Treatment of locally advanced or metastatic EGFR-mutated non-small cell lung cancer

Abstract

Disclosed herein are methods of improving the safety and efficacy of a therapy comprising a bispecific epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody for the treatment of locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC).

Description

Treatment Of Locally Advanced Or Metastatic EGFR-Mutated Non-Small Cell Lung Cancer CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 652,818, filed on 29 May 2024 and U.S. Provisional Application No.63 / 753,028, filed on 3 February 2025, each of which is incorporated herein by reference in their entirety. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing, which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on May 23, 2025, is named JBI6908WOPCT1_SL.xml, and is 44,016 bytes in size. TECHNICAL FIELD

[0003] Disclosed herein are methods of improving the safety and efficacy of a therapy comprising a bispecific epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody for the treatment of locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC). BACKGROUND

[0004] The role of both epidermal growth factor receptor (EGFR, ErbB1 or HER1) and hepatocyte growth factor receptor (c-Met) in cancer is well established, making these targets attractive for cancer therapy. Both receptors signal through the same survival and anti-apoptotic pathways (ERK and AKT).

[0005] Worldwide, lung cancer is one of the most common cancers, with non- small cell lung cancer (NSCLC) making up 80 to 85 percent of all lung cancer cases. Among the most common driver mutations in NSCLC are alterations in EGFR. EGFR exon 19 deletion (ex19del) or EGFR exon 21 L858R mutations are the most common EGFR mutations. 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. Most tumors that become resistant to EGFR TKIs increase c-Met expression, amplify the c-Met gene, or increase its only known ligand, Hepatocyte Growth Factor.SUMMARY

[0006] Disclosed herein are methods of improving the safety and efficacy of a therapy comprising a bispecific epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody for the treatment of locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) in a subject or a population of subjects, the methods comprising: administering to the subject or the population of subjects: a therapeutically effective amount of a subcutaneous composition comprising hyaluronidase and a bispecific EGFR / c-Met antibody, the antibody comprising: a first heavy chain (HC1) comprising a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a first light chain (LC1) comprising a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6, a second heavy chain (HC2) comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, and a second light chain (LC2) comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 12, wherein the improvement in safety and efficacy comprises an improvement in median duration of response (DoR), an improvement in median progression free survival (PFS), an improvement in overall survival (OS), a reduction in rate of venous thromboembolism (VTE), or any combination thereof, and wherein the improvement in safety and efficacy is relative to the safety and efficacy of a reference therapy comprising a bispecific EGFR / c-Met antibody administered to a reference subject or reference population of subjects, the referencesubject or reference population having been administered a therapeutically effective amount of an intravenous composition comprising the bispecific EGFR / c-Met antibody without hyaluronidase, instead of the subcutaneous composition. BRIEF DESCRIPTIONS OF THE DRAWINGS

[0007] 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:

[0008] FIG.1 illustrates the PALOMA-3 study design.aAll patients were required to undergo brain imaging at baseline; subsequent imaging was performed every 6 weeks in patients with baseline brain metastases or as clinically indicated.bSC amivantamab was co-formulated with hyaluronidase (rHuPH20) at a concentration of 160 mg / mL.cC1 for IV: Days 1-2 (Day 2 applies to IV split dose only [350mg on Day 1 and the remainder on Day 2]), 8, 15, and 22; C1 for SC: Days 1, 8 , 15, and 22; After C1 for all: Days 1, 15 (28-day cycles).dFor calculating primary and key secondary outcomes, it was estimated that a sample size of 400 patients would provide >95% power for a one-sided alpha of 0.05 allocated to each of the co-primary endpoints, and 80% power with a one-sided alpha of 0.025 allocated to ORR. A hierarchical testing approach at a two-sided alpha of 0.05 was used for the co-primary endpoints (noninferiority), followed by objective response rate (noninferiority) and progression-free survival (superiority), with a combined two-sided alpha of 0.05.eTwo definitions of the same endpoint was used as per regional health authority guidance.fMeasured between C2D1 and C2D15. AUC, area under the concentration-time curve; C, cycle; Ctrough, observed serum concentration of amivantamab at steady state; D, day; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; Ex19del, Exon 19 deletion; IV, intravenous; min, minutes; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PO, orally; PFS, progression free survival; PS, performance status; SC, subcutaneous.

[0009] FIG.2 illustrates the Consolidated Standards of Reporting Trials (CONSORT) diagram of patient disposition.

[0010] FIG.3 illustrates time to amivantamab discontinuation. Shown is a Kaplan-Meier estimate of time to treatment discontinuation. The efficacy populationincluded all patients who had undergone randomization. Tick marks indicate censoring of data.

[0011] FIG.4A, FIG.4B, and FIG.4C illustrate observed concentration-time profiles, Ctrough, and AUCD1-D15of amivantamab. Shown are concentration-time profiles for the subcutaneous and intravenous amivantamab-lazertinib groups (FIG.4A). Also shown are the box plots for the observed Ctroughconcentrations at cycle-2-day-1 and cycle-4-day-1 (FIG.4B) and the AUCD1-D15 of amivantamab (FIG.4C). The upper and lower end of the boxes indicate the 25th and 75th quartiles, the triangles indicate the means, the horizontal lines within the boxes indicate the medians, and the error bars indicate 95% confidence intervals. AUC denotes area under the curve, C cycle, Ctroughtrough concentration, and D day.

[0012] FIG.5A and FIG.5B illustrate the best percentage change from baseline in target lesions. Shown are waterfall plots of the best percent change from baseline in target lesions in the subcutaneous group (FIG.5A) and in the intravenous group (FIG.5B) by investigator assessment. Target lesions were measured as the sum of the longest diameters. The number of patients with measurable disease at baseline was 206 in the subcutaneous group and 212 in the intravenous group; 190 and 195 patients, respectively, had post-baseline tumor assessments. SoD denotes sum of diameters.

[0013] FIG.6A, FIG.6B, and FIG.6C illustrate the objective response forest plot, progression-free survival, and overall survival. Shown is a forest plot of investigator-assessed objective response rate in each patient subgroup by investigator assessment (FIG.6A). Also shown are Kaplan-Meier estimates of progression-free survival (FIG.6B), and overall survival (FIG.6C). The efficacy population included all the patients who had undergone randomization. In FIG.6A, the shaded area indicates 95% confidence intervals for the relative risk in all patients; the subgroup analyses were not part of the hypothesis testing and results are reported without adjustment for multiplicity. In FIG.6B and FIG.6C, the dashed lines indicate the median progression- free survival and overall survival, respectively, in the two groups, and the tick marks indicate censoring of data. Objective response rate and progression-free survival were tested as part of the hierarchical testing approach. The 95% confidence intervals for overall survival were not adjusted for multiplicity and should not be used in place of hypothesis testing. ECOG denotes Eastern Cooperative Oncology Group, and TKI tyrosine kinase inhibitor.

[0014] FIG.7A and FIG.7B illustrate the response duration. Shown is a Kaplan-Meier estimate of response duration among confirmed (FIG.7A) and all (FIG. 7B) responders in the efficacy population. The efficacy population included all patients who had undergone randomization. Included in this analysis were the 55 (confirmed) and 62 (including unconfirmed) responders (out of the 206 patients with measurable disease at baseline by RECIST v1.1) in the subcutaneous group and the 57 (confirmed) and 69 (including unconfirmed) responders (out of 212 patients) in the intravenous group, respectively. Tick marks indicate censoring of data. CI denotes confidence internal, and NE not estimable.

[0015] FIG.8 illustrates infusion-related reactions and infusion-related adverse events. Shown is a two-sided bar plot of infusion-related reactions and infusion-related adverse events occurring in at least 2% of patients. The safety population included all the patients who had undergone randomization and received at least one dose of any trial treatment.

[0016] FIG.9A and FIG.9B illustrate the incidence of infusion-related reactions by treatment cycle. Shown are the proportions of patients who received any study experiencing infusion-related reactions based on treatment cycles. Infusion-related reaction was counted only once per time frame per patient and the event experienced by the patient with the worst toxicity was used.

[0017] FIG.10 illustrates the percentage of patients with venous thromboembolism (VTE).

[0018] FIG.11 illustrates the best response. Subjects without post-baseline tumor assessment were not included. CR, complete response; INV, investigator-assessed; NE, not estimable; PD, progressive disease, PR, partial response; SD, stable disease; SoD, sum of diameters.

[0019] FIG.12 illustrates the duration of response in confirmed responders. Subjects without post-baseline tumor assessment were not included. INV, investigator- assessed; PD, progressive disease, PR, partial response. DETAILED DESCRIPTION

[0020] 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 theterminology 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.

[0021] Unless specifically stated otherwise, any description as to a possible mechanism or mode of action or reason for improvement is meant to be illustrative only, and the disclosed methods are not to be constrained by the correctness or incorrectness of any such suggested mechanism or mode of action or reason for improvement.

[0022] Where a range of numerical values is recited or established herein, the range includes the endpoints thereof and all the individual integers and fractions within the range, and also includes each of the narrower ranges therein formed by all the various possible combinations of those endpoints and internal integers and fractions to form subgroups of the larger group of values within the stated range to the same extent as if each of those narrower ranges was explicitly recited. Where a range of numerical values is stated herein as being greater than a stated value, the range is nevertheless finite and is bounded on its upper end by a value that is operable within the context of the methods as described herein. Where a range of numerical values is stated herein as being less than a stated value, the range is nevertheless bounded on its lower end by a non-zero value. It is not intended that the scope of the methods be limited to the specific values recited when defining a range. All ranges are inclusive and combinable.

[0023] It is to be appreciated that certain features of the disclosed methods which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.

[0024] As used herein, the singular forms “a,” “an,” and “the” include the plural.

[0025] Various terms relating to aspects of the description are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definitions provided herein.

[0026] When values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. Reference to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise.

[0027] As used herein, “about” when used in reference to numerical ranges, cutoffs, or specific values is used to indicate that the recited values may vary by up to as much as 10% from the listed value. As many of the numerical values used herein are experimentally determined, it should be understood by those skilled in the art that such determinations can, and often times will, vary among different experiments. The values used herein should not be considered unduly limiting by virtue of this inherent variation. Thus, the term “about” is used to encompass variations of ± 10% or less, variations of ± 5% or less, variations of ± 1% or less, variations of ± 0.5% or less, or variations of ± 0.1% or less from the specified value.

[0028] The term “comprising” is intended to include examples encompassed by the terms “consisting essentially of” and “consisting of;” similarly, the term “consisting essentially of” is intended to include examples encompassed by the term “consisting of.”

[0029] “Bispecific EGFR / c-Met antibody” refers to an antibody molecule having an EGFR binding arm and a c-Met binding arm. The EGFR and c-Met binding arms can comprise full length heavy chains and light chains or antigen-binding fragments thereof. “Antigen-binding fragments” refers to a portion of the bispecific antibody that retains the antigen binding properties of the full-length antibody. Exemplary antibody fragments are heavy chain complementarity determining regions (HCDR) 1, 2, and 3, light chain complementarity determining regions (LCDR) 1, 2, and 3, a heavy chain variable region (VH), or a light chain variable region (VL). Antibody fragments include: a Fab fragment, a monovalent fragment consisting of the VL, VH, constant light (CL), and (constant heavy 1) CH1 domains; a F(ab)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the VH and CHI domains; a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; and a domain antibody (dAb) fragment (Ward et al., Nature 341:544- 546, 1989), which consists of a VH domain. VH and VL domains can be engineered and linked together via a synthetic linker to form various types of single chain antibody designs where the VH / VL domains 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’l Pub. Nos. WO1998 / 44001, WO1988 / 01649, WO1994 / 13804, and WO1992 / 01047. These antibody fragments are obtained using techniques well known to those of skill in the art, and the fragments are screened for utility in the same manner as are full lengthantibodies. The antigen binding sites are defined using various terms: (i) Complementarity Determining Regions (CDRs), three in the VH (HCDR1, HCDR2, HCDR3), and three in the VL (LCDR1, LCDR2, LCDR3) are based on sequence variability (Wu and Kabat J Exp Med 132:211-50, 1970; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991); and (ii) “Hypervariable regions” (“HVR” or “HV”), three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3) refer to the regions of the antibody variable domains which are hypervariable in structure as defined by Chothia and Lesk (Chothia and Lesk Mol Biol 196:901-17, 1987). Other terms include “IMGT- CDRs” (Lefranc et al., Dev Comparat Immunol 27:55-77, 2003) and “Specificity Determining Residue Usage” (SDRU) (Almagro Mol Recognit 17:132-43, 2004). The International ImMunoGeneTics (IMGT) database (www_imgt) provides a standardized numbering and definition of antigen-binding sites. The correspondence between CDRs, HVs and IMGT delineations is described in Lefranc et al., Dev Comparat Immunol 27:55-77, 2003.

