2.8) Table 21. Body Weight (at Dosage Recommended Baseline) DoseD STRENGTHS--------------------- [0401 I ti 350 / 7 L 50 / L l ti i i l d i l 3) -----------------------------CONTRAINDICATIONS---------------------------------

[0402] None. (4) -------------------------WARNINGS AND PRECAUTIONS----------------------•Infusion-Related Reactions (IRR): Interrupt infusion at the first sign of IRRs. Reduce the infusion rate or permanently discontinue RYBREVANT based on severity. (2.6, 5.1) 125103693.007525 / JBI6936 • Interstitial Lung Disease (ILD) / Pneumonitis: Monitor for new or worsening symptoms indicative of ILD. Immediately withhold RYBREVANT in patients with suspected ILD / pneumonitis and permanently discontinue if ILD / pneumonitis is confirmed. (2.6, 5.2) • Venous Thromboembolic (VTE) Events with Concomitant Use with Lazertinib: Prophylactic anticoagulation is recommended for the first four months of treatment. Monitor for signs and symptoms of VTE and treat as medically appropriate. Withhold RYBREVANT and lazertinib based on severity. Once anticoagulant treatment has been initiated, resume RYBREVANT and lazertinib at the same dose at the discretion of the healthcare provider. Permanently discontinue RYBREVANT and continue lazertinib for recurrent VTE despite therapeutic anticoagulation. (2.6, 5.3) • Dermatologic Adverse Reactions: Can cause severe rash including toxic epidermal necrolysis (TEN) and acneiform dermatitis. Withhold, reduce the dose, or permanently discontinue RYBREVANT based on severity. (2.6, 5.4) • Ocular Toxicity: Promptly refer patients with worsening eye symptoms to an ophthalmologist. Withhold, reduce the dose, or permanently discontinue RYBREVANT based on severity. (2.6, 5.5) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. (5.6, 8.1, 8.3) ------------------------------ADVERSE REACTIONS------------------------------- [• The most common adverse reactions (≥ 20%) were rash, nail toxicity, infusion-related reaction, musculoskeletal pain, stomatitis, edema, VTE, paresthesia, fatigue, diarrhea, constipation, COVID-19, hemorrhage, dry skin, decreased appetite, pruritus, nausea, and ocular toxicity. (6.1) • The most common Grade 3 or 4 laboratory abnormalities (≥ 2%) were decreased albumin, decreased sodium, increased ALT, decreased potassium, decreased hemoglobin, increased AST, increased GGT, and increased magnesium. (6.1)

[0404] RYBREVANT in Combination with Carboplatin and Pemetrexed • The most common adverse reactions (≥ 20%) were rash, nail toxicity, infusion-related reaction, fatigue, nausea, stomatitis, constipation, edema, decreased appetite, musculoskeletal pain, vomiting, and COVID-19. (6.1) 126103693.007525 / JBI6936 • The most common Grade 3 or 4 laboratory abnormalities (≥ 2%) were decreased neutrophils, decreased leukocytes, decreased platelets, decreased hemoglobin, decreased potassium, decreased sodium, increased alanine aminotransferase, increased gamma glutamyl transferase, and decreased albumin. (6.1)

[0405] RYBREVANT as a Single Agent • The most common adverse reactions (≥ 20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting. (6.1) • The most common Grade 3 or 4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased alkaline phosphatase, increased glucose, increased gamma-glutamyl transferase, and decreased sodium. (6.1)

[0406] To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov / medwatch. -----------------------USE IN SPECIFIC POPULATIONS------------------------

[0407] Lactation: Advise not to breastfeed. (8.2)

[0408] See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 09 / 2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 First-Line Treatment of NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations 1.2 Previously Treated NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations 1.3 First-Line Treatment of NSCLC with EGFR Exon 20 Insertion Mutations 1.4 Previously Treated NSCLC with EGFR Exon 20 Insertion Mutations 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage Information 2.2 Patient Selection 127103693.007525 / JBI6936 2.3 Recommended Dosage of RYBREVANT in Combination with Carboplatin and Pemetrexed for the treatment of NSCLC – Every 3-week dosing 2.4 Recommended Dosage of RYBREVANT in Combination with Lazertinib or RYBREVANT as a Single Agent - Every 2-week dosing 2.5 Recommended Premedications 2.6 Dosage Modifications for Adverse Reactions 2.7 Preparation 2.8 Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Infusion-Related Reactions 5.2 Interstitial Lung Disease / Pneumonitis 5.3 Venous Thromboembolic (VTE) Events with Concomitant Use of RYBREVANT and Lazertinib 5.4 Dermatologic Adverse Reactions 5.5 Ocular Toxicity 5.6 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 128103693.007525 / JBI6936 12.6 Immunogenicity 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 First Line Treatment of NSCLC with Exon 19 deletion or Exon 21 L858R Substitution Mutation - MARIPOSA 14.2 Previously Treated NSCLC Patients with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations - MARIPOSA-2 14.3 First Line Treatment of NSCLC with Exon 20 Insertion Mutations - PAPILLON 14.4 Previously Treated NSCLC with Exon 20 Insertion Mutations - CHRYSALIS 16 HOW SUPPLIED / STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 129103693.007525 / JBI6936 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 First-Line Treatment of NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations

[0409] RYBREVANT, in combination with lazertinib, is indicated for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test [see Dosage and Administration (2.2)]. 1.2 Previously Treated NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations

[0410] RYBREVANT, in combination with carboplatin and pemetrexed, is indicated for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor [see Dosage and Administration (2.2)]. 1.3 First-Line Treatment of NSCLC with EGFR Exon 20 Insertion Mutations

[0411] RYBREVANT, in combination with carboplatin and pemetrexed, is indicated for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test [see Dosage and Administration (2.2)]. 1.4 Previously Treated NSCLC with EGFR Exon 20 Insertion Mutations

[0412] RYBREVANT is indicated as a single agent for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test [see Dosage and Administration (2.2)], whose disease has progressed on or after platinum-based chemotherapy. 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage Information • Administer premedications before each RYBREVANT infusion as recommended [see Dosage and Administration (2.5)]. 130103693.007525 / JBI6936 • Administer diluted RYBREVANT intravenously according to the infusion rates in Tables 29 and 9, with the initial dose as a split infusion on Week 1 on Day 1 and Day 2 [see Dosage and Administration (2.8)]. • Administer RYBREVANT via peripheral line for Week 1 Day 1 and 2 and Week 2 to reduce the risk of infusion-related reactions [see Dosage and Administration (2.8)]. • When administering RYBREVANT in combination with carboplatin and pemetrexed, infuse pemetrexed first, carboplatin second, and RYBREVANT last [see Dosage and Administration (2.8)]. • When administering RYBREVANT in combination with lazertinib, administer lazertinib orally any time before the RYBREVANT infusion [see Dosage and Administration (2.8)]. • When administering RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis to prevent venous thromboembolic (VTE) events for the first four months of treatment [see Dosage and Administration (2.4)]. 2.2 Patient Selection

[0413] Select patients for treatment with RYBREVANT based on the presence of a mutation as detected by an FDA-approved test. Table 22: Patient Selection Indication Treatment Regimen Source for Testing131103693.007525 / JBI6936 Previously Treated NSCLC with EGFR Exon RYBREVANT as a 20 Insertion Mutations [see Indications and single agent U (14)2.3 Recommended Dosage of RYBREVANT in Combination with Carboplatin and Pemetrexed for the Treatment of NSCLC – Every 3-week dosing

[0414] The recommended dosage of RYBREVANT, administered in combination with carboplatin and pemetrexed is based on baseline body weight is provided in Table 23. Table 23: Recommended Dosage for RYBREVANT in Combination with Carboplatin and Pemetrexed Body weight Recommended at BaselineaDose Dosing Schedule

[0415] The recommended order of administration and regimen for RYBREVANT in combination with carboplatin and pemetrexed are provided in Table 24. Table 24: Order of Administration and Regimen for RYBREVANT in Combination with Carboplatin and Pemetrexed RYBREVANT in Combination with Carboplatin and Pemetrexed T nt132103693.007525 / JBI6936 Carboplatin Carboplatin AUC 5 Every 3 weeks for up to 12 intravenously weeks.2.4 Recommended Dosage of RYBREVANT in Combination with Lazertinib or RYBREVANT as a Single Agent - Every 2-week dosing

[0416] The recommended dosage of RYBREVANT in combination with lazertinib or RYBREVANT as a single agent, based on baseline body weight, are provided in Table 25. Administer RYBREVANT until disease progression or unacceptable toxicity. Table 25: Recommended Dosage Schedule for RYBREVANT in Combination with Lazertinib or RYBREVANT as a Single Agent Body weight Recommended at BaselineaDose Dosing ScheduleRYBREVANT in Combination with Lazertinib Order of Administration

[0417] When given in combination with lazertinib, administer RYBREVANT any time after lazertinib when given on the same day. Refer to the lazertinib prescribing information for recommended lazertinib dosing information. Administer RYBREVANT in combination with lazertinib until disease progression or unacceptable toxicity. Concomitant Medications 133103693.007525 / JBI6936

[0418] When initiating treatment with RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis to prevent venous thromboembolic (VTE) events for the first four months of treatment [see Warnings and Precautions (5.3)]. If there are no signs or symptoms of VTE during the first four months of treatment, consider discontinuation of anticoagulant prophylaxis at the discretion of the healthcare provider. Refer to the lazertinib prescribing information for information about concomitant medications.

[0419] When initiating treatment with RYBREVANT in combination with lazertinib, administer alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream and encourage patients to limit sun exposure during and for 2 months after treatment, to wear protective clothing and use broad-spectrum UVA / UVB sunscreen to reduce the risk of dermatologic adverse reactions [see Warnings and Precautions (5.4)]. Consider prophylactic measures (e.g., use of oral antibiotics) to reduce the risk of dermatologic adverse reactions. Refer to the lazertinib prescribing information for information about concomitant medications. 2.5 Recommended Premedications

[0420] Prior to the initial infusion of RYBREVANT (Week 1, Day 1 and 2), administer premedications as described in Table 26 to reduce the risk of infusion-related reactions [see Warnings and Precautions (5.1)].

[0421] Glucocorticoid administration is required for Week 1, Day 1 and 2 dose only and upon re-initiation after prolonged dose interruptions, then as necessary for subsequent infusions (see Table 26). Administer both antihistamine and antipyretic prior to all infusions. Table 26: Premedications Dosing Window Pri r tq y . +Required at second dose (Week 1 Day 2); optional for subsequent doses.134103693.007525 / JBI6936 2.6 Dosage Modifications for Adverse Reactions

[0422] The recommended dose reductions for adverse reactions for RYBREVANT are listed in Table 27. Table 27: Dose Reductions for Adverse Reactions for RYBREVANT Dose at which the 1stDose Reduction 2ndDose Reduction 3rdDose Reduction adverse reaction

[0423] The recommended dosage modifications and management for adverse reactions for RYBREVANT are provided in Table 28. Table 28: Recommended Dosage Modifications and Management for Adverse Reactions for RYBREVANT Adverse Reaction Severity Dosage Modifications Infusion-related reactionsGrade 1 to 2• Interrupt RYBREVANT infusion if IRR is e e s135103693.007525 / JBI6936 Venous Thromboembolic Grade 2 or 3 • Withhold RYBREVANT and lazertinib. (VTE) Events [Applies to • Administer anticoagulant treatment as clinically th bi ti ith i i d, ly d, ve ly er136103693.007525 / JBI6936 Recommended Dosage Modifications for Adverse Reactions for RYBREVANT in Combination with Lazertinib

[0424] When administering RYBREVANT in combination with lazertinib, if there is an adverse reaction requiring dose reduction after withholding treatment and resolution, reduce the dose of RYBREVANT first. Refer to the lazertinib prescribing information for information about dosage modifications for lazertinib. Recommended Dosage Modifications for Adverse Reactions for RYBREVANT in Combination with Carboplatin and Pemetrexed

[0425] When administering RYBREVANT in combination with carboplatin and pemetrexed, modify the dosage of one or more drugs. Withhold or discontinue RYBREVANT as shown in Table 28. Refer to prescribing information for carboplatin and pemetrexed for additional dosage modification information. 2.7 Preparation Dilute and prepare RYBREVANT for intravenous infusion before administration. Check that the RYBREVANT solution is colorless to pale yellow. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if discoloration or visible particles are present. Determine the dose required and number of RYBREVANT vials needed based on patient’s baseline weight [see Dosage and Administration (2.3)]. Each vial of RYBREVANT contains 350 mg of amivantamab-vmjw. Withdraw and then discard a volume of either 5% Dextrose Injection or 0.9% Sodium Chloride Injection from the 250 mL infusion bag equal to the volume of RYBREVANT to be added (i.e., discard 7 mL diluent from the infusion bag for each RYBREVANT vial). Only use infusion bags made of polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE), or polyolefin blend (PP+PE). Withdraw 7 mL of RYBREVANT from each vial and add it to the infusion bag. The final volume in the infusion bag should be 250 mL. Discard any unused portion left in the vial. Gently invert the bag to mix the solution. Do not shake. 137103693.007525 / JBI6936 Diluted solutions should be administered within 10 hours (including infusion time) at room temperature 15°C to 25°C (59°F to 77°F). 2.8 Administration • Administer the diluted RYBREVANT solution [see Dosage and Administration (2.7)] by intravenous infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.2 micrometer). • Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP, or PE. • The administration set with filter, must be primed with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection prior to the initiation of each RYBREVANT infusion. • Do not infuse RYBREVANT concomitantly in the same intravenous line with other agents. RYBREVANT in Combination with Carboplatin and Pemetrexed • Administer RYBREVANT in combination with carboplatin and pemetrexed infusions every 3 weeks intravenously until disease progression or unacceptable toxicity according to the infusion rates in Table 29. • Administer RYBREVANT via a peripheral line on Week 1 and Week 2 to reduce the risk of infusion-related reactions during initial treatment [see Warnings and Precautions (5.1)]. • RYBREVANT may be administered via central line for subsequent weeks. • For the initial infusion, prepare RYBREVANT as close to administration time as possible to allow for the possibility of extended infusion time in the event of an infusion-related reaction. • Administer the pemetrexed infusion first, carboplatin infusion second, and the RYBREVANT infusion last. Table 29: Infusion Rates of RYBREVANT in Combination with Carboplatin and Pemetrexed for Treatment of NSCLC Body Weight Less Than 80 kg138103693.007525 / JBI6936 Week 1 Day 2 1050 mg 33 50 Week 2 1400 mg 65 k 14rs for day 1 and 6-8 hours for day 2. Subsequent infusion time is approximately 2 hours. 139103693.007525 / JBI6936 RYBREVANT in Combination with Lazertinib or RYBREVANT as a Single Agent • Administer RYBREVANT as a single agent infusion every 2 weeks intravenously until disease progression or unacceptable toxicity according to the infusion rates in Table 30. • Administer RYBREVANT via a peripheral line on Week 1 and Week 2, to reduce the risk of infusion-related reactions during initial treatment [see Warnings and Precautions (5.1)]. • RYBREVANT may be administered via central line for subsequent weeks. • For the initial infusion, prepare RYBREVANT as close to administration time as possible to allow for the possibility of extended infusion time in the event of an infusion-related reaction. • When given in combination with lazertinib, administer RYBREVANT any time after lazertinib when given on the same day. Table 30: Infusion Rates of RYBREVANT in Combination with Lazertinib or RYBREVANT as Single Agent Body Weight Less Than 80 kg Week Dose Initial Subsequent140103693.007525 / JBI6936 Week 4 1400 mg 125 Week 5 1400 mg 125 k d on 1an - ours or ay . u sequent n us on tme s approxmate y ours. 3 DOSAGE FORMS AND STRENGTHS

[0426] Injection: 350 mg / 7 mL (50 mg / mL) colorless to pale yellow solution in a single-dose vial. 4 CONTRAINDICATIONS

[0427] None. 5 WARNINGS AND PRECAUTIONS 5.1 Infusion-Related Reactions

[0428] RYBREVANT can cause infusion-related reactions (IRR); signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting. The median time to IRR onset is approximately 1 hour. RYBREVANT with Lazertinib

[0429] RYBREVANT in combination with lazertinib can cause infusion-related reactions. In MARIPOSA, [see Adverse Reactions (6.1)], IRRs occurred in 63% of patients treated with RYBREVANT in combination with lazertinib, including Grade 3 in 5% and Grade 4 in 1% of patients. The incidence of infusion modifications due to IRR was 54%, and IRRs leading to dose reduction of RYBREVANT occurred in 0.7% of patients. Infusion-related reactions leading to permanent discontinuation of RYBREVANT occurred in 4.5% of patients receiving RYBREVANT in combination with lazertinib. RYBREVANT with Carboplatin and Pemetrexed