[0030] Immunoglobulins can be assigned to five major classes, namely 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 can 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. The disclosed bispecific EGFR / c-Met antibodies can be murine, human, human-adapted, humanized, and chimeric antibodies.

[0031] The term “biosimilar” (of an approved reference product / biological drug, i.e., reference listed drug such as amivantamab) refers to a biological product that is highly similar to the reference product notwithstanding minor differences in clinically inactive components with no clinically meaningful differences between the biosimilar and the reference product 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 product notwithstanding minor differences in clinically inactive components; (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 extent 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.

[0032] “Hyaluronidase” refers to a class of enzymes that degrade hyaluronan. Hyaluronidases are endoglycosidases used to increase the dispersion and absorption of other co-administered drugs when administered subcutaneously (e.g., subcutaneous injections, subcutaneous infusion such as hypodermoclysis). Hyaluronidases include, but are not limited to, bacterial hyaluronidases (EC 4.2.2.1 or EC 4.2.99.1), hyaluronidases from leeches, other parasites and crustaceans (EC 3.2.1.36), and mammalian-type hyaluronidases (EC 3.2.1.35). Hyaluronidase (recombinant human) has a molecular weight of approximately 61 kDa. Hyaluronidases include those of non-human origin including, but not limited to, murine, canine, feline, leporine, avian, bovine, ovine, porcine, equine, piscine, ranine, bacterial, and any from leeches, other parasites, and crustaceans. Exemplary human hyaluronidases include HYAL1, HYAL2, HYAL3, HYAL4, and PH20. Also included amongst hyaluronidases are soluble hyaluronidases, including, ovine and bovine PH20, and soluble forms of PH20. Exemplary hyaluronidases include those set forth in U.S. Pub. No.2013 / 0302275, which is incorporated by reference herein, including, for example, hyaluronidases set forth as SEQ ID NOs: SEQ ID NOS: 6, 7-31, 69, 70, 71, 72, 856-861, 869-921 from U.S. Pub.No.2013 / 0302275 (which are incorporated herein by reference), mature forms thereof (lacking the signal sequence), allelic variants thereof, and truncated forms thereof that exhibit hyaluronidase activity, including C-terminal truncated variants that are soluble.

[0033] As used herein, PH20 refers to a type of hyaluronidase that occurs in sperm and is neutral-active.

[0034] Soluble PH20 refers to a polypeptide characterized by its solubility under physiological conditions. Generally, a soluble PH20 lacks all or a portion of a glycophosphatidyl anchor (GPI) attachment sequence, or does not otherwise sufficiently anchor to the cell membrane. For example, a soluble PH20 can be a C-terminally truncated variant of a PH20 lacking a contiguous sequence of amino acids that corresponds to all or a portion of a GPI anchor attachment sequence. Hence, upon expression from a cell, a soluble PH20 is secreted into the medium.

[0035] Soluble human PH20 (sHuPH20) includes human PH20 polypeptides that lack a contiguous sequence of amino acids from the C-terminus of human PH20 that includes all or a portion of the GPI anchor sequence (C-terminally truncated PH20 polypeptides) such that upon expression, the polypeptides are soluble under physiological conditions. For example, soluble human PH20 polypeptides are C- terminally truncated polypeptides of human PH20 in its precursor form or in its mature form lacking the signal sequence, or allelic variants thereof as set forth in SEQ ID NOs: 26-32 herein and as disclosed in U.S. Pub. No.20130302275 as SEQ ID NOs: 6, 7, and 68-72 of that reference which are incorporated herein by reference.

[0036] U.S. Pub. No.2004 / 0268425, which is incorporated by reference herein, describes members of the soluble, neutral active Hyaluronidase Glycoprotein family, particularly the human soluble PH-20 Hyaluronidase Glycoproteins (also referred to as sHASEGPs). U.S. Pub. No.20100143457, which is incorporated herein by reference, describes shorter active soluble PH20 (i.e., 36-469, -470, 471, and longer forms i.e., 36- 495 to 36-500) the sequences of which are also incorporated herein by reference.

[0037] Hyaluronidase activity refers to the ability to enzymatically catalyze the cleavage of hyaluronic acid. The United States Pharmacopeia (USP) XXII assay for hyaluronidase determines hyaluronidase activity indirectly by measuring the amount of higher molecular weight hyaluronic acid, or hyaluronan, (HA) substrate remaining after the enzyme is allowed to react with the HA for 30 min at 37 °C (USP XXII-NF XVII (1990) 644-645 United States Pharmacopeia Convention, Inc, Rockville, MD). A Reference Standard solution can be used in an assay to ascertain the relative activity, inunits, of any hyaluronidase. In vitro assays to determine the hyaluronidase activity of hyaluronidases, such as PH20, including modified PH20 polypeptides, are known in the art and described herein. Exemplary assays include the microturbidity assay that measures cleavage of hyaluronic acid by hyaluronidase indirectly by detecting the insoluble precipitate formed when the uncleaved hyaluronic acid binds with serum albumin. Reference Standards can be used, for example, to generate a standard curve to determine the activity in Units of the hyaluronidase being tested.

[0038] Specific activity refers to Units of activity per mg protein. The milligrams of hyaluronidase is defined by the absorption of a solution of at 280 nm assuming a molar extinction coefficient of approximately 1.7, in units of M-1 cm-1.

[0039] Neutral active refers to the ability of a PH20 polypeptide to enzymatically catalyze the cleavage of hyaluronic acid at neutral pH, such as at a pH between or about between pH 6.0 to pH 7.8.

[0040] Human recombinant DNA-derived hyaluronidase enzyme PH20 (rHuPH20) is a glycosylated single-chain protein produced by CHO cells containing a DNA plasmid encoding residues 36-482 of SEQ ID NO: 26, resulting in a heterogeneous mixture of soluble forms of human hyaluronidase (PH20) that begin at residue 36 and terminate at residues 478, 479, 480, 481, and 482 of SEQ ID NO: 26, including any one of SEQ ID NOs: 21, 25, 24, 23 and 22..

[0041] “Variant” refers to a polypeptide or a polynucleotide that differs from a reference polypeptide or a reference polynucleotide by one or more modifications for example, substitutions, insertions, or deletions.

[0042] “Treat,” “treatment,” and like terms include reducing the severity and / or frequency of symptoms, eliminating symptoms and / or the underlying cause of the symptoms, reducing the frequency or likelihood of symptoms and / or their underlying cause, improving or remediating damage caused, directly or indirectly, by the NSCLC. Treatment also includes prolonging survival as compared to the expected survival of a subject not receiving treatment.

[0043] “Therapeutically effective amount” refers to an amount of the disclosed subcutaneous composition comprising hyaluronidase and a bispecific EGFR / c-Met antibody and / or an amount of lazertinib effective, at dosages and for periods of time necessary, to achieve a desired treatment. A therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability to elicit a desired response in the subject. Exemplary indicators of atherapeutically effect amount include, for example, improved well-being of the patient, reduction of a tumor burden, arrested or slowed growth of a tumor, and / or absence of metastasis of cancer cells to other locations in the body.

[0044] “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” can be used interchangeably herein.

[0045] “Reference subject” or “reference population of subjects” refers to a subject or population of subjects having a locally advanced or metastatic EGFR-mutated NCSLC who have been administered a therapeutically effective amount of an intravenous composition comprising the disclosed bispecific EGFR / c-Met antibodies without hyaluronidase, instead of the subcutaneous composition. The reference subject or reference population of subjects can have substantially the same disease progression as the subject or population of subjects that are treated with the therapeutically effective amount of the subcutaneous composition comprising hyaluronidase and the bispecific EGFR / c-Met antibodies. Exemplary reference subjects or reference population of subjects are those described in Example 4 herein. In some embodiments, the population of subjects and reference population of subjects contain at least two subjects. In some embodiments, the population of subjects and reference population of subjects contain a number of subjects that allow for a statistically significant analysis of the improvement in safety and efficacy.

[0046] “Infusion-related reactions” or “IRRs” may occur in some patients to whom the bi-specific EGFR / c-Met antibody, such as amivantamab, is administered. Signs and symptoms of IRRs may include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and / or vomiting. Systemic IRRs, including severe reactions, upon the introduction of a new protein therapeutic infusion may also occur.

[0047] Disclosed herein are methods of improving the safety and efficacy of a therapy comprising a bispecific epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody for the treatment of locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) in a subject or a population of subjects, the methods comprising: administering to the subject or the population of subjects a therapeutically effective amount of a subcutaneous composition comprising hyaluronidase and a bispecific EGFR / c-Met antibody, the antibody comprising:a first heavy chain (HC1) comprising a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a first light chain (LC1) comprising a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6, a second heavy chain (HC2) comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, and a second light chain (LC2) comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 12, wherein the improvement in safety and efficacy comprises an improvement in median duration of response (DoR), an improvement in median progression free survival (PFS), an improvement in overall survival (OS), a reduction in rate of venous thromboembolism (VTE), or any combination thereof, and wherein the improvement in safety and efficacy is relative to the safety and efficacy of a reference therapy comprising a bispecific EGFR / c-Met antibody administered to a reference subject or a reference population of subjects, the reference subject or reference population having been administered a therapeutically effective amount of an intravenous composition comprising the bispecific EGFR / c- Met antibody without hyaluronidase, instead of the subcutaneous composition.

[0048] The improvement in safety and efficacy can comprise an improvement in median DoR. In some embodiments, the methods are performed on a population of subjects and the methods provide an improvement in median DoR as compared to a reference population of subjects.

[0049] The improvement in safety and efficacy can comprise an improvement in median PFS. In some embodiments, the methods are performed on a population of subjects and the methods an improvement in median PFS as compared to a reference population of subjects.

[0050] The improvement in safety and efficacy can comprise an improvement in OS. In some embodiments, the methods are performed on a subject and the methods provide an improvement in OS compared to a reference subject. In some embodiments, the methods are performed on a subject and the methods provide an improvement in OS compared to a reference population of subjects. In some embodiments, the methods are performed on a population of subjects and the methods provide an improvement in OS compared to a reference population of subjects.

[0051] The improvement in safety and efficacy can comprise a reduction in rate of VTE. In some embodiments, the methods are performed on a subject and the methods provide a reduction in rate of VTE as compared to a reference subject. In some embodiments, the methods are performed on a subject and the methods provide a reduction in rate of VTE as compared to a reference population of subjects. In some embodiments, the methods are performed on a population of subjects and the methods provide a reduction in rate of VTE as compared to a reference population of subjects.

[0052] The improvement in safety and efficacy can comprise any combination of an improvement in median DoR, an improvement in median PFS, an improvement in OS, and a reduction in rate of VTE.