[0430] Based on the pooled safety population [see Adverse Reactions (6.1)], IRR occurred in 50% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed, including Grade 3 (3.2%) adverse reactions. The incidence of infusion modifications due to IRR was 46%, and 2.8% of patients permanently discontinued RYBREVANT due to IRR. 141103693.007525 / JBI6936 RYBREVANT as a Single Agent

[0431] In CHRYSALIS, [see Adverse Reactions (6.1)], IRR occurred in 66% of patients treated with RYBREVANT as a single agent. Among patients receiving treatment on Week 1 Day 1, 65% experienced an IRR, while the incidence of IRR was 3.4% with the Day 2 infusion, 0.4% with the Week 2 infusion, and cumulatively 1.1% with subsequent infusions. Of the reported IRRs, 97% were Grade 1-2, 2.2% were Grade 3, and 0.4% were Grade 4. The median time to onset was 1 hour (range 0.1 to 18 hours) after start of infusion. The incidence of infusion modifications due to IRR was 62%, and 1.3% of patients permanently discontinued RYBREVANT due to IRR.

[0432] Premedicate with antihistamines, antipyretics, and glucocorticoids and infuse RYBREVANT as recommended [see Dosage and Administration (2.5)]. Administer RYBREVANT via a peripheral line on Week 1 and Week 2 to reduce the risk of infusion-related reactions [see Dosage and Administration (2.8)].

[0433] Monitor patients for signs and symptoms of infusion reactions during RYBREVANT infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Interrupt infusion if IRR is suspected. Reduce the infusion rate or permanently discontinue RYBREVANT based on severity [see Dosage and Administration (2.6)]. 5.2 Interstitial Lung Disease / Pneumonitis

[0434] RYBREVANT can cause severe and fatal interstitial lung disease (ILD) / pneumonitis. RYBREVANT with Lazertinib

[0435] In MARIPOSA [see Adverse Reactions (6.1)], ILD / pneumonitis occurred in 3.1% of patients treated with RYBREVANT in combination with lazertinib, including Grade 3 in 1% and Grade 4 in 0.2% of patients. There was one fatal case of ILD / pneumonitis and 2.9% of patients permanently discontinued RYBREVANT and lazertinib due to ILD / pneumonitis [see Adverse Reactions (6.1)]. RYBREVANT with Carboplatin and Pemetrexed

[0436] Based on the pooled safety population [see Adverse Reactions (6.1)], ILD / pneumonitis occurred in 2.1% treated with RYBREVANT in combination with carboplatin 142103693.007525 / JBI6936 and pemetrexed with 1.8% of patients experiencing Grade 3 ILD / pneumonitis.2.1% discontinued RYBREVANT due to ILD / pneumonitis. RYBREVANT as a Single Agent

[0437] In CHRYSALIS, [see Adverse Reactions (6.1)], ILD / pneumonitis occurred in 3.3% of patients treated with RYBREVANT as a single agent, with 0.7 % of patients experiencing Grade 3 ILD / pneumonitis. Three patients (1%) permanently discontinued RYBREVANT due to ILD / pneumonitis.

[0438] Monitor patients for new or worsening symptoms indicative of ILD / pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold RYBREVANT in patients with suspected ILD / pneumonitis and permanently discontinue if ILD / pneumonitis is confirmed [see Dosage and Administration (2.6)]. 5.3 Venous Thromboembolic (VTE) Events with Concomitant Use of RYBREVANT and Lazertinib

[0439] RYBREVANT in combination with lazertinib can cause serious and fatal venous thromboembolic (VTE) events, including deep vein thrombosis and pulmonary embolism. The majority of these events occurred during the first four months of therapy [see Adverse Reactions (6.1)].

[0440] In MARIPOSA [see Adverse Reactions (6.1)], VTEs occurred in 36% of patients receiving RYBREVANT in combination with lazertinib, including Grade 3 in 10% and Grade 4 in 0.5% of patients. On-study VTEs occurred in 1.2% of patients (n=5) while receiving anticoagulation therapy. There were two fatal cases of VTE (0.5%), 9% of patients had VTE leading to dose interruptions of RYBREVANT, 1% of patients had VTE leading to dose reductions of RYBREVANT, and 3.1% of patients had VTE leading to permanent discontinuation of RYBREVANT. The median time to onset of VTEs was 84 days (range: 6 to 777). Administer prophylactic anticoagulation for the first four months of treatment [see Dosage and Administration (2.4)]. The use of Vitamin K antagonists is not recommended. Monitor for signs and symptoms of VTE events and treat as medically appropriate.

[0441] Withhold RYBREVANT and lazertinib based on severity [see Dosage and Administration (2.6)]. Once anticoagulant treatment has been initiated, resume RYBREVANT and lazertinib at the same dose level at the discretion of the healthcare provider [see Dosage and Administration (2.4)]. In the event of VTE recurrence despite therapeutic anticoagulation, 143103693.007525 / JBI6936 permanently discontinue RYBREVANT. Treatment can continue with lazertinib at the same dose level at the discretion of the healthcare provider [see Dosage and Administration (2.6)]. Refer to the lazertinib prescribing information for recommended lazertinib dosage modification. 5.4 Dermatologic Adverse Reactions

[0442] RYBREVANT can cause severe rash including toxic epidermal necrolysis (TEN), dermatitis acneiform, pruritus, and dry skin. RYBREVANT with Lazertinib

[0443] In MARIPOSA, [see Adverse Reactions (6.1)], rash occurred in 86% of patients treated with RYBREVANT in combination with lazertinib, including Grade 3 in 26% of patients. The median time to onset of rash was 14 days (range: 1 to 556 days). Rash leading to dose interruptions of RYBREVANT occurred in 37% of patients, rash leading to dose reductions of RYBREVANT occurred in 23% of patients, and rash leading to permanent discontinuation of RYBREVANT occurred in 5% of patients. RYBREVANT with Carboplatin and Pemetrexed

[0444] Based on the pooled safety population [see Adverse Reactions (6.1)], rash occurred in 82% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed, including Grade 3 (15%) adverse reactions. Rash leading to dose reductions occurred in 14% of patients, and 2.5% permanently discontinued RYBREVANT and 3.1% discontinued pemetrexed. RYBREVANT as a Single Agent

[0445] In CHRYSALIS, [see Adverse Reactions (6.1)], rash occurred in 74% of patients treated with RYBREVANT as a single agent, including Grade 3 rash in 3.3% of patients. The median time to onset of rash was 14 days (range: 1 to 276 days). Rash leading to dose reduction occurred in 5% of patients, and RYBREVANT was permanently discontinued due to rash in 0.7% of patients [see Adverse Reactions (6.1)].

[0446] Toxic epidermal necrolysis (TEN) occurred in one patient (0.3%) treated with RYBREVANT as a single agent.

[0447] Instruct patients to limit sun exposure during and for 2 months after treatment with RYBREVANT. Advise patients to wear protective clothing and use broad-spectrum 144103693.007525 / JBI6936 UVA / UVB sunscreen. Alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream is recommended for dry skin.

[0448] When initiating treatment with RYBREVANT, administer alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream to reduce the risk of dermatologic adverse reactions. Consider prophylactic measures (e.g., use of oral antibiotics) to reduce the risk of dermatologic adverse reactions. If skin reactions develop, start topical corticosteroids and topical and / or oral antibiotics. For Grade 3 reactions, add oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. Withhold, reduce the dose, or permanently discontinue RYBREVANT based on severity [see Dosage and Administration (2.6)]. 5.5 Ocular Toxicity

[0449] RYBREVANT can cause ocular toxicity including keratitis, blepharitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, eye pruritus, and uveitis. RYBREVANT with Lazertinib

[0450] In MARIPOSA [see Adverse Reactions (6.1)], ocular toxicity occurred in 16% of patients treated with RYBREVANT in combination with lazertinib, including Grade 3 or 4 ocular toxicity in 0.7% of patients. Withhold, reduce the dose, or permanently discontinue RYBREVANT and continue lazertinib based on severity [see Dosage and Administration (2.4)]. RYBREVANT with Carboplatin and Pemetrexed

[0451] Based on the pooled safety population [see Adverse Reactions (6.1)], ocular toxicity occurred in 16% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed. All events were Grade 1 or 2. RYBREVANT as a Single Agent

[0452] In CHRYSALIS, [see Adverse Reactions (6.1)], keratitis occurred in 0.7% and uveitis occurred in 0.3% of patients treated with RYBREVANT. All events were Grade 1-2.

[0453] Promptly refer patients with new or worsening eye symptoms to an ophthalmologist. Withhold, reduce the dose, or permanently discontinue RYBREVANT based on severity [see Dosage and Administration (2.6)]. 145103693.007525 / JBI6936 5.6 Embryo-Fetal Toxicity

[0454] Based on its mechanism of action and findings from animal models, RYBREVANT can cause fetal harm when administered to a pregnant woman. Administration of other EGFR inhibitor molecules to pregnant animals has resulted in an increased incidence of impairment of embryo-fetal development, embryo lethality, and abortion. Advise females of reproductive potential of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of RYBREVANT. [see Use in Specific Populations (8.1, 8.3)]. 6 ADVERSE REACTIONS

[0455] The following adverse reactions are discussed elsewhere in the labeling:

[0456] Infusion-Related Reactions [see Warnings and Precautions (5.1)]

[0457] Interstitial Lung Disease / Pneumonitis [see Warnings and Precautions (5.2)]

[0458] Venous Thromboembolic Events [see Warnings and Precautions (5.3)]

[0459] Dermatologic Adverse Reactions [see Warnings and Precautions (5.4)]

[0460] Ocular Toxicity [see Warnings and Precautions (5.5)] 6.1 Clinical Trials Experience

[0461] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. RYBREVANT in Combination with Lazertinib

[0462] The data described in the WARNINGS AND PRECAUTIONS reflect exposure to RYBREVANT in combination with lazertinib in the MARIPOSA study in 421 patients with previously untreated locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R substitution mutations [see Clinical Studies (14.1)]. Patients received RYBREVANT intravenously at 1050 mg (for patients < 80 kg) or 1400 mg (for patients ≥ 80 kg) once weekly for 4 weeks, then every 2 weeks thereafter starting at week 5 in combination with lazertinib, 240 mg orally once daily, until disease progression or unacceptable toxicity. Among 421 patients who received RYBREVANT in combination with lazertinib, 73% were exposed for 6 months or longer and 59% were exposed for greater than one year. The most common adverse reactions (≥ 20%) were rash, nail toxicity, infusion-related reaction, edema, musculoskeletal pain, stomatitis, VTE, paresthesia, fatigue, diarrhea, constipation, COVID-19, 146103693.007525 / JBI6936 dry skin, hemorrhage, decreased appetite, pruritus, nausea, and ocular toxicity. The most common Grade 3 or 4 laboratory abnormalities (≥ 2%) were decreased albumin, increased ALT, decreased sodium, decreased hemoglobin, increased AST, increased GGT and increased magnesium. RYBREVANT in Combination with Carboplatin and Pemetrexed

[0463] The pooled safety population described in the WARNINGS AND PRECAUTIONS also reflect exposure to RYBREVANT in combination with carboplatin and pemetrexed in 281 patients in two studies: • MARIPOSA-2 [see Clinical Studies (14.2)] in 130 patients with previously treated locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations whose disease has progressed on or after treatment with osimertinib. • PAPILLON [see Clinical Studies (14.3)] in 151 patients with previously untreated, locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.

[0464] Patients received RYBREVANT intravenously at 1400 mg (for patients < 80 kg) or 1750 mg (for patients ≥ 80 kg) once weekly through 4 weeks, then every 3 weeks with a dose of 1750 mg (for patients < 80 kg) or 2100 mg (for patients ≥ 80 kg) starting at Week 7 until disease progression or unacceptable toxicity, in combination with carboplatin at area under the curve AUC 5 once every 3 weeks, for up to 12 weeks, and pemetrexed at 500 mg / m2 once every 3 weeks until disease progression or unacceptable toxicity. Among 281 patients who received RYBREVANT in combination with carboplatin and pemetrexed, 65% were exposed for 6 months or longer and 24% were exposed for greater than one year. In the safety population, the most common (≥ 20%) adverse reactions were rash, nail toxicity, infusion-related reaction, fatigue, nausea, stomatitis, constipation, edema, decreased appetite, musculoskeletal pain, vomiting, and COVID-19. The most common Grade 3 to 4 laboratory abnormalities (≥ 2%) were decreased neutrophils, decreased leukocytes, decreased platelets, decreased hemoglobin, decreased potassium, decreased sodium, increased alanine aminotransferase, increased gamma-glutamyl transferase, and decreased albumin. RYBREVANT as a Single Agent

[0465] The data in the WARNINGS AND PRECAUTIONS also reflect exposure to RYBREVANT as a single agent in CHRYSALIS [see Clinical Studies (14.4)] in 302 patients 147103693.007525 / JBI6936 with locally advanced or metastatic NSCLC. Patients received RYBREVANT at 1050 mg (for patient baseline body weight < 80 kg) or 1400 mg (for patient baseline body weight ≥ 80 kg) once weekly for 4 weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity. Among 302 patients who received RYBREVANT as a single agent, 36% were exposed for 6 months or longer and 12% were exposed for greater than one year. In the safety population, the most common (≥ 20%) adverse reactions were rash, infusion-related reaction, paronychia, musculoskeletal pain, dyspnea, nausea, edema, cough, fatigue, stomatitis, constipation, vomiting and pruritus. The most common Grade 3 to 4 laboratory abnormalities (≥ 2%) were increased gamma glutamyl transference, decreased sodium, decreased potassium and increased alkaline phosphatase. First-line Treatment of NSCLC with Exon 19 deletions or Exon 21 L858R substitution mutations

[0466] The safety data described below reflect exposure to RYBREVANT in combination with lazertinib in 421 previously untreated patients with locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R substitution mutation in the MARIPOSA [see Clinical Studies (14.1)]. Patients received RYBREVANT intravenously at 1,050 mg (for patients < 80 kg) or 1,400 mg (for patients ≥ 80 kg) once weekly for 4 weeks, then every 2 weeks thereafter starting at week 5 in combination with lazertinib, 240 mg orally once daily. Among the 421 patients who received RYBREVANT in combination with lazertinib, 73% were exposed to RYBREVANT for ≥ 6 months and 59% were exposed to RYBREVANT for > 1 year.

[0467] The median age of patients who received RYBREVANT in combination with lazertinib was 64 years (range: 25 to 88); 64% were female; 59% were Asian, 38% were White, 1.7% were American Indian or Alaska Native, 0.7% were Black or African American, 1% were of unknown or other races; and 13% were Hispanic or Latino, 67% had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1, 33% had ECOG PS of 0, 60% had EGFR exon 19 deletions, and 40% had EGFR exon 21 L858R substitution mutations.

[0468] Serious adverse reactions occurred in 49% of patients who received RYBREVANT in combination with lazertinib. Serious adverse reactions occurring in ≥ 2% of patients included VTE (11%), pneumonia (4%), rash, and ILD / pneumonitis (2.9% each), COVID-19 (2.4%), pleural effusion and infusion-related reaction (2.1% each). Fatal adverse reactions occurred in 7% of patients who received RYBREVANT in combination with lazertinib 148103693.007525 / JBI6936 due to death not otherwise specified (1.2%); sepsis and respiratory failure (1% each); pneumonia, myocardial infarction and sudden death (0.7% each); cerebral infarction, pulmonary embolism (PE), and COVID-19 infection (0.5% each); and ILD / pneumonitis, acute respiratory distress syndrome (ARDS), and cardiopulmonary arrest (0.2% each).

[0469] Permanent discontinuation of RYBREVANT due to an adverse reaction occurred in 34% of patients. Adverse reactions which resulted in permanent discontinuation in ≥ 1% of patients included rash, infusion-related reactions, nail toxicity, VTE, ILD / pneumonitis, pneumonia, edema, hypoalbuminemia, fatigue, paresthesia and dyspnea.

[0470] Dosage interruption of RYBREVANT due to an adverse reaction occurred in 88% of patients. Adverse reactions which required dosage interruption in ≥ 5% of patients were infusion-related reactions, rash, nail toxicity, COVID-19, VTE, increased ALT, edema, and hypoalbuminemia.