[0053] In some embodiments, the methods of improving the safety and efficacy of a therapy comprising a bispecific EGFR / c-Met antibody for the treatment of locally advanced or metastatic EGFR-mutated NSCLC in a subject comprise: administering to the subject a therapeutically effective amount of a subcutaneous composition comprising hyaluronidase and a bispecific EGFR / c-Met antibody, the antibody comprising: a HC1 comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a LC1 comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6, a HC2 comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, anda LC2 comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 12, wherein the improvement in safety and efficacy comprises an improvement in overall survival (OS), a reduction in rate of venous thromboembolism (VTE), or a combination thereof, and wherein the improvement in safety and efficacy is relative to the safety and efficacy of a reference therapy comprising a bispecific EGFR / c-Met antibody administered to a reference subject or a reference population of subjects, the reference subject or reference population having been administered a therapeutically effective amount of an intravenous composition comprising the bispecific EGFR / c- Met antibody without hyaluronidase, instead of the subcutaneous composition.

[0054] In some embodiments, the subject or population of subjects has locally advanced or metastatic EGFR-mutated NSCLC that is positive for an EGFR L858R mutation or an EGFR Exon 19 deletion (Ex19del).

[0055] In some embodiments, the subject or population of subjects has progressed on or after treatment with osimertinib and platinum-based chemotherapy.

[0056] The methods can comprise administering to the subject or population of subjects a combination therapy comprising (i) the therapeutically effective amount of the subcutaneous composition and (ii) a therapeutically effective amount of an oral composition comprising lazertinib. The reference can comprise a subject or population of subjects having been administered a combination therapy comprising (i) the therapeutically effective amount of the intravenous composition and (ii) a therapeutically effective amount of the oral composition comprising lazertinib. Lazertinib is an oral, highly potent, mutant-selective, and irreversible third-generation EGFR TKI that targets both the Exon 19del and the Exon 21 L858R EGFR activating mutations, as well as the T790M resistance mutation. Lazertinib has demonstrated efficacy in participants with EGFR-mutated NSCLC, with activity observed in both systemic and central nervous system lesions, demonstrating its ability to cross the blood-brain barrier. In some embodiments, the oral composition comprises 240 mg of the lazertinib and is administered once daily.

[0057] In some embodiments, the methods comprise: administering to the subject or population of subjects:a therapeutically effective amount of an oral composition comprising lazertinib and a therapeutically effective amount of a subcutaneous composition comprising hyaluronidase and a bispecific EGFR / c-Met antibody, the antibody comprising: a HC1 comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a LC1 comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6, a HC2 comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, and a LC2 comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 12, wherein the improvement in safety and efficacy comprises an improvement in median duration of response (DoR), an improvement in median progression free survival (PFS), an improvement in overall survival (OS), a reduction in rate of venous thromboembolism (VTE), or any combination thereof, and wherein the improvement in safety and efficacy is relative to the safety and efficacy of a reference therapy comprising a bispecific EGFR / c-Met antibody administered to a reference subject or reference population of subjects, the reference subject or population having been administered a therapeutically effective amount of an oral composition comprising lazertinib and a therapeutically effective amount of an intravenous composition comprising the bispecific EGFR / c-Met antibody without hyaluronidase, instead of the subcutaneous composition.

[0058] In some embodiments, the methods comprise: administering to a subject or a population of subjects having a locally advanced or metastatic NSCLC that is positive for an EGFR L858R mutation or an EGFR Exon 19 deletion (Ex19del) that has progressed on or after treatment with osimertinib and platinum-based chemotherapy: a therapeutically effective amount of an oral composition comprising lazertinib anda therapeutically effective amount of a subcutaneous composition comprising hyaluronidase and a bispecific EGFR / c-Met antibody, the antibody comprising: a HC1 comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a LC1 comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6, a HC2 comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, and a LC2 comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 12, wherein the improvement in safety and efficacy comprises an improvement in median duration of response (DoR), an improvement in median progression free survival (PFS), an improvement in overall survival (OS), a reduction in rate of venous thromboembolism (VTE), or any combination thereof, and wherein the improvement in safety and efficacy is relative to the safety and efficacy of a reference therapy comprising a bispecific EGFR / c-Met antibody administered to a reference subject or a reference population of subjects, the reference subject or reference population having been administered a therapeutically effective amount of an oral composition comprising lazertinib and a therapeutically effective amount of an intravenous composition comprising the bispecific EGFR / c- Met antibody without hyaluronidase, instead of the subcutaneous composition.

[0059] The subcutaneous composition can comprise about 2,000 Units / mL of hyaluronidase and about 160 mg / mL of the bispecific antibody. In some embodiments, the subjects have a body weight of less than 80 kg and the subcutaneous composition comprises about 1,600 mg of the bispecific antibody and about 20,000 units of the hyaluronidase. In some embodiments, the subjects have a body weight greater than or equal to 80 kg and the subcutaneous composition comprises about 2,240 mg of the bispecific antibody and about 28,000 units of the hyaluronidase.

[0060] The methods can comprise two treatment cycles, wherein the first treatment cycle is from week 1 to week 4 and the second treatment cycle is from week 5onwards. The second treatment cycle can be divided into 28-day periods, which occur every four weeks starting on week 5. The methods can comprise administering the subcutaneous composition weekly for the first four weeks (weekly during the first treatment cycle) and every two weeks thereafter (every two weeks during the second treatment cycle). In some embodiments, the methods comprise administering the subcutaneous composition on days 1, 8, 15, and 22 of the first treatment cycle. In some embodiments, the methods comprise, after the weekly administering during the first treatment cycle, administering the subcutaneous composition on days 1 and 15 of each 28-day period during the second treatment cycle.

[0061] In some embodiments, the methods can comprise administering the subcutaneous composition weekly, for a total of 5 doses, from weeks 1 to 5; administering no dose of the subcutaneous composition during week 6; and administering the subcutaneous composition every two weeks starting at week 7 onwards.

[0062] The intravenous composition that is administered to the reference subject or reference population can be administered at a dose of 1,050 mg for subjects with a body weight of less than 80 kg, or 1,400 mg for subjects with a body weight of ≥80 kg, weekly for the first four weeks and every two weeks thereafter, with the first dose split over 2 days (350 mg on Day 1, the remainder on Day 2).

[0063] The method can provide an improvement in median DoR, an improvement in median PFS, an improvement in OS, a reduction in rate of VTE, or a combination thereof, as compared to a reference subject or reference population receiving about 240 mg of lazertinib administered orally once daily and the intravenous composition comprising about 1,050 mg to about 1,400 mg of the bispecific antibody without hyaluronidase administered intravenously as a split dose on days 1-2, and on days 8, 15, and 22 during a first treatment cycle and on days 1 and 15 of each subsequent 28 day period.

[0064] The methods can provide a median DoR of about 11 months or more. In some embodiments, the methods are performed on a population of subjects and the methods provide a median DoR of about 11 months or more as compared to the reference population of subjects.

[0065] The methods can provide a median PFS of about 6 months or more. In some embodiments, the methods are performed on a population of subjects and themethods provide a median PFS of about 6 months or more as compared to the reference population of subjects.

[0066] The methods can provide an OS of about 12 months or more. In some embodiments, the methods are performed on a subject and the methods provide an OS of about 12 months or more as compared to the reference subject. In some embodiments, the methods are performed on a subject and the methods provide an OS of about 12 months or more as compared to the reference population of subjects. In some embodiments, the methods are performed on a population of subjects and the methods provide an OS of about 12 months or more as compared to the reference population of subjects.

[0067] The methods can provide a reduction in rate of VTE of about 10% or less. In some embodiments, the methods are performed on a subject and the methods provide a reduction in rate of VTE of about 10% or less as compared to the reference subject. In some embodiments, the methods are performed on a subject and the methods provide a reduction in rate of VTE of about 10% or less as compared to the reference population of subjects. In some embodiments, the methods are performed on a population of subjects and the methods provide a reduction in rate of VTE of about 10% or less as compared to the reference population of subjects.

[0068] The HC1 of the bispecific antibody can comprise a VH1 comprising the amino acid sequence of SEQ ID NO: 13; the LC1 of the bispecific antibody can comprise a VL1 comprising the amino acid sequence of SEQ ID NO: 14; the HC2 of the bispecific antibody can comprise a VH2 comprising the amino acid sequence of SEQ ID NO: 15; and the LC2 of the bispecific antibody can comprise a VL2 comprising the amino acid sequence of SEQ ID NO: 16.

[0069] In some embodiments, the HC1 of the bispecific antibody comprises a HC1 constant domain 3 (HC1 CH3) and a HC variable region 1 (VH1). In some embodiments, the HC2 of the bispecific antibody comprises a HC2 constant domain 3 (HC2 CH3) and a HC variable region 2 (VH2). In some embodiments, the HC1 of the bispecific antibody comprises a HC1 CH3 and a VH1 and the HC2 of the bispecific antibody comprises a HC2 CH3 and a VH2. In some embodiments, the HC1 of the bispecific antibody comprises a HC1 constant domain 2 and constant domain 3 (HC1 CH2-CH3) and a VH1. In some embodiments, the HC2 of the bispecific antibody comprises a HC2 constant domain 2 and constant domain 3 (HC2 CH2-CH3) and a VH2. In some embodiments, the HC1 of the bispecific antibody comprises a HC1 CH2-CH3and a VH1 and the HC2 of the bispecific antibody comprises a HC2 CH2-CH3 and a VH2.

[0070] In some embodiments, the bispecific antibody comprises asymmetric stabilizing mutations in the HC1 CH2-CH3 region, in the HC2 CH2-CH3 region, or both. “Asymmetric stabilizing mutations” refers to mutations in the HC1 CH2-CH3 region and in the HC2 CH2-CH3 region that favor (e.g., stabilize) heterodimer formation between the HC1 CH2-CH3 region and the HC2 CH2-CH3 region over homodimer formation between the HC1 CH2-CH3 region or the HC2 CH2-CH3 region. Exemplary asymmetric stabilizing mutations in the HC1 CH2-CH3 region and the HC2 CH2-CH3 region, or in the HC2 CH2-CH3 region and the HC1 CH2-CH3 region, are (wherein residue numbering is according to the EU Index): F405L and K409R, respectively; wild-type and F405L / R409K, respectively; T366W and T366S / L368A / Y407V, respectively; T366Y / F405A and T394W / Y407T, respectively; T366W / F405W and T394S / Y407A, respectively; F405W / Y407A and T366W / T394S, respectively; L351Y / F405A / Y407V and T394W, respectively; T366I / K392M / T394W and F405A / Y407V, respectively; T366L / K392M / T394W and F405A / Y407V, respectively; L351Y / Y407A and T366A / K409F, respectively; L351Y / Y407A and T366V / K409F, respectively; Y407A and T366A / K409F, respectively; D399K / E356K and K409D / K392D, respectively; or D399K / E356K / E357K and K409D / K392D / K370, respectively.

[0071] In some embodiments, the bispecific antibody comprises K409R in the c-Met binding arm and F405L in the EGFR binding arm.

[0072] The HC1 of the bispecific antibody can comprise the amino acid sequence of SEQ ID NO: 17, the LC1 of the bispecific antibody can comprise the amino acid sequence of SEQ ID NO: 18, the HC2 of the bispecific antibody can comprise the amino acid sequence of SEQ ID NO: 19, and the LC2 of the bispecific antibody can comprise the amino acid sequence of SEQ ID NO: 20.

[0073] In some embodiments, the bispecific antibody is amivantamab. Amivantamab (JNJ-61186372) is a low fucose, fully human IgG1-based bispecificantibody directed against EGFR and cMET tyrosine kinase receptors that is approved by the FDA for patients with EGFR Exon 20ins mutations after treatment with chemotherapy. Amivantamab shows activity against tumors with primary activating EGFR mutations (Exon 19 deletion [Exon 19del], Exon 21 leucine 858 to arginine substitution ([L858R], and Exon 20ins mutations), EGFR resistance mutations (tyrosine 790 to methionine [T790M] or cysteine 797 to serine [C797S] mutations), overexpressed wild type EGFR, and activation of the cMet pathway.

[0074] The composition can comprise an amount of hyaluronidase enzyme that results in an increase in the dispersion of the bispecific antibody during the subcutaneous administration. The hyaluronidase enzyme has no adverse effect on the molecular integrity of the bispecific antibody. Furthermore, the hyaluronidase enzyme merely modifies the delivery of the bispecific antibody to the systemic circulation but does not possess any properties that could provide or contribute to the therapeutic effects of systemically absorbed bispecific antibody. The hyaluronidase enzyme is not systemically bioavailable and does not adversely affect the molecular integrity of the bispecific antibody at the recommended storage conditions of the composition. A number of suitable hyaluronidase enzymes are known. The preferred enzyme is a human hyaluronidase enzyme, such as a soluble human PH20 hyaluronidase, preferably the recombinant human hyaluronidase enzyme product known as rHuPH20. The amino acid sequence of soluble human PH20 hyaluronidases include the soluble human PH20 known as rHuPH20 and available under CAS Registry No.757971-58-7. Soluble human PH20 hyaluronidases are described in Int’l Pub. No. WO2004 / 078140 and U.S. Patent No.7,767,429 incorporated herein by reference, in their entirety. In some embodiments, soluble hyaluronidases include those whose sequence are set forth in any of SEQ ID NOs: 21-25. Soluble PH20 hyaluronidase, when expressed in a cell, include a signal sequence for trafficking in the cell. Thus, in some embodiments, the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 26. In some embodiments, the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 22, namely residues 36-482 of wild type human hyaluronidase. In some embodiments, the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 23. In some embodiments, the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 24. In some embodiments, the soluble PH20 hyaluronidase comprises rHuPH20 comprising the amino acid sequence of SEQ ID NO: 25. In some embodiments, the amino acid sequence of the soluble PH20 hyaluronidasecomprises SEQ ID NO: 21. In some embodiments, the soluble PH20 hyaluronidases, when expressed in a cell, comprise a mixture of species that can include any one of SEQ ID NOs: 21, 22, 23, 24, and 25 in various abundance. The average molecular weight is 61 kDa.

[0075] rHuPH20 refers to the composition produced upon expression in a cell, such as CHO cell, of nucleic acids that encode residues 36-482 of SEQ ID NO: 26, generally linked to the native or a heterologous signal sequence (residues 1-35 of SEQ ID NO: 26). rHuPH20 is produced by expression of a nucleic acid molecule, such as encoding amino acids 1-482 (set forth in SEQ ID NO: 26) in a mammalian cell. Translational processing removes the 35 amino acid signal sequence. As produced in the culture medium there is heterogeneity at the C-terminus such that the product, designated rHuPH20, includes a mixture of species that can include one or more of the polypeptides 36-480, 36-481, and 36-482 of SEQ ID NO: 26, and some shorter polypeptides, in various abundance. Typically, rHuPH20 is produced in cells, such as CHO cells, for example DG44 CHO cells, that facilitate correct N-glycosylation to retain activity. In some embodiments, the hyaluronidase is a soluble human PH20 (rHuPH20) comprising the amino acid sequence of SEQ ID NO: 25. In some embodiments, the hyaluronidase is a soluble human PH20 (rHuPH20) comprising the amino acid sequence of SEQ ID NO: 21. In some embodiments, the hyaluronidase is a soluble human PH20 (rHuPH20) comprising the amino acid sequence of SEQ ID NO: 22. In some embodiments, the hyaluronidase is a soluble human PH20 (rHuPH20) comprising the amino acid sequence of SEQ ID NO: 23. In some embodiments, the hyaluronidase is a soluble human PH20 (rHuPH20) comprising the amino acid sequence of SEQ ID NO: 24.

[0076] The subcutaneous composition can comprise: about 144 mg / mL to about 176 mg / mL of the bispecific antibody; about 10 mM to about 50 mM of acetate and / or a pharmaceutically acceptable acetate salt; about 6.8% (w / v) to about 10.2% (w / v) of sucrose; about 0.036% (w / v) to about 0.084% (w / v) of polysorbate 80 (PS80); about to 0.8 mg / mL to about 1.2 mg / mL of methionine; about 16 μg / mL to about 24 μg / mL of ethylenediaminetetraacetic acid (EDTA); and about 2,000 U / mL of the hyaluronidase, wherein the composition has a pH from about 5.2 to about 6.2.

[0077] The subcutaneous composition can comprise about 144 mg / mL, about 145 mg / mL, about 146 mg / mL, about 147 mg / mL, about 148 mg / mL, about 149 mg / ml, about 150 mg / mL, about 151 mg / mL, about 152 mg / mL, about 153 mg / mL, about 154 mg / mL, about 155 mg / mL, about 156 mg / mL, about 157 mg / mL, about 158 mg / mL, about 159 mg / mL, about 160 mg / mL, about 161 mg / mL, about 162 mg / mL, about 163 mg / mL, about 164 mg / mL, about 165 mg / mL, about 166 mg / mL, about 167 mg / mL, about 168 mg / mL, about 169 mg / mL, about 170 mg / mL, about 171 mg / mL, about 172 mg / mL, about 173 mg / mL, about 174 mg / mL, about 175 mg / mL, or about 176 mg / mL of the bispecific antibody. The subcutaneous composition can comprise about 160 mg / mL of the bispecific antibody.

[0078] The subcutaneous composition can have about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, or about 50 mM of the acetate and / or the pharmaceutically acceptable acetate salt. The subcutaneous composition can comprise about 30 mM of the acetate and / or the pharmaceutically acceptable acetate salt. In some embodiments, the acetate comprises glacial acetic acid. In some embodiments, the pharmaceutically acceptable acetate salt comprises sodium acetate trihydrate.

[0079] The subcutaneous composition can comprise about 6.8% (w / v), about 7.2% (w / v), about 7.6% (w / v), about 8.0% (w / v), about 8.4% (w / v), about 8.8% (w / v), about 9.2% (w / v), about 9.6% (w / v), about 10.0% (w / v), or about 10.2% (w / v) of sucrose. The subcutaneous composition can comprise about 8.5% (w / v) sucrose.

[0080] The subcutaneous composition can comprise about 0.036% (w / v), about 0.040% (w / v), about 0.044% (w / v), about 0.048% (w / v), about 0.052% (w / v), about 0.056% (w / v), about 0.060% (w / v), about 0.064% (w / v), about 0.068% (w / v), about 0.072% (w / v), about 0.076% (w / v), about 0.080% (w / v), or about 0.084% (w / v) of PS80. The subcutaneous composition can comprise about 0.06% (w / v) PS80.

[0081] The subcutaneous composition can comprise about 0.8 mg / mL, about 0.9 mg / mL, about 1.0 mg / mL, about 1.1 mg / mL, or about 1.2 mg / mL of methionine. In some embodiments, the methionine comprises L-methionine. The composition can comprise about 1 mg / mL of L-methionine.

[0082] The subcutaneous composition can comprise about 16 µg / mL, about 17 µg / mL, about 18 µg / mL, about 19 µg / mL, about 20 µg / mL, about 21 µg / mL, about 22 µg / mL, about 23 µg / mL, or about 24 µg / mL of EDTA. The subcutaneous composition can comprise about 20 µg / mL of EDTA.

[0083] The subcutaneous composition can have a pH from about 5.2 to about 6.2, a pH to about 5.0 to 6.2, or a pH 5.1 to 5.7. The subcutaneous composition can have a pH of about 5.7.

[0084] In some embodiments, the subcutaneous composition comprises: about 160 mg / mL of the bispecific antibody, wherein the HC1 of the bispecific antibody comprises the amino acid sequence of SEQ ID NO: 17, the LC1 of the bispecific antibody comprises the amino acid sequence of SEQ ID NO: 18, the HC2 of the bispecific antibody comprises the amino acid sequence of SEQ ID NO: 19, and the LC2 of the bispecific antibody comprises the amino acid sequence of SEQ ID NO: 20, about 30 mM acetate and / or pharmaceutically acceptable acetate salt, about 8.5% sucrose, about 1 mg / mL L-methionine polysorbate 80 to a final concentration of about 0.06% (w / v) EDTA to a final concentration of about 20 µg / mL, rHuPH20 to a final concentration of about 2,000 U / mL, and a pH of about 5.7.

[0085] The methods can further comprise administering an anticoagulant to the population of subjects. In some embodiments, the methods comprise administering the anticoagulant to the population of subjects for the first four months. EMBODIMENTS