[0471] Dose reductions of RYBREVANT due to an adverse reaction occurred in 46% of patients. Adverse reactions requiring dose reductions in ≥ 5% of patients were rash and nail toxicity.

[0472] The most common adverse reactions (≥ 20%) were rash, nail toxicity, infusion- related reaction, musculoskeletal pain, stomatitis, edema, VTE, paresthesia, fatigue, diarrhea, constipation, COVID-19, hemorrhage, dry skin, decreased appetite, pruritus, and nausea. The most common Grade 3 or 4 laboratory abnormalities (≥ 2%) were decreased albumin, decreased sodium, increased ALT, decreased potassium, decreased hemoglobin, increased AST, increased GGT, and increased magnesium.

[0473] Table 31 summarizes the adverse reactions (≥ 10%) in MARIPOSA. 149103693.007525 / JBI6936 Table 31: Adverse Reactions (≥ 10%) in Patients with NSCLC with Exon 19 Deletion or Exon 21 L858R Substitution Mutations in MARIPOSA RYREVANT in combination with lazertinib Osimertinib 421 42 4150103693.007525 / JBI6936 * Grouped terms + Applicable for RYBREVANT only

[0474] Clinically relevant adverse reactions in < 10% of patients who received RYBREVANT in combination with lazertinib included ILD / pneumonitis (3.1%).

[0475] Table 32 summarizes the laboratory abnormalities in MARIPOSA. Table 32: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with NSCLC with EGFR Exon 19 Deletion or Exon 21 L858R Substitution Mutations in MARIPOSA+RYBREVANT in combination with lazertinib Osimertinib 4p p . Previously Treated Non-Small Cell Lung Cancer (NSCLC) with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations

[0476] The safety data described below reflect exposure to RYBREVANT in combination with carboplatin and pemetrexed was evaluated in MARIPOSA-2 [see Clinical Studies (14.2)]. Eligible patients had locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations with progressive disease on or after treatment with osimertinib. Patients with asymptomatic or previously treated and stable intracranial 151103693.007525 / JBI6936 metastases were eligible. Patients received RYBREVANT intravenously at 1400 mg (for patients < 80 kg) or 1750 mg (for patients ≥ 80 kg) once weekly through 4 weeks, then every 3 weeks with a dose of 1750 mg (for patients < 80 kg) or 2100 mg (for patients ≥ 80 kg) starting at Week 7 until disease progression or unacceptable toxicity, in combination with carboplatin at area under the curve AUC 5 once every 3 weeks, for up to 12 weeks, and pemetrexed at 500 mg / m2once every 3 weeks until disease progression or unacceptable toxicity. Among patients who received RYBREVANT (n=130), 52% were exposed for 6 months or longer and 7% were exposed for greater than one year. The median treatment duration was 6.3 months (range: 0 to 14.7 months).

[0477] The median age was 62 years (range: 36 to 84 years); 62% were female; 48% were Asian, 46% were White, 2.3% Black or African American, 1.5% race not reported, 1.5% race unknown, 0.8% Alaska native; 7% were Hispanic or Latino; and 87% had baseline body weight < 80 kg.

[0478] Serious adverse reactions occurred in 32% of patients who received RYBREVANT in combination with carboplatin and pemetrexed. Serious adverse reactions in > 2% of patients included dyspnea (3.1%), thrombocytopenia (3.1%), sepsis (2.3%), and pulmonary embolism (2.3%). Fatal adverse reactions occurred in 2.3% of patients who received RYBREVANT in combination with carboplatin and pemetrexed; these included respiratory failure, sepsis, and ventricular fibrillation (0.8% each).

[0479] Permanent discontinuation of RYBREVANT due to adverse reactions occurred in 11% of patients. The most frequent adverse reactions leading to discontinuation of RYBREVANT in ≥ 5% of patients were infusion-related reactions.

[0480] Dose interruptions of RYBREVANT due to an adverse reaction occurred in 60% of patients. Infusion-related reactions (IRR) requiring infusion interruptions occurred in 52% of patients. Adverse reactions requiring dose interruption in ≥ 5% of patients included infusion-related reaction, rash and fatigue.

[0481] Dose reductions of RYBREVANT due to an adverse reaction occurred in 17% of patients. Adverse reactions requiring dose reductions in ≥ 2% of patients included rash.

[0482] The most common adverse reactions ≥ 20% were rash, infusion-related reactions, fatigue, nail toxicity, nausea, constipation, edema, stomatitis, decreased appetite, musculoskeletal pain, vomiting, and COVID-19. 152103693.007525 / JBI6936

[0483] Table 33 summarizes the adverse reactions in MARIPOSA-2. Table 33: Adverse Reactions (≥ 10%) in Previously Treated Patients with NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations Treated with RYBREVANT in Combination with Carboplatin and Pemetrexed in MARIPOSA-2 RYBREVANT + Ad erse Reaction Carbo latin + Pemetrexed Carbo latin + Pemetrexed 4153103693.007525 / JBI6936

[0484] Clinically relevant adverse reactions in < 10% of patients who received RYBREVANT in combination with carboplatin and pemetrexed include: abdominal pain, hemorrhoids, dizziness, visual impairment, trichomegaly, keratitis, and interstitial lung disease.

[0485] Table 34 summarizes the laboratory abnormalities in MARIPOSA-2. Table 34: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations Treated with RYBREVANT in Combination with Carboplatin and Pemetrexed in MARIPOSA-2 RYBREVANT + Carboplatin + Pemetrexed Carboplatin + Pemetrexed rg ons

[0486] The safety data described below reflect exposure to RYBREVANT in combination with carboplatin and pemetrexed at the recommended dosage in the PAPILLON trial [see Clinical Studies (14.3)] in 151 patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. Among patients who received RYBREVANT in combination with carboplatin and pemetrexed the median exposure was 9.7 months (range: 0.0 to 26.9 months). In patients that received carboplatin and pemetrexed alone, the median exposure was 6.7 months (range 0.0 to 25.3). 154103693.007525 / JBI6936

[0487] The median age was 61 years (range: 27 to 86 years); 56% were female; 64% were Asian, 32% were White, 1.3% were Black or African American, race was not reported in 1.3% of patients; 89% were not Hispanic or Latino; 86% had baseline body weight < 80 kg.

[0488] Serious adverse reactions occurred in 37% of patients who received RYBREVANT in combination with carboplatin and pemetrexed. Serious adverse reactions in ≥ 2% of patients included rash, pneumonia, interstitial lung disease (ILD), pulmonary embolism, vomiting, and COVID-19. Fatal adverse reactions occurred in 7 patients (4.6%) due to pneumonia, cerebrovascular accident, cardio-respiratory arrest, COVID-19, sepsis, and death not otherwise specified.

[0489] Permanent discontinuation of RYBREVANT due to an adverse reaction occurred in 11% of patients. Adverse reactions resulting in permanent discontinuation of RYBREVANT in ≥ 1% of patients were rash and ILD.

[0490] Dose interruptions of RYBREVANT due to an adverse reaction occurred in 64% of patients. Infusion-related reactions (IRR) requiring infusion interruptions occurred in 38% of patients. Adverse reactions requiring dose interruption in ≥ 5% of patients included rash and nail toxicity.

[0491] Dose reductions of RYBREVANT due to an adverse reaction occurred in 36% of patients. Adverse reactions requiring dose reductions in ≥ 5% of patients included rash and nail toxicity.

[0492] The most common adverse reactions (≥ 20%) were rash, nail toxicity, stomatitis, infusion-related reaction, fatigue, edema, constipation, decreased appetite, nausea, COVID-19, diarrhea, and vomiting. The most common Grade 3 to 4 laboratory abnormalities (≥ 2%) were decreased albumin, increased alanine aminotransferase, increased gamma-glutamyl transferase, decreased sodium, decreased potassium, decreased magnesium, and decreases in white blood cells, hemoglobin, neutrophils, platelets, and lymphocytes.

[0493] Table 35 summarizes the adverse reactions in PAPILLON. 155103693.007525 / JBI6936 Table 35: Adverse Reactions (≥ 10%) in Patients with Metastatic NSCLC with Exon 20 Insertion Mutations Who Received RYBREVANT in Combination with Carboplatin and Pemetrexed in PAPILLON RYBREVANT in Combination with Carboplatin2 Grouped Term 156103693.007525 / JBI6936

[0494] Clinically relevant adverse reactions in < 10% of patients who received RYBREVANT in combination with carboplatin and pemetrexed included pulmonary embolism, deep vein thrombosis, skin ulcer, conjunctivitis, and interstitial lung disease (ILD) / pneumonitis.