[0086] The following list of embodiments is intended to complement, rather than displace or supersede, the previous descriptions. Embodiment 1. A method of improving the safety and efficacy of a therapy comprising a bispecific epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody for the treatment of locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) in a subject or a population of subjects, the method comprising: administering to the subject or the population of subjects a therapeutically effective amount of a subcutaneous composition comprising hyaluronidase and a bispecific EGFR / c-Met antibody, the antibody comprising: a first heavy chain (HC1) comprising a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a first light chain (LC1) comprising a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6, a second heavy chain (HC2) comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, and a second light chain (LC2) comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 12, wherein the improvement in safety and efficacy comprises an improvement in median duration of response (DoR), an improvement in median progression free survival (PFS), an improvement in overall survival (OS), a reduction in rate of venous thromboembolism (VTE), or any combination thereof, and wherein the improvement in safety and efficacy is relative to the safety and efficacy of a reference therapy comprising a bispecific EGFR / c-Met antibody administered to a reference subject or a reference population of subjects, the reference subject or reference population having been administered a therapeutically effective amount of an intravenous composition comprising the bispecific EGFR / c- Met antibody without hyaluronidase, instead of the subcutaneous composition. Embodiment 2. The method of embodiment 1, wherein the improvement comprises an improvement in median duration of response (DoR). Embodiment 3. The method of embodiment 1, wherein the improvement comprises an improvement in median progression free survival (PFS). Embodiment 4. The method of embodiment 1, wherein the improvement comprises an improvement in overall survival (OS).Embodiment 5. The method of embodiment 1, wherein the improvement comprises a reduction in rate of VTE. Embodiment 6. The method of any of the previous embodiments, wherein the population of subjects has locally advanced or metastatic EGFR-mutated NSCLC that is positive for an EGFR L858R mutation or an EGFR Exon 19 deletion (Ex19del). Embodiment 7. The method of any of the previous embodiments, wherein the population of subjects has progressed on or after treatment with osimertinib and platinum-based chemotherapy. Embodiment 8. The method of any of the previous embodiments, wherein the method comprises administering to the population of subjects a combination therapy comprising (i) the therapeutically effective amount of the subcutaneous composition and (ii) a therapeutically effective amount of an oral composition comprising lazertinib, the reference population of subjects having been administered a combination therapy comprising (i) the therapeutically effective amount of the intravenous composition and (ii) a therapeutically effective amount of the oral composition comprising lazertinib. Embodiment 9. The method of embodiment 8, wherein the oral composition comprises 240 mg of the lazertinib and is administered once daily. Embodiment 10. The method of any of the previous embodiments, wherein the subcutaneous composition comprises about 2,000 Units / mL of hyaluronidase and about 160 mg / mL of the bispecific antibody. Embodiment 11. The method of embodiment 10, wherein for subjects with a body weight of less than 80 kg, the subcutaneous composition comprises about 1,600 mg of the bispecific antibody and about 20,000 units of the hyaluronidase. Embodiment 12. The method of embodiment 10, wherein for subjects with a body weight greater than or equal to 80 kg, the subcutaneous composition comprisesabout 2,240 mg of the bispecific antibody and about 28,000 units of the hyaluronidase. Embodiment 13. The method of any one of the previous embodiments, comprising administering the subcutaneous composition weekly for the first four weeks and every two weeks thereafter. Embodiment 14. The method of embodiment 13, comprising administering the subcutaneous composition on days 1, 8, 15, and 22 of a first treatment cycle. Embodiment 15. The method of embodiment 13 or 14, comprising, after the administering during the first treatment cycle, administering the subcutaneous composition on days 1 and 15 of each 28-day period during the second treatment cycle Embodiment 16. The method of any of embodiments 1-12, comprising: administering the subcutaneous composition weekly, for a total of 5 doses, from Weeks 1 to 5; administering no dose of the subcutaneous composition during Week 6; and administering the subcutaneous composition every two weeks starting at Week 7 onwards. Embodiment 17. The method of any of the previous embodiments, wherein the intravenous composition is administered to the reference population at a dose of 1050 mg for subjects with a body weight of less than 80 kg, or 1400 mg for subjects with a body weight of ≥80 kg, weekly for the first four weeks and every two weeks thereafter, with the first dose split over 2 days (350 mg on Day 1, the remainder on Day 2). Embodiment 18. The method of any one of the previous embodiments, wherein the method provides an improvement in median DoR, an improvement in median PFS, an improvement in OS, a reduction in rate of VTE, or a combination thereof, as compared to a subject receiving about 240 mg of lazertinib administered orally once daily and the intravenous composition comprising about 1,050 mg to about 1,400 mg of the bispecific antibody without hyaluronidaseadministered intravenously as a split dose on days 1-2, and on days 8, 15, and 22 during the first cycle and on days 1 and 15 of each subsequent 28 day period during a second cycle. Embodiment 19. The method of any one of the previous embodiments, wherein the method provides a median DoR of about 11 months or more. Embodiment 20. The method of any one of the previous embodiments, wherein the method provides a median PFS of about 6 months or more. Embodiment 21. The method of any one of the previous embodiments, wherein the method provides an OS of about 12 months or more. Embodiment 22. The method of any one of the previous embodiments, wherein the method provides a reduction in rate of VTE of about 10% or less. Embodiment 23. The method of any one of the previous embodiments, wherein: the HC1 of the bispecific antibody comprises a variable region 1 (VH1) comprising the amino acid sequence of SEQ ID NO: 13; the LC1 of the bispecific antibody comprises a variable region 1 (VL1) comprising the amino acid sequence of SEQ ID NO: 14; the HC2 of the bispecific antibody comprises a variable region 2 (VH2) comprising the amino acid sequence of SEQ ID NO: 15; and the LC2 of the bispecific antibody comprises a variable region 2 (VL2) comprising the amino acid sequence of SEQ ID NO: 16. Embodiment 24. The method of any one of the previous embodiments, wherein: the HC1 of the bispecific antibody comprises the amino acid sequence of SEQ ID NO: 17; the LC1 of the bispecific antibody comprises the amino acid sequence of SEQ ID NO: 18; the HC2 of the bispecific antibody comprises the amino acid sequence of SEQ ID NO: 19; andthe LC2 of the bispecific antibody comprises the amino acid sequence of SEQ ID NO: 20. Embodiment 25. The method of any one of the previous embodiments, wherein the bispecific antibody is amivantamab. Embodiment 26. The method of any one of the previous embodiments, wherein the hyaluronidase is a soluble human PH20 (rHuPH20) comprising the amino acid sequence of SEQ ID NO: 21. Embodiment 27. The method of any one of the previous embodiments, wherein the composition comprises: about 144 mg / mL to about 176 mg / mL of the bispecific antibody; about 10 mM to about 50 mM of acetate and / or a pharmaceutically acceptable acetate salt; about 6.8% (w / v) to about 10.2% (w / v) of sucrose; about 0.036% (w / v) to about 0.084% (w / v) of polysorbate 80 (PS80); about to 0.8 mg / mL to about 1.2 mg / mL of methionine; about 16 μg / mL to about 24 μg / mL of ethylenediaminetetraacetic acid (EDTA); and about 2,000 U / mL of the hyaluronidase, wherein the composition has a pH from about 5.2 to about 6.2. Embodiment 28. The method of embodiment 27, wherein the composition comprises about 160 mg / mL of the bispecific antibody. Embodiment 29. The method of embodiment 27 or 28, wherein the composition comprises about 30 mM of the acetate and / or the pharmaceutically acceptable acetate salt. Embodiment 30. The method of any one of embodiments 27-29, wherein the acetate comprises glacial acetic acid.Embodiment 31. The method of any one of embodiments 27-29, wherein the pharmaceutically acceptable acetate salt comprises sodium acetate trihydrate. Embodiment 32. The method of any one of embodiments 27-31, wherein the composition comprises about 8.5% (w / v) sucrose. Embodiment 33. The method of any one of embodiments 27-32, wherein the composition comprises about 0.06% (w / v) PS80. Embodiment 34. The method of any one of embodiments 27-33, wherein the methionine comprises L-methionine. Embodiment 35. The method of embodiment 34, wherein the composition comprises about 1 mg / mL of L-methionine. Embodiment 36. The method of any one of embodiments 27-35, wherein the composition comprises about 20 µg / mL of EDTA. Embodiment 37. The method of any one of embodiments 27-36, wherein the composition has a pH of about 5.7. Embodiment 38. The method of any one of the previous embodiments, wherein the composition comprises: about 160 mg / mL of the bispecific antibody, about 30 mM acetate and / or pharmaceutically acceptable acetate salt, about 8.5% sucrose, about 1 mg / mL L-methionine polysorbate 80 to a final concentration of about 0.06% (w / v) EDTA to a final concentration of about 20 µg / mL, rHuPH20 to a final concentration of about 2,000 U / mL, a pH of about 5.7, and wherein the HC1 of the bispecific antibody comprises the amino acid sequence of SEQ ID NO: 17, the LC1 of the bispecific antibody comprises the amino acid sequence of SEQ ID NO: 18, the HC2 of the bispecific antibody comprises the amino acidsequence of SEQ ID NO: 19, and the LC2 of the bispecific antibody comprises the amino acid sequence of SEQ ID NO: 20. Embodiment 39. The method of any one of the previous embodiments, further comprising administering an anticoagulant to the population of subjects. Embodiment 40. The method of embodiment 39, comprising administering the anticoagulant to the population of subjects for the first four months. Embodiment 41. A method of improving the safety and efficacy of a therapy comprising a bispecific epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody for the treatment of locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) in a subject, the method comprising: administering to the subject a therapeutically effective amount of a subcutaneous composition comprising hyaluronidase and a bispecific EGFR / c-Met antibody, the antibody comprising: a first heavy chain (HC1) comprising a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a first light chain (LC1) comprising a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6, a second heavy chain (HC2) comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, and a second light chain (LC2) comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 12,wherein the improvement in safety and efficacy comprises an improvement in overall survival (OS), a reduction in rate of venous thromboembolism (VTE), or a combination thereof, and wherein the improvement in safety and efficacy is relative to the safety and efficacy of a reference therapy comprising a bispecific EGFR / c-Met antibody administered to a reference subject or a reference population of subjects, the reference subject or reference population having been administered a therapeutically effective amount of an intravenous composition comprising the bispecific EGFR / c- Met antibody without hyaluronidase, instead of the subcutaneous composition. Embodiment 42. The methods of any one of the previous embodiments, wherein a subcutaneous dose of amivantamab is missed between weeks 1 to 4 comprising administering the missed dose within 24 hours. Embodiment 43. The methods of any one of the previous embodiments, wherein a subcutaneous dose of amivantamab is missed from week 5 onward comprising administering the missed dose within 7 days. Embodiment 44. The methods of any one of the previous embodiments, wherein a subcutaneous dose of amivantamab is missed from week 5 onward and wherein the missed dose is not given within 7 days comprising administering the next dose per the usual dosing schedule. Embodiment 45. The methods of any one of the previous embodiments, comprising subcutaneous amivantamab dose modifications comprising, (i) dosing is interrupted for Grade 3 or 4 adverse reactions until the adverse reaction resolves to ≤ Grade 1 or baseline and wherein the dose interruption is 7 days or less, restarting dosing at the current dose; or (ii) dosing is interrupted for Grade 3 or 4 adverse reactions until the adverse reaction resolves to ≤ Grade 1 or baseline and wherein the dose interruption is longer than 7 days, restarting dose according to Table ATable A Dose*Dose after 1stDose after 2ndDose after 3rdinterruption for interruption for interruption for adverse reaction adverse reaction adverse reaction 1600 mg 1050 mg 700 mg Discontinue 2240 mg 1600 mg 1050 mg Rybrevant subcutaneous formulation * Dose at which the adverse reaction occurred. Embodiment 46. The methods of any one of the previous embodiments, comprising reducing the risk of subcutaneous amivantamab administration-related reactions comprising, (i) interrupting administration for grade 1 - 3 reactions and upon recovery of symptoms resuming administration; or (ii) interrupting administration for grade 1 - 3 reactions and upon recovery of symptoms resuming administration and wherein the next dose comprises administering one or more concomitant medicinal products or equivalents according to Table BTable B Premedication Dose Route of Recommended administration dosing window prior to Rybrevant subcutaneous formulation administration Antihistamine*Diphenhydramine (25 to Intravenous 15 to 30 minutes 50 mg) or equivalent Oral 30 to 60 minutes Antipyretic*Paracetamol / Acetaminophen Intravenous 15 to 30 minutes (650 to 1000 mg) or Oral 30 to 60 minutes equivalent Glucocorticoid†Dexamethasone (20 mg) or Intravenous 45 to 60 minutes equivalent Oral At least 60 minutes Glucocorticoid Dexamethasone (10 mg) or Intravenous 45 to 60 minutes equivalent Oral 60 to 90 minutes * Required at all doses. † Required at initial dose (Week 1, Day 1) or at the next subsequent dose in the event of an administration-related reaction. Optional for subsequent doses.Embodiment 47. The methods of any one of the previous embodiments, comprising administering prophylactic anticoagulants. Embodiment 48. The methods of any one of the previous embodiments, comprising administering prophylactic anticoagulants wherein the prophylactic anticoagulant is a direct acting oral anticoagulant (DOAC) or a low‑molecular weight heparin (LMWH), or equivalents thereof.Embodiment 49. The methods of any one of the previous embodiments, comprising administering prophylactic anticoagulants wherein the prophylactic anticoagulant is a direct acting oral anticoagulant (DOAC) or a low‑molecular weight heparin (LMWH), or equivalents thereof, and not a Vitamin K antagonist. Embodiment 50. The methods of any one of the previous embodiments, wherein a VTE event occurred and is associated with clinical instability (e.g., respiratory failure or cardiac dysfunction) comprising withholding amivantamab and / or lazertinib until the subject is clinically stable. Embodiment 51. The methods of any one of the previous embodiments, wherein a VTE event occurred and is associated with clinical instability (e.g., respiratory failure or cardiac dysfunction) comprising withholding amivantamab and / or lazertinib until the subject is clinically stable and thereafter resuming amivantamab and / or lazertinib at the same dose. Embodiment 52. The methods of any one of the previous embodiments, wherein a VTE event occurred and is associated with clinical instability (e.g., respiratory failure or cardiac dysfunction) comprising withholding amivantamab and / or lazertinib until the subject is clinically stable and thereafter resuming amivantamab and / or lazertinib at the same dose and whereupon recurrence of VTE discontinuing amivantamab and continuing lazertinib at the same dose. EXAMPLES

[0087] 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. Subcutaneous delivery of amivantamab in patients with advanced solid malignancies

[0088] The subcutaneous (SC) delivery of amivantamab was evaluated in a phase 1 dose escalation study in patients with advanced solid tumors who may derive benefit from EGFR or MET–directed therapy (PALOMA; NCT04606381). Eligible tumor types included non-small cell lung cancer (NSCLC), squamous cell carcinoma ofthe head and neck (SCCHN), hepatocellular cancer (HCC), colorectal cancer (CRC), renal cell cancer (RCC), medullary thyroid cancer (MTC), gastroesophageal cancer (GEC), mesothelioma, breast cancer (BC) and ovarian cancer (OC). Eligible patients have progressed after standard of care therapy for metastatic disease, were ineligible for, or have declined current standard therapies.