[0495] Table 36 summarizes the laboratory abnormalities in PAPILLON. Table 36: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with Metastatic NSCLC with EGFR Exon 20 Insertion Mutations Who Received RYBREVANT in Combination with Carboplatin and Pemetrexed in PAPILLON RYBREVANT in Combination with Carboplatin ine e o a o use o ca cu a e e a e va e o o ase o e u e o pa e s with a baseline value and at least one post-treatment value.3The denominator used to calculate the rate varied from 119 to 154 based on the number of patients with a baseline value and at least one post-treatment value. Previously Treated NSCLC Exon 20 Insertion Mutations

[0496] The safety data described below reflect exposure to RYBREVANT at the recommended dosage in 129 patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations in the CHRYSALIS trial [see Clinical Studies (14.4)], whose 157103693.007525 / JBI6936 disease had progressed on or after platinum-based chemotherapy. Among patients who received RYBREVANT, 44% were exposed for 6 months or longer and 12% were exposed for greater than one year.

[0497] The median age was 62 years (range: 36 to 84 years); 61% were female; 55% were Asian, 35% were White, and 2.3% were Black; and 82% had baseline body weight < 80 kg.

[0498] Serious adverse reactions occurred in 30% of patients who received RYBREVANT. Serious adverse reactions in ≥ 2% of patients included pulmonary embolism, pneumonitis / ILD, dyspnea, musculoskeletal pain, pneumonia, and muscular weakness. Fatal adverse reactions occurred in 2 patients (1.5%) due to pneumonia and 1 patient (0.8%) due to sudden death.

[0499] Permanent discontinuation of RYBREVANT due to an adverse reaction occurred in 11% of patients. Adverse reactions resulting in permanent discontinuation of RYBREVANT in ≥ 1% of patients were pneumonia, IRR, pneumonitis / ILD, dyspnea, pleural effusion, and rash.

[0500] Dose interruptions of RYBREVANT due to an adverse reaction occurred in 78% of patients. Infusion-related reactions (IRR) requiring infusion interruptions occurred in 59% of patients. Adverse reactions requiring dose interruption in ≥ 5% of patients included dyspnea, nausea, rash, vomiting, fatigue, and diarrhea.

[0501] Dose reductions of RYBREVANT due to an adverse reaction occurred in 15% of patients. Adverse reactions requiring dose reductions in ≥ 2% of patients included rash and paronychia.

[0502] The most common adverse reactions (≥ 20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting. The most common Grade 3 to 4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased glucose, increased alkaline phosphatase, increased gamma-glutamyl transferase, and decreased sodium.

[0503] Table 37 summarizes the adverse reactions in CHRYSALIS. 158103693.007525 / JBI6936 Table 37: Adverse Reactions (≥ 10%) in Patients with NSCLC with Exon 20 Insertion Mutations Whose Disease Has Progressed on or after Platinum-based Chemotherapy and Received RYBREVANT in CHRYSALIS RYBREVANT1Adverse Reactions (N=129) %)verse react ons were gra e usng verson .

[0504] Clinically relevant adverse reactions in < 10% of patients who received RYBREVANT included ocular toxicity, ILD / pneumonitis, and toxic epidermal necrolysis (TEN).

[0505] Table 38 summarizes the laboratory abnormalities in CHRYSALIS. 159103693.007525 / JBI6936 Table 38: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients With Metastatic NSCLC with EGFR Exon 20 Insertion Mutations Whose Disease Has Progressed on or After Platinum-based Chemotherapy and Who Received RYBREVANT in CHRYSALIS RYBREVANT+Laboratory Abnormality (N=129) ne8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary

[0506] Based on the mechanism of action and findings in animal models, RYBREVANT can cause fetal harm when administered to a pregnant woman. There are no available data on the use of RYBREVANT in pregnant women or animal data to assess the risk of RYBREVANT in pregnancy. Disruption or depletion of EGFR in animal models resulted in impairment of embryo-fetal development including effects on placental, lung, cardiac, skin, and neural development. The absence of EGFR or MET signaling has resulted in embryo lethality, malformations, and post-natal death in animals (see Data). Advise pregnant women of the potential risk to a fetus.

[0507] In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 160103693.007525 / JBI6936 Data Animal Data

[0508] No animal studies have been conducted to evaluate the effects of amivantamab- vmjw on reproduction and fetal development; however, based on its mechanism of action, RYBREVANT can cause fetal harm or developmental anomalies. In mice, EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal / postnatal survival and development. Reduction or elimination of embryo-fetal or maternal EGFR signaling can prevent implantation, can cause embryo-fetal loss during various stages of gestation (through effects on placental development) and can cause developmental anomalies and early death in surviving fetuses. Adverse developmental outcomes were observed in multiple organs in embryos / neonates of mice with disrupted EGFR signaling. Similarly, knock out of MET or its ligand HGF was embryonic lethal due to severe defects in placental development, and fetuses displayed defects in muscle development in multiple organs. Human IgG1 is known to cross the placenta; therefore, amivantamab-vmjw has the potential to be transmitted from the mother to the developing fetus. 8.2 Lactation Risk Summary

[0509] There are no data on the presence of amivantamab-vmjw in human milk, the effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions from RYBREVANT in breast-fed children, advise women not to breastfeed during treatment with RYBREVANT and for 3 months after the last dose. 8.3 Females and Males of Reproductive Potential

[0510] RYBREVANT can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing

[0511] Verify pregnancy status of females of reproductive potential prior to initiating RYBREVANT. 161103693.007525 / JBI6936 Contraception Females

[0512] Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of RYBREVANT. 8.4 Pediatric Use

[0513] The safety and efficacy of RYBREVANT have not been established in pediatric patients. 8.5 Geriatric Use • Of the 421 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with lazertinib in the MARIPOSA study, 45% were ≥ 65 years of age and 12% were ≥ 75 years of age. • Of the 130 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with carboplatin and pemetrexed in the MARIPOSA-2 study, 40% were ≥ 65 years of age and 10% were ≥ 75 years of age. • Of the 151 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with carboplatin and pemetrexed in the PAPILLON study, 37% were ≥ 65 years of age and 8% were ≥ 75 years of age. • Of the 302 patients with locally advanced or metastatic NSCLC treated with RYBREVANT as a single agent in the CHRYSALIS study, 39% were ≥ 65 years of age and 11% were ≥ 75 years of age.

[0514] No clinically important differences in safety or efficacy were observed between patients who were ≥ 65 years of age and younger patients. 11 DESCRIPTION

[0515] Amivantamab-vmjw is a low-fucose human immunoglobulin G1-based bispecific antibody directed against the EGF and MET receptors, produced by mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology that has a molecular weight of approximately 148 kDa. RYBREVANT®(amivantamab-vmjw) injection for 162103693.007525 / JBI6936 intravenous infusion is a sterile, preservative-free, colorless to pale yellow solution in single-dose vials. The pH is 5.7.

[0516] Each RYBREVANT vial contains 350 mg (50 mg / mL) amivantamab-vmjw, EDTA disodium salt dihydrate (0.14 mg), L-histidine (2.3 mg), L-histidine hydrochloride monohydrate (8.6 mg), L-methionine (7 mg), polysorbate 80 (4.2 mg), sucrose (595 mg), and water for injection, USP. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action

[0517] Amivantamab-vmjw is a bispecific antibody that binds to the extracellular domains of EGFR and MET.