[0089] The study objectives were to evaluate the feasibility of administration, safety, and pharmacokinetics (PK) of a low concentration formulation, 50 mg / mL of amivantamab ± rHuPH20 (Part 1) and a high concentration formulation, 160 mg / mL of amivantamab ± rHuPH20 (Part 2). The low concentration formulation (50 mg / mL) amivantamab was administered either with (Ami-LC-MD [mix and deliver]) or without (Ami-LC) rHuPH20 (Part 1, Cohorts 1a and 1b, respectively). The high concentration formulation (160 mg / mL) amivantamab was administered either with (Ami-HC-CF [coformulated]) or without (Ami-HC) rHuPH20 (Part 2, Cohorts 2a and 2b, respectively). Patients in Part 1 and Part 2 received a dosage of amivantamab at 1050 mg and 2,000 Units / mL rHuPH20 (1400 mg and 2000 Units / mL rHuPH20 for bodyweight ≥80 kg) SC (weekly for the first 4 weeks and every other week thereafter). This study also evaluated administering the full dose of amivantamab on the first day.

[0090] Results: The full safety, PK, bioavailability, and receptor occupancy data of patients enrolled in Part 1 (n=16) and Part 2 (n=17) were evaluated. Compared to IV administration, initial SC experience demonstrated that the co-formulation of high concentration amivantamab with rHuPH20 shortened the needed infusion time from 2–4 hours to less than 5 minutes, with initial bioavailability of approximately 65% of IV administration. Saturation of soluble free EGFR and MET was achieved after the first SC dose. The incidence of IRRs was 18.2%, with all events of grade 1–2 severity as compared to 67.3% of patients who received the recommended phase 2 dose (RP2D) of IV amivantamab across the CHRYSALIS study (Park Ann Oncol 32[suppl_5]:S981). The full amivantamab SC dose was safely given at first administration to 14 patients, obviating the need for split dosing.

[0091] No increased risk of IRR was observed with the full initial amivantamab dosing; IRR was reported in 3 / 14 (21%) patients who received the full dose (C1D1) and 3 / 19 (16%) with the split dose.

[0092] The AE profile, outside of IRRs, of SC amivantamab was comparable to IV amivantamab. Grade ≥3 AEs occurred in 27.3% of patients, with most reported as single events. A single grade 3 event (hypokalemia) was reported as treatment-related.No treatment-related AEs leading to dose reductions or discontinuations were reported. Two patients (6.1%) had grade 1 injection-site reactions, which were transient and did not impact subsequent dosing.

[0093] Pharmacokinetics, pharmacodynamics, and immunogenicity: Maximum serum concentration of amivantamab was achieved 2–3 days following SC administration (data not shown). Higher exposure was obtained with rHuPH20; the estimated bioavailability with SC administration using formulations with rHuPH20 was approximately 65%. Saturation of soluble free EGFR and MET was achieved in all cohorts after the first full dose (data not shown). No anti-drug antibodies were detected in the patients tested (N=33 total in both Part 1 and Part 2 groups).

[0094] Conclusions: Initial SC amivantamab ± rHuPH20 was well tolerated with improvements in time and ease of administration and associated with a meaningful reduction in IRRs compared with intravenous (IV) administration, eliminating the need for split dosing. Example 2. Amivantamab and lazertinib in patients with EGFR-mutant non-small cell lung (NSCLC) after progression on osimertinib and platinum-based chemotherapy

[0095] Methods: A clinical trial cohort evaluated amivantamab and lazertinib in patients with EGFR exon 19 deletion or L858R NSCLC whose disease progressed on 1st / 2nd-line osimertinib followed by platinum-chemo as last line of therapy (target population, n=106) and among a more heavily pretreated population (n=56) whose disease progressed after osimertinib and platinum-chemo ± other therapies without regard to number and sequence of these therapies. Patients received 1050 mg IV amivantamab (1400 mg, ≥80 kg) + 240 mg oral lazertinib. Response was assessed per RECIST v1.1 (European Journal of Cancer, vol.45, pp.228-247 (2009)) and is reported for efficacy-evaluable patients, defined as those who had a ≥6 mo of follow-up for response durability.

[0096] Results: 162 patients were enrolled in the cohort (median 62 y, 65% women, 61% Asian, median of 3 [range, 2–14] prior lines of therapy). Median time between last osimertinib treatment to first dose of amivantamab + lazertinib was 6.3 mo and 2.0 mo for the target and heavily pretreated populations, respectively. Of 50 efficacy-evaluable patients in the target population, the ORR was 36% (95% CI, 23–51), with 1 complete response (CR) and 17 partial responses (PRs), and the clinical benefitrate (CBR) was 58% (95% CI, 43–72). Median duration of response (mDOR) was not reached. At a median follow-up of 8.3 mo, 7 responders (39%) have achieved a DOR lasting ≥6 mo. Of 56 efficacy-evaluable patients in the heavily-pretreated population (8.7-mo median follow-up), ORR was 29% (95% CI, 17–42), with 1 CR and 15 PRs. CBR was 55% (95% CI, 42–69) and mDOR was 8.6 mo (95% CI, 4.2–NR). Preliminary evidence of CNS antitumor activity was reported among 8 patients with baseline brain lesions (7 non-target, 1 target) who had not received radiation within 1 year prior to study enrollment.

[0097] Infusion-related reaction (IRR) (65%) was the most frequent adverse event (AE) reported, followed by paronychia (49%), rash (41%), and stomatitis (39%). Most common grade ≥3 treatment-related AEs (TRAEs) were infusion-related reactions (7%), acneiform dermatitis (5%), and hypoalbuminemia (4%). TRAEs leading to discontinuation of either or both ami and laz occurred in 12% and 7%, respectively. Example 3. Subcutaneous delivery of amivantamab, co-formulated with rHuPH20

[0098] The proposed preliminary recommended phase 2 dose (RP2D) for once every two weeks (Q2W) amivantamab dosing regimens is 1600 mg for patients with a BW <80 kg and 2240 mg for participants with a BW ≥80 kg. This preliminary subcutaneous dose comprises amivantamab at the concentration of 160 mg / mL co- formulated with rHuPH20 (amivantamab SC-CF).

[0099] The proposed recommended dosing regimens for amivantamab SC-CF are selected to ensure that the resulting exposures are similar to those observed with the IV RP2D regimens. Bioavailability was estimated by comparing the observed AUC following SC dosing (cohorts with and without rHuPH20 formulations) to the corresponding observed AUC following IV dosing. The SC cohorts were dosed at the IV RP2D (1050 mg for participants with a BW <80 kg and 1400 mg for participants with a BW ≥80 kg). At this dose, saturation of soluble free EGFR and cMet was achieved after the first SC dose. Moreover, all 33 participants were negative for anti-amivantamab antibodies. Following the first dose in Cycle 2 (after the weekly induction dosing in Cycle 1), the mean (CV%, n) area under the concentration time curves (AUC)C2D1- C2D15 were 95,416 µg×h / mL (45.4%, 7) and 75,378 µg×h / mL (27.0%, 5) for cohorts from 160mg / ml with and without rHuPH20, respectively.

[0100] Co formulation of amivantamab with rHuPH20 (i.e., amivantamab SC- CF) provided improved bioavailability (65% vs 51%), compared to formulations withoutrHuPH20, in addition to shortening the needed for injection time by approximately eight- fold. Based on the estimated bioavailability, a preliminary RP2D of 1,600 mg for participants with a BW <80 kg and 2,240 mg for participants with a BW ≥80 kg was proposed.

[0101] Emerging data indicates a lower incidence of IRRs (18.7% overall and 0 Grade ≥3) than previously reported with amivantamab IV (65.9% overall and 2.3% Grade ≥3). As a result of the reduced incidence and severity of IRRs, the study demonstrated the feasibility of a single day infusion of amivantamab SC for the first dose.

[0102] Based on the current clinical data and analysis supported by preliminary modeling, amivantamab SC-CF will be administered at the preliminary RP2D of 1,600 mg for participants <80 kg body weight and 2,240 mg for participants >80 kg body weight.

[0103] Cohort 1 will assess the combination of amivantamab SC-CF (Q2W) and lazertinib in subjects with treatment-naïve locally advanced or metastatic NSCLC harboring an EGFR exon 19del or exon 21 L858R mutation. Participants will receive amivantamab on Cycle 1 Days 1, 8, 15, and 22 and on Day 1 and 15 of each subsequent 28-day cycle, starting with Cycle 2. Amivantamab SC-CF will be administered SC by manual injection at 1,600 mg (2,240 mg if body weight ≥80 kg). Lazertinib will be given 240 mg orally once daily.

[0104] Cohort 4 will assess the feasibility of amivantamab SC-CF (Q2W) as a switch therapy in subjects who received ≥3 months of amivantamab IV as per standard of care. Participants will receive amivantamab on Cycle 1 Days 1, 8, 15, and 22 and on Day 1 and 15 of each subsequent 28-day cycle, starting with Cycle 2. Amivantamab SC-CF will be administered by manual injection at 1,600 mg (2,240 mg if body weight ≥80 kg ). Example 4. Subcutaneous Amivantamab plus Lazertinib in Refractory EGFR-mutated NSCLC

[0105] Background: Phase 3 studies of intravenous amivantamab have shown efficacy across EGFR-mutated advanced non-small cell lung cancer (NSCLC). A subcutaneous formulation could improve tolerability and reduce administration time.

[0106] Methods: This phase 3 trial randomized patients with EGFR-mutated advanced NSCLC following disease progression on osimertinib and platinum-based chemotherapy to receive subcutaneous or intravenous amivantamab, both combined withlazertinib. Co-primary noninferiority endpoints were trough concentrations (Ctrough) (on cycle-2-day-1 or cycle-4-day-1) and cycle-2 area under the curve (AUCD1-D15).

[0107] Results: Overall, 418 patients underwent randomization (206 to the subcutaneous and 212 to the intravenous group). Geometric mean ratios of Ctroughfor subcutaneous to intravenous were 1.15 (90% CI, 1.04 to 1.26) at cycle-2-day-1 and 1.42 (90% CI, 1.27 to 1.61) at cycle-4-day-1; ratio for cycle-2 AUCD1-D15was 1.03 (90% CI, 0.98 to 1.09). Objective response rates were 30% in the subcutaneous and 33% in the intravenous group, with a median progression-free survival of 6.1 and 4.3 months, respectively. At 12 months, 65% of patients were alive in the subcutaneous and 51% in the intravenous group (hazard ratio for death, 0.62; 95% CI, 0.42 to 0.92; P=0.02). Fewer patients experienced infusion-related reactions (13% versus 66%) and venous thromboembolism (9% versus 14%) in the subcutaneous than the intravenous group. Median (range) administration time was <5 minutes (range, 0 to 18) minutes for subcutaneous versus 2-5 hours (range, 0.2 to 9.9) for intravenous amivantamab.

[0108] Conclusions: Subcutaneous amivantamab-lazertinib is noninferior to intravenous amivantamab-lazertinib, with an improved safety profile and greater convenience. Introduction

[0109] Amivantamab is an epidermal growth factor receptor (EGFR)-c-MET bispecific antibody with immune cell-directing activity. The intravenous formulation of amivantamab is approved as a combination with chemotherapy in the first-line setting (phase 3 PAPILLON trial) and as a monotherapy following disease progression on platinum-based chemotherapy (phase 1 CHRYSALIS trial) in patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations.

[0110] Amivantamab has been combined with lazertinib, a central nervous system-penetrant, third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI). Amivantamab-lazertinib demonstrated superior progression-free survival versus osimertinib in patients with treatment-naïve, EGFR-mutated advanced NSCLC based on the phase 3 MARIPOSA trial. Infusion-related reactions are observed in two-thirds of patients receiving intravenous amivantamab, with most occurring on cycle-1-day-1 and being grade 1 to 2. The initial dose of intravenous amivantamab is split over 2 days toreduce infusion-related reactions, with a combined infusion time of 10 to 14 hours. The subcutaneous formulation of amivantamab was first evaluated in the phase 1 PALOMA trial, revealing low rates of infusion-related reactions and associated symptoms, and an administration time of 7 minutes or less for the every-2-week and every-3-week regimens.