[0518] In in vitro and in vivo studies amivantamab-vmjw was able to disrupt EGFR and MET signaling functions in mutation models of exon 19 deletions, exon 21 L858R substitutions, and exon 20 insertions through blocking ligand binding or degradation of EGFR and MET. The presence of EGFR and MET on the surface of tumor cells also allows for targeting of these cells for destruction by immune effector cells, such as natural killer cells and macrophages, through antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms, respectively. Treatment with amivantamab in combination with lazertinib increased in vivo anti-tumor activity compared to either agent alone in a mouse xenograft model of human NSCLC with an EGFR L858R mutation. 12.2 Pharmacodynamics

[0519] The exposure-response relationship and time-course of pharmacodynamic response of amivantamab-vmjw have not been fully characterized in patients with NSCLC with EGFR mutations. 12.3 Pharmacokinetics

[0520] Amivantamab-vmjw exposures increased proportionally over a dosage range from 350 to 1750 mg (0.33 to 1.7 times the lowest approved recommended dosage) when RYBREVANT was administered as a single agent. Steady-state concentrations of RYBREVANT were reached by week 13 for both the 3-week and 2-week dosing regimen and the systemic accumulation was 1.9-fold. 163103693.007525 / JBI6936 Distribution

[0521] The amivantamab-vmjw mean (%CV) volume of distribution is 5 (24%) L. Elimination

[0522] The mean (% CV) linear clearance (CL) is 0.26 L / day (30%) and mean terminal half-life is 14 days (33%). Specific Populations

[0523] No clinically meaningful differences in the pharmacokinetics of amivantamab-vmjw were observed based on age (range: 21-88 years), body weight (31 to 140 kg), sex, race (White, Asian or Black or African American) and ethnicity (Hispanic / Latino or not Hispanic / Latino), mild or moderate renal impairment (eGFR 30 to 89 mL / min) or mild hepatic impairment [(total bilirubin ≤ ULN and AST > ULN) or (ULN < total bilirubin ≤ 1.5 times ULN)]. The effect of severe renal impairment (eGFR 15 to 29 mL / min), end-stage renal disease (eGFR < 15 mL / min) or moderate to severe hepatic impairment (total bilirubin > 1.5 times ULN and any AST) on amivantamab-vmjw pharmacokinetics has not been studied. Body Weight

[0524] Increases in body weight increased the volume of distribution and clearance of amivantamab-vmjw. Amivantamab-vmjw exposures are 30 to 40% lower in patients who weighed ≥ 80 kg compared to patients with body weight < 80 kg at the same dose. Exposures of amivantamab-vmjw were comparable between patients who weighed < 80 kg and received 1050 mg dose and patients who weighed ≥ 80 kg and received 1400 mg dose. 12.6 Immunogenicity

[0525] The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies (ADA) in the studies described below with the incidence of anti-drug antibodies in other studies, including those of amivantamab-vmjw or amivantamab products.

[0526] During treatment in studies CHRYSALIS, CHRYSALIS-2, PAPILLON, MARIPOSA, and MARIPOSA-2 (up to 39 months), 4 of the 1862 (0.2%) patients who received RYBREVANT as a single agent or in combination developed a treatment-emergent anti- 164103693.007525 / JBI6936 amivantamab-vmjw antibodies. Given the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, safety or efficacy of RYBREVANT is unknown. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

[0527] No studies have been performed to assess the potential of amivantamab-vmjw for carcinogenicity or genotoxicity. Fertility studies have not been performed to evaluate the potential effects of amivantamab-vmjw. In 6-week and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs. 14 CLINICAL STUDIES 14.1 First Line Treatment of NSCLC with Exon 19 deletion or Exon 21 L858R Substitution Mutation - MARIPOSA

[0528] The efficacy of RYBREVANT, in combination with lazertinib, was evaluated in MARIPOSA [NCT04487080], a randomized, active-controlled, multicenter trial. Eligible patients were required to have untreated locally advanced or metastatic NSCLC with either exon 19 deletions or exon 21 L858R substitution EGFR mutations identified by local testing, not amenable to curative therapy. Patients with asymptomatic or previously treated and stable intracranial metastases w...

Claims

103693.007525 / JBI6936 What is claimed is:

1. A method of reducing an adverse reaction associated with the use of amivantamab in combination with carboplatin and pemetrexed for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the method comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, and who experiences a grade 1 or grade 2 infusion-related adverse reaction: interrupting the intravenous amivantamab infusion, monitoring the subject until the grade 1 or grade 2 infusion-related adverse reaction resolves, resuming the intravenous amivantamab infusion at 50% of the infusion rate at which the grade 1 or grade 2 infusion-related adverse reaction occurred, and, if there are no additional infusion-related adverse reactions after 30 minutes, increasing the infusion rate; who experiences a grade 3 infusion-related adverse reaction: interrupting the intravenous amivantamab infusion, monitoring the subject until the grade 3 infusion- related adverse reaction resolves, resuming the intravenous amivantamab infusion at 50% of the infusion rate at which the grade 3 infusion-related adverse reaction occurred, and, if there are no additional infusion-related adverse reactions after 30 minutes, increasing the infusion rate; or who experiences a grade 4 infusion-related adverse reaction: permanently discontinuing administration of the amivantamab.

2. The method of claim 1, comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, and who experiences a grade 1 or grade 2 infusion-related adverse reaction: interrupting the 181103693.007525 / JBI6936 intravenous amivantamab infusion, monitoring the subject until the grade 1 or grade 2 infusion-related adverse reaction resolves, resuming the intravenous amivantamab infusion at 50% of the infusion rate at which the grade 1 or grade 2 infusion-related adverse reaction occurred, and, if there are no additional infusion-related adverse reactions after 30 minutes, increasing the infusion rate.

3. The method of claim 1, comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, and who experiences a grade 3 infusion-related adverse reaction: interrupting the intravenous amivantamab infusion, monitoring the subject until the grade 3 infusion-related adverse reaction resolves, resuming the intravenous amivantamab infusion at 50% of the infusion rate at which the grade 3 infusion-related adverse reaction occurred, and, if there are no additional infusion-related adverse reactions after 30 minutes, increasing the infusion rate.

4. The method of any one of the previous claims, further comprising, for grade 1, grade 2, or grade 3 infusion-related reactions, administering an antihistamine, an antipyretic, and a glucocorticoid prior to resuming the intravenous amivantamab infusion.

5. The method of claim 4, wherein the antihistamine comprises diphenhydramine.

6. The method of claim 4, wherein the antipyretic comprises acetaminophen.

7. The method of claim 4, wherein the glucocorticoid comprises dexamethasone.

8. The method of claim 3, further comprising permanently discontinuing administration of the amivantamab if the grade 3 infusion-related adverse reaction is a recurrent grade 3 infusion-related adverse reaction.

9. The method of claim 1, comprising: 182103693.007525 / JBI6936 to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, and who experiences a grade 4 infusion-related adverse reaction: permanently discontinuing administration of the amivantamab.

10. The method of any one of the previous claims, wherein the therapeutically effective amount of amivantamab comprises for subjects who weigh less than 80 kg, 1400 mg weekly from week 1 to week 4 and 1750 mg every three weeks starting at week 7 for subjects who weigh greater than or equal to 80 kg, 1750 mg weekly from week 1 to week 4 and 2100 mg every three weeks starting at week 7; the therapeutically effective amount of pemetrexed comprises 500 mg / m2every three weeks; and the therapeutically effective amount of carboplatin comprises AUC 5 every three weeks for up to 12 weeks.

11. A method of reducing an adverse reaction associated with the use of amivantamab in combination with carboplatin and pemetrexed for the treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the method comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who is suspected of experiencing interstitial lung disease / pneumonitis of any grade: withholding administration of the amivantamab; or who experiences interstitial lung disease / pneumonitis of any grade: permanently discontinuing administration of the amivantamab. 183103693.007525 / JBI6936 12. The method of claim 11, comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who is suspected of experiencing interstitial lung disease / pneumonitis of any grade: withholding administration of the amivantamab.

13. The method of claim 11, comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences interstitial lung disease / pneumonitis of any grade: permanently discontinuing administration of the amivantamab.

14. The method of any one of claims 11-13, wherein the therapeutically effective amount of amivantamab comprises for subjects who weigh less than 80 kg, 1400 mg weekly from week 1 to week 4 and 1750 mg every three weeks starting at week 7 for subjects who weigh greater than or equal to 80 kg, 1750 mg weekly from week 1 to week 4 and 2100 mg every three weeks starting at week 7; the therapeutically effective amount of pemetrexed comprises 500 mg / m2every three weeks; and the therapeutically effective amount of carboplatin comprises AUC 5 every three weeks for up to 12 weeks.