[0111] PALOMA-3 is a phase 3, international, randomized trial assessing the noninferiority of pharmacokinetics, efficacy, and safety of subcutaneous versus intravenous amivantamab, both combined with lazertinib, in patients with EGFR- mutated, advanced NSCLC following disease progression on osimertinib and platinum- based chemotherapy. Methods

[0112] Patients - Eligible patients were 18 years or older, had confirmed advanced or metastatic NSCLC harboring classical EGFR exon 19 deletions (Ex19del) or exon 21 L858R mutations with disease progression on or after osimertinib (or another approved 3rd-generation EGFR-TKI) and platinum-based chemotherapy, irrespective of sequence.

[0113] Oversight - The trial was conducted in accordance with the provisions of the Declaration of Helsinki, Good Clinical Practice guidelines (as defined by the International Council for Harmonisation), applicable regulatory requirements, country / territory-specific requirements and the policy on bioethics and human biologic samples of the trial sponsor, Janssen Research and Development.

[0114] Trial Design and Treatment - Patients were randomized in a 1:1 ratio to receive subcutaneous amivantamab-lazertinib or intravenous amivantamab-lazertinib in 28-day cycles (FIG.1). Subcutaneous amivantamab (concentration, 160 mg / mL), co- formulated with hyaluronidase (rHuPH20) was administered by manual injection at a dose of 1600 mg (2240 mg for a body weight of ≥80 kg) for the first 4 weeks and every 2 weeks thereafter. Intravenous amivantamab (concentration, 50 mg / mL) was administered at the approved dose of 1050 mg (1400 mg for a body weight of ≥80 kg) on the same interval as subcutaneous amivantamab, with the first infusion split over 2 days (350 mg on cycle-1-day-1, the remainder on cycle-1-day-2). Lazertinib was administered orally at a dose of 240 mg daily.

[0115] Randomization was stratified according to history of brain metastases (yes or no), EGFR mutation type (Ex19del versus L858R), race (Asian versus non- Asian), and type of last therapy (osimertinib versus chemotherapy).

[0116] An increased risk of venous thromboembolism (VTE) associated with amivantamab-lazertinib was initially observed in the MARIPOSA trial. Consequently, the study protocol was amended to recommend prophylactic anticoagulation for the first 4 months of amivantamab-lazeritnib treatment.

[0117] Outcomes - The co-primary outcomes for pharmacokinetic noninferiority were trough concentrations (Ctrough; either pre-dose on cycle-2-day-1 or at steady state [cycle-4-day-1], per regional health authority requests), and area under the curve from cycle-2 day-1 to day-15 (AUCD1-D15). Key secondary outcomes were objective response rate and progression-free survival. Overall survival was a predefined exploratory endpoint.

[0118] Assessments - Disease assessments (computed tomography, magnetic resonance imaging, or other imaging) were performed within 28 days before randomization, then at 6 weeks (maximum, 7 weeks) after randomization and subsequently every 6 weeks (within a 1-week window) for the first 18 months and every 12 weeks (within a 1-week window) thereafter until disease progression. All response assessments were performed by the investigator according to Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 definitions. All patients underwent brain imaging at baseline; subsequent imaging was performed every 6 weeks in patients with baseline brain metastases or as clinically indicated.

[0119] Adverse events, vital signs, and laboratory tests were assessed at each visit and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Pharmacokinetic and immunogenicity assessments for amivantamab were conducted using validated assays on blood serum and plasma samples collected throughout the trial, until end of treatment.

[0120] Statistical analysis - The pharmacokinetic analysis included patients who received all doses without modification and provided the required pharmacokinetic samples through the final required sample relevant to the endpoint. Efficacy analysis included all patients who were randomized. Safety analysis included all patients who had received at least one dose of any treatment. For calculating primary and key secondary outcomes, it was estimated that a sample size of 400 patients would provide >95% powerfor a one-sided alpha of 0.05 allocated to each of the co-primary endpoints, and 80% power with a one-sided alpha of 0.025 allocated to objective response rate.

[0121] The primary hypotheses were that the lower bounds of the 90% confidence interval (CI) for the geometric mean ratios for subcutaneous versus intravenous amivantamab would be ≥80% (noninferiority margin of 20%) for both co- primary endpoints. Objective response rate was analyzed using logistic regression, with noninferiority established if the lower bound of the relative risk ratio’s 95% CI was at least 60%. Progression-free survival was evaluated using the P value generated from the stratified log-rank test with EGFR mutation type, Asian race, history of brain metastasis, and last therapy as stratification factors. The hazard ratio and 95% CI were estimated using a stratified Cox regression model with treatment as the sole explanatory variable. Medians and corresponding 95% CIs were estimated by the Kaplan-Meier method. A hierarchical testing approach was used for the co-primary endpoints (noninferiority, at a two-sided alpha of 0.05), followed by objective response rate (noninferiority) and then progression-free survival (superiority). The key secondary endpoints were tested using a combined two-sided alpha of 0.05.

[0122] Analyses of additional secondary or other outcomes including subgroup analyses were not part of hypothesis testing in the trial, and these results are reported as descriptive statistics without adjustment for multiplicity. Results

[0123] Patients and Treatment - From August 2022 to October 2023, 635 patients were screened, and 418 patients randomized (206 to receive subcutaneous amivantamab-lazertinib and 212 to receive intravenous amivantamab-lazertinib; FIG.2). Overall, 416 patients received at least one dose of trial treatment. Pharmacokinetic samples were available from 414 patients. Demographics and baseline characteristics were well balanced; the median number of prior therapy lines was 2 (range, 1 to 5 [subcutaneous] and 1 to 4 [intravenous]; Table 1). Most patients were female, were Asian or White, and had never smoked, which is representative of the broader population of patients with EGFR-mutated NSCLC (Table 2). Table 1. Demographic and Clinical Characteristics of the Patients at Baseline*Subcutaneous Intravenous group group Characteristic, n (%) (n=206) (n=212) Age Median (range) — years 61 (35–82) 62 (29–81) Distribution — no. (%) <65 years 133 (64) 120 (57) ≥65 to <75 years 55 (27) 70 (33) ≥75 years 18 (9) 22 (10)Sex — no. (%)Female 138 (67) 141 (67) Male 68 (33) 71 (34)Race or ethnic group — no. (%)†Asian 126 (61) 129 (61) White 78 (38) 77 (36) Black or African American 1 (0.5) 3 (1) Multiple 0 1 (0.5) Not reported 1 (0.5) 2 (0.9) Body weight Median (range) — kg 61.8 (35–130) 60.1 (33–150) Distribution — no. (%) <80 kg 184 (89) 184 (87) ≥80 kg 22 (11) 28 (13) Region of enrollment — no. (%)† North America 19 (9) 30 (14) South America 11 (5) 17 (8) Europe 38 (18) 40 (19) Asia 126 (61) 120 (57) Oceania 12 (6) 5 (2) ECOG performance-status score — no. (%) 0 58 (28) 61 (29) 1 148 (72) 151 (71)History of smoking — no. (%)No 141 (68) 145 (68) Yes 65 (32) 67 (32) Median time from initial diagnosis (range) — mo 34.5 (2.8–191.3) 33.7 (6.05–156.9) Median time from metastatic diagnosis (range) — mo 32.7 (0.9–169.0) 29.7 (0.6–142.6) Histologic type — no. (%) Adenocarcinoma 204 (99) 207 (98) Large cell carcinoma 1 (0.5) 1 (0.5) Squamous cell carcinoma 1 (0.5) 3 (1) Other 0 1 (0.5) EGFR mutation type at randomization — no. (%) Exon 19 deletion 135 (66) 138 (65)L858R 71 (34) 74 (35) History of brain metastasis Yes 70 (34) 72 (34) No 136 (66) 140 (66) Last therapy before randomization Osimertinib 91 (44) 96 (45) Chemotherapy 115 (56) 116 (55) *ECOG denotes Eastern Cooperative Oncology Group performance status, EGFR epidermal growth factor receptor, NSCLC non-small cell lung cancer, and TKI tyrosine kinase inhibitor. †Russia was counted as part of Europe; Turkey and Israel were counted as part of Asia. Table 2. Representativeness of Study Participants Category Details Disease under investigation EGFR-mutated (Ex19del or L858R) NSCLC Special considerations related to: Sex EGFR-mutated NSCLC is prevalent in more females (44%) than males (24%). Age The median age of patients was 63 years from a meta-analysis* of 456 NSCLC studies. Race or ethnic group The highest prevalence of EGFR-mutated NSCLC is found in Asian populations (39%), followed by 17% in Caucasians, 17% in African Americans, and 27% in mixed populations. In a prospective analysis of 1482 Asian patients, EGFR mutations were observed in 51% of patients with advanced NSCLC of adenocarcinoma histology, where the most commonly detected mutations were Ex19del (alone: 22%; in combination with others: 24%) and L858R (alone: 21%; in combination with others: 23%). Geography Consistent with the estimates by race, the Asia- Pacific region exhibited the highest prevalence of EGFR-mutated NSCLC, ranging from 38%* to 47%†. In contrast, the lowest prevalence was observed in Oceania (12%†). Model estimates indicate that Ex19del is most prevalent in South America (67%) and least prevalent in Oceania (40%). On the other hand, L858R is most prominent in Asia (41%) and least prominent in South America (28%).Other considerations EGFR-mutated NSCLC is more commonly observed in patients with no history of smoking (49% vs 22% for those with history of smoking*) and adenocarcinoma histology (38% vs 12% for non- adenocarcinoma*). The prevalence of EGFR Ex19del and L858R are similar among NSCLC disease stages (I, 34%; II, 30%; III, 34%; IV, 38%).* Overall representativeness of The demographic and epidemiologic characteristics this trial of the PALOMA-3 patient population were generally consistent with the current data for patients with EGFR-mutated NSCLC. Most patients that met the eligibility criteria of our trial were female, did not have a history of smoking, and were of Asian or White ethnicity. EGFR, epidermal growth factor receptor; Ex19del, exon 19 deletion; NSCLC, non-small cell lung cancer.

[0124] At a median follow-up of 7.0 months (range, 0.1 to 14.4), median treatment duration was 4.7 (range, 0.1 to 13.2) in the subcutaneous group and 4.1 months (range, 0.0 to 13.2) in the intravenous group. The median duration of amivantamab administration on cycle-1-day-1 was 4.8 minutes (range, 0 to 18) in the subcutaneous group and 5.0 hours (range, 0.2 to 9.9) in the intravenous group; corresponding values on cycle-3-day-1 were 4.8 minutes (range, 0 to 12) and 2.3 hours (range, 0.5 to 4.4). At data cutoff, the assigned treatment was still being administered in 92 (45%) and 96 (46%) patients in the subcutaneous and intravenous groups, respectively. Time to amivantamab discontinuation is shown in FIG.3.