15. A method of reducing an adverse reaction associated with the use of amivantamab in combination with carboplatin and pemetrexed for the treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the method comprising: 184103693.007525 / JBI6936 to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences a grade 1 dermatologic adverse reaction: reassessing after two weeks; who experiences a grade 2 dermatologic adverse reaction: reassessing after two weeks, and if the grade 2 dermatologic adverse reaction does not improve, administering a reduced dose of the amivantamab to the subject; who experiences a grade 3 dermatologic adverse reaction: withholding the amivantamab and resuming administration of the amivantamab at a reduced dose if the grade 3 dermatologic adverse reaction becomes a grade 2 or lower dermatologic adverse reaction, or permanently discontinuing the treatment if no improvement in the grade 3 dermatologic adverse reaction occurs within 2 weeks; or who experiences a grade 4 dermatologic adverse reaction or severe bullous, blistering, or exfoliating skin: permanently discontinuing administration of the amivantamab.

16. The method of claim 15, comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences a grade 1 dermatologic adverse reaction: reassessing after two weeks.

17. The method of claim 15, comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has 185103693.007525 / JBI6936 progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences a grade 2 dermatologic adverse reaction: reassessing after two weeks, and if the grade 2 dermatologic adverse reaction does not improve, administering a reduced dose of the amivantamab to the subject.

18. The method of claim 15, comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences a grade 3 dermatologic adverse reaction: withholding the amivantamab and resuming administration of the amivantamab at a reduced dose if the grade 3 dermatologic adverse reaction becomes a grade 2 or lower dermatologic adverse reaction, or permanently discontinuing the treatment if no improvement in the grade 3 dermatologic adverse reaction occurs within 2 weeks.

19. The method of any one of claims 15-18, wherein the reduced dose of amivantamab comprises 1050 mg or 700 mg if the adverse reactions occurred at an amivantamab dose of 1400 mg, 1400 mg or 1050 mg if the adverse reactions occurred at an amivantamab dose of 1750 mg, or 1750 mg or 1400 mg if the adverse reactions occurred at an amivantamab dose of 2100 mg.

20. The method of any one of claims 15-19, further comprising administering an antihistamine and an antipyretic prior to resuming the intravenous amivantamab infusion.

21. The method of claim 20, wherein the antihistamine comprises diphenhydramine and the antipyretic comprises acetaminophen.

22. The method of claim 15, comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has 186103693.007525 / JBI6936 progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences a grade 4 dermatologic adverse reaction or severe bullous, blistering, or exfoliating skin: permanently discontinuing administration of the amivantamab.

23. The method of any one of claims 15-22, wherein the therapeutically effective amount of amivantamab comprises for subjects who weigh less than 80 kg, 1400 mg weekly from week 1 to week 4 and 1750 mg every three weeks starting at week 7 for subjects who weigh greater than or equal to 80 kg, 1750 mg weekly from week 1 to week 4 and 2100 mg every three weeks starting at week 7; the therapeutically effective amount of pemetrexed comprises 500 mg / m2every three weeks; and the therapeutically effective amount of carboplatin comprises AUC 5 every three weeks for up to 12 weeks.

24. A method of reducing an adverse reaction associated with the use of amivantamab in combination with carboplatin and pemetrexed for the treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the method comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences at least one other grade 3 adverse reaction: withholding amivantamab until the at least one other grade 3 adverse reaction reduces to less than or equal to grade 1 or baseline and resuming the amivantamab at the same dose if the subject recovers from the grade 3 adverse reaction within 1 week; resuming the amivantamab at a reduced dose if the subject recovers from the grade 3 adverse reaction after 1 week but within 4 weeks; or permanently discontinuing the amivantamab if the subject does not recover from the grade 3 adverse reaction within 4 weeks; or 187103693.007525 / JBI6936 who experiences at least one other grade 4 adverse reaction: withholding amivantamab until the at least one other grade 4 adverse reaction reduces to less than or equal to grade 1 or baseline and resuming the amivantamab at a reduced dose if the subject recovers from the grade 4 adverse reaction within 4 weeks; or permanently discontinuing the amivantamab if the subject does not recover from the grade 4 adverse reaction within 4 weeks or if the grade 4 infusion-related adverse reaction is a recurrent grade 4 infusion-related adverse reaction.

25. The method of claim 24, comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences at least one other grade 3 adverse reaction: withholding amivantamab until the at least one other grade 3 adverse reaction reduces to less than or equal to grade 1 or baseline and resuming the amivantamab at the same dose if the subject recovers from the grade 3 adverse reaction within 1 week; resuming the amivantamab at a reduced dose if the subject recovers from the grade 3 adverse reaction after 1 week but within 4 weeks; or permanently discontinuing the amivantamab if the subject does not recover from the grade 3 adverse reaction within 4 weeks.

26. The method of claim 24, comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of an intravenous carboplatin infusion and a therapeutically effective amount of an intravenous pemetrexed infusion to treat the locally advanced or metastatic NSCLC, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor and who experiences at least one other grade 4 adverse reaction: withholding amivantamab until the at least one other grade 4 adverse reaction reduces to less than or equal to grade 1 or baseline and 188103693.007525 / JBI6936 resuming the amivantamab at a reduced dose if the subject recovers from the grade 4 adverse reaction within 4 weeks; or permanently discontinuing the amivantamab if the subject does not recover from the grade 4 adverse reaction within 4 weeks or if the grade 4 infusion-related adverse reaction is a recurrent grade 4 infusion-related adverse reaction.

27. The method of any one of claims 24-26, wherein the therapeutically effective amount of amivantamab comprises for subjects who weigh less than 80 kg, 1400 mg weekly from week 1 to week 4 and 1750 mg every three weeks starting at week 7 for subjects who weigh greater than or equal to 80 kg, 1750 mg weekly from week 1 to week 4 and 2100 mg every three weeks starting at week 7; the therapeutically effective amount of pemetrexed comprises 500 mg / m2every three weeks; and the therapeutically effective amount of carboplatin comprises AUC 5 every three weeks for up to 12 weeks.

28. The method of any one of claims 24-27, wherein the reduced dose of amivantamab comprises 1050 mg or 700 mg if the adverse reactions occurred at an amivantamab dose of 1400 mg, 1400 mg or 1050 mg if the adverse reactions occurred at an amivantamab dose of 1750 mg, or 1750 mg or 1400 mg if the adverse reactions occurred at an amivantamab dose of 2100 mg.

29. The method of any one of claims 24-28, further comprising administering an antihistamine and an antipyretic prior to resuming the intravenous amivantamab infusion.

30. The method of claim 29, wherein the antihistamine comprises diphenhydramine and the antipyretic comprises acetaminophen.

31. A method of treating locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations in a subject whose NSCLC has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the method comprising administering to the subject an approved drug product comprising amivantamab, in combination with carboplatin and pemetrexed. 189103693.007525 / JBI6936 32. A method of improving median progression free survival (PFS) in a population of subjects having locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations whose NSCLC has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the method comprising administering to the population of subjects an approved drug product comprising amivantamab, in combination with carboplatin and pemetrexed.

33. The method of claim 32, wherein the median PFS is 5.6 months to 8.4 months.

34. The method of claim 32 or 33, wherein the median PFS is 6.3 months.

35. A method of improving overall response rate (ORR) in a population of subjects having locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations whose NSCLC has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the method comprising administering to the population of subjects an approved drug product comprising amivantamab, in combination with carboplatin and pemetrexed.

36. The method of claim 35, wherein the ORR is 44% to 62%.

37. The method of claim 35 or 36, wherein the ORR is 53%.

38. A method of improving median duration of response (DOR) in a population of subjects having locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations whose NSCLC has progressed on or after treatment with an EGFR tyrosine kinase inhibitor, the method comprising administering to the population of subjects an approved drug product comprising amivantamab, in combination with carboplatin and pemetrexed.

39. The method of claim 36, wherein the DOR is greater than or equal to 5.5 months.

40. The method of claim 38 or 39, wherein the DOR is 6.9 months. 190103693.007525 / JBI6936 41. The method of any one of claims 31-40, comprising administering amivantamab intravenously at 1,400 mg for patients who weigh less than 80 kg or 1,750 mg for patients who weigh greater than or equal to 80 kg once weekly through 4 weeks, then every 3 weeks with a dose of 1,750 mg for patients who weigh less than 80 kg or 2,100 mg for patients who weigh great than or equal to 80 kg starting at Week 7 until disease progression or unaccepztable toxicity.

42. The method of claim 41, comprising administering 500 mg / m2of pemetrexed every three weeks until disease progression or unacceptable toxicity and administering AUC 5 of carboplatin every three weeks for up to 12 weeks. 191

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