[0125] Pharmacokinetics - The mean (% coefficient of variation) of Ctrough at cycle-2-day-1 was 365 (33) µg / mL and 314 (32) µg / mL in the subcutaneous and intravenous groups, respectively; the corresponding values at cycle-4-day-1 were 224 (39) µg / mL and 162 (42) µg / mL (Table 3). The geometric mean ratio for Ctroughcomparing the subcutaneous versus the intravenous group was 1.15 (90% CI 1.04 to 1.26) at cycle-2-day-1 and 1.43 (90% CI 1.27 to 1.61) at cycle-4-day-1. Cycle-2 AUCD1-D15 mean (% coefficient of variation) was 142236 (31) µg•h / mL and 135552 (24) µg•h / mL in the subcutaneous and intravenous groups, respectively. The geometric mean ratio for cycle-2 AUCD1-D15 was 1.03 (90% CI 0.98 to 1.09). These results indicate that the noninferiority criterion was met. Observed amivantamab concentration-time profiles, Ctrough, and AUCD1-D15 are shown in FIG.4.Table 3. Co-primary Pharmacokinetic and Key Efficacy Endpoints* Subcutaneous Intravenous group group Treatment Effect P (n=206) (n=212) (95% CI) Value Coprimary endpointsCtrough— µg / mL Geometric mean ratio (%CV) (90% CI) Predose on cycle-2- day-1 365 (32.7) 314 (31.7) 1.15 (1.04–1.26) Cycle-4-day-1 (steady state) 224 (39.1) 162 (41.5) 1.43 (1.27–1.61) AUCD1-D15— µg•h / mL Geometric mean ratio (%CV) (90% CI) Cycle 2 142236 (30.7) 135552 (24.0) 1.03 (0.98–1.09) Secondary Endpoints Objective response† Patients (95% CI) — Relative risk for % 30 (24–37) 33 (26–39) noninferiority, 0.92 0.001 (0.70–1.23) Progression-free survival Median (95% CI) — 6.1 (4.3–8.1 Hazard ratio, 0.84 mo ) 4.3 (4.1–5.7) (0.64–1.10) 0.20 Patients (95% CI) — % At 6 months 50 (43–58) 42 (35–50) At 12 months 37 (28–46) 20 (8–35) Overall survival Median (95% CI) — 12.85 (12.85– NE (10.2– Hazard ratio, 0.62 mo NE) NE) (0.42–0.92) 0.017 Patients (95% CI) — % At 6 months 85 (79–89) 75 (68–80) At 12 months 65 (52–74) 51 (37–64) *The pharmacokinetic population for evaluating the co-primary endpoints included all patients who received all doses in Cycle 1 to 3, and patients who received all doses up to Cycle 2 Day 1 without dose modifications and provided pharmacokinetic samples either pre-dose on Cycle 2 Day 1 or Cycle 4 Day 1. The efficacy population included all the patients who had undergone randomization. NE denotes not estimable, BICR blinded independent central review, and CI confidence interval. †The objective response (complete or partial response as best response) and response duration was assessed by the investigator among all responders. For overall survival, 95% CIs were not adjusted for multiplicity and should not be used in place of hypothesis testing; P-value is nominal.

[0126] Anti-amivantamab antibodies were detected in 2 (1%) patients in the subcutaneous group and none in the intravenous group. Anti-rHuPH20 antibodies occurred in 15 (8%) patients in the subcutaneous group.

[0127] Efficacy - An objective response (complete or partial) was reported in 30% of patients (95% CI, 24 to 37) in the subcutaneous group and 33% (95% CI, 26 to 39) in the intravenous group (relative risk, 0.92; 95% CI, 0.70 to 1.23; Table 3 and FIG. 5). The objective response rate in the subcutaneous group met the noninferiority criterion (P=0.001) by retaining at least 60% of the objective response rate in the intravenous group. Objective response for all prespecified subgroups is shown in FIG.6A. Among confirmed responders, median response duration was 11.2 months (95% CI, 6.1 to not estimable) in the subcutaneous group and 8.3 months (95% CI, 5.4 to not estimable) in the intravenous group; 29% and 14% of patients, respectively, had a response duration longer than 6 months (FIG.7 and Table 4). Table 4. Response Endpoints* Subcutaneous group Intravenous group (n=206) (n=212) Objective response† Patients (95% CI) including all responders — % 30 (24–37) 33 (26–39) Patients (95% CI) including only confirmed responders — 27 (21–33) 27 (21–33) % Best overall response — no. (%)† Complete response 1 (0.5) 1 (0.5) Partial response 61 (30) 68 (32) Stable disease 93 (45) 81 (38) Progressive disease 37 (18) 42 (20) Not evaluable 14 (7) 20 (9) Response durationMedian (95% CI) among all responders — mo 11.2 (6.1–NE) 7.1 (5.3–NE) Median (95% CI) among confirmed responders — mo 11.2 (6.1–NE) 8.3 (5.4–NE) DCR, % (95% CI) 75 (69-81) 71 (64-77) Time to response Median (Range) — mo 1.5 (1.2–6.9) 1.5 (1.2–9.9) *The efficacy population included all the patients who had undergone randomization. NE denotes not estimable, BICR blinded independent central review, and CI confidence interval. †The objective response (complete or partial response as best response) was assessed using RECIST v1.1 and analyzed using logistic regression.Among all responders.

[0128] The percentage of patients exhibiting stable disease was 45% in the subcutaneous group and 38% in the intravenous. The median progression-free survival was 6.1 months (95% CI, 4.3 to 8.1) in the subcutaneous group and 4.3 months (95% CI, 4.1 to 5.7) in the intravenous group (hazard ratio for disease progression or death, 0.84; 95% CI, 0.64 to 1.10; P=0.20; FIG.6B).

[0129] Death occurred in 43 patients in the subcutaneous group and 62 in the intravenous group, with 35 and 50 deaths, respectively, caused by progressive disease. The percentage of patients who were alive at 6 and 12 months, respectively, was 85% (95% CI, 79 to 89) and 65% (95% CI, 52 to 74) in the subcutaneous group and 75% (95% CI, 68 to 80) and 51% (95% CI, 37 to 64) in the intravenous group (hazard ratio for death, 0.62; 95% CI, 0.42 to 0.92, nominal P=0.02; FIG.6C).

[0130] Safety - Most patients had at least one adverse event (Table 5). The most common grade 3 or higher adverse events (at least 5% in any group) were dermatitis acneiform (9% and 6% in the subcutaneous and intravenous groups, respectively) and lymphopenia (<1% and 8%). Serious adverse events were reported in 29% and 30% of patients in the subcutaneous and intravenous groups, respectively (Table 6). Table 5. Adverse Events* Subcutaneous group Intravenous group Adverse Event — no. (%) (n=206) (n=210) Any event 204 (99) 209 (100) Grade ≥3 107 (52) 118 (56) Any serious event 59 (29) 64 (31) Any event resulting in death 7 (3) 10 (5) Any event leading to: Interruption of any study agent† 127 (62) 127 (60) Reduction of any study agent 63 (31) 52 (25) Discontinuation of any study agent 26 (13) 29 (14) Adverse events reported in ≥15% All Grade A Grade of patients in either group ≥3 ll ≥3 Paronychia 111 (54) 8 (4) 108 (51) 3 (1) Hypoalbuminemia 96 (47) 9 (4) 77 (37) 8 (4)Rash 95 (46) 8 (4) 91 (43) 8 (4) Dermatitis acneiform 64 (31) 18 (9) 69 (33) 12 (6) Nausea 60 (29) 1 (0.5) 52 (25) 3 (1) Stomatitis 57 (28) 1 (0.5) 69 (33) 5 (2) Peripheral edema 52 (25) 6 (3) 58 (28) 1 (0.5) Increased alanine aminotransferase 46 (22) 6 (3) 56 (27) 8 (4) Decreased appetite 45 (22) 1 (0.5) 52 (25) 3 (1) Fatigue 44 (21) 3 (2) 43 (21) 5 (2) Vomiting 44 (21) 2 (1) 41 (20) 1 (0.5) Diarrhea 43 (21) 3 (1) 39 (19) 2 (1) Constipation 42 (20) 0 42 (20) 1 (0.5) Headache 42 (20) 1 (0.5) 36 (17) 1 (0.5) Increased aspartate aminotransferase 42 (20) 2 (1) 45 (21) 3 (1) Anemia 39 (19) 4 (2) 40 (19) 5 (2) Pruritus 33 (16) 0 25 (12) 0 Hypocalcemia 33 (16) 0 27 (13) 0 Myalgia 32 (16) 0 13 (6) 0 Asthenia 31 (15) 4 (2) 23 (11) 2 (1) Thrombocytopenia 29 (14) 4 (2) 33 (16) 2 (1) Infusion-related reaction 27 (13) 1 (0.5) 138 (66) 8 (4) *The safety population included all the patients who had undergone randomization and received at least one dose of any trial treatment. †Excluding infusion / administration-related reactions. Events in this category are listed according to decreasing incidence in the subcutaneous group. Table 6. Treatment-Emergent Serious Adverse Events Occurring in At Least 2 Patients* Subcutaneous group Intravenous group Event — no. (%)† (n=206) (n=210) Pneumonitis 9 (4) 6 (3) COVID-19 4 (2) 4 (2) Alanine aminotransferase 4 (2) 3 (1) increased Pneumonia 3 (1) 7 (3) Interstitial lung disease 3 (1) 1 (0.5)Fatigue 3 (1) 1 (0.5) Deep vein thrombosis 2 (1) 4 (2) Asthenia 2 (1) 2 (1) Respiratory failure 2 (1) 1 (0.5) Vomiting 2 (1) 0 Femur fracture 2 (1) 0 Dyspnea 1 (0.5) 2 (1) Pulmonary embolism 1 (0.5) 2 (1) Skin infection 1 (0.5) 2 (1) Aspartate aminotransferase 1 (0.5) 2 (1) increased Back pain 1 (0.5) 2 (1) Cerebral infarction 0 3 (1) Nausea 0 3 (1) Infusion related reaction 0 2 (1) Hypoalbuminemia 0 2 (1) Rash 0 2 (1) *The safety population included all the patients who had undergone randomization and received at least one dose of any trial treatment. †Events in this category are listed according to decreasing incidence in the subcutaneous group.

[0131] The proportion of patients experiencing an infusion-related reaction was 13% in the subcutaneous group and 66% in the intravenous group (FIG.8), with 1 (0.5%) and 8 (4%) patients, respectively, experiencing a grade 3 event (no grade 4 or 5 events were reported). The proportion of patients experiencing infusion-related adverse events was between 0% and 6% in the subcutaneous group and 2% to 20% in the intravenous group. Most infusion-related reactions occurred during cycle-1 (FIG.9). There were no discontinuations due to infusion-related reactions in the subcutaneous group versus 4 (2%) patients in the intravenous group.

[0132] VTE was reported in 9% of patients in the subcutaneous group and 14% of patients in the intravenous group, with pulmonary embolism and deep-vein thrombosis as most common (Table 7 and FIG.10). Among all VTEs, most occurred in the first 4 months (74% and 67% in the subcutaneous and intravenous groups, respectively). Overall, 79% and 81% of patients in the subcutaneous and intravenous groups, respectively, received prophylactic anticoagulation. Among those receiving anticoagulation, VTE was reported in 7% and 12% of patients, respectively; the rates ofVTE among patients who did not receive anticoagulation were 17% and 26%, respectively (Table 8, Table 9, and FIG.10). Grade 3 or higher bleeding events occurred in 2% and 0.5% of patients receiving anticoagulation in the subcutaneous and intravenous groups, respectively. Table 7. Venous Thromboembolism Events* Subcutaneous group Intravenous group Event — no. (%) (n=206) (n=210) Any venous 19 (9) 30 (14) thromboembolic event Grade 1 1 (0.5) 7 (3) Grade 2 16 (8) 16 (8) Grade 3 2 (1) 6 (3) Grade 4 0 1 (0.5) Grade 5 0 0 Any venous thromboembolic event 0 0 leading to death Any venous thromboembolic event leading to discontinuation 0 2 (1) of any agent Venous thromboembolic events† Pulmonary embolism 6 (3) 9 (4) Deep vein thrombosis 5 (2) 11 (5) Embolism venous 3 (1) 3 (1) Venous thrombosis limb 3 (1) 3 (1) Embolism 2 (1) 3 (1) Thrombosis 2 (1) 1 (0.5) Subclavian vein 1 (0.5) 0 thrombosis Superficial vein 1 (0.5) 0 thrombosis Pulmonary infarction 0 1 (0.5) Venous thrombosis 0 3 (1) *The safety population included all the patients who had undergone randomization and received at least one dose of any trial treatment. †Events in this category are listed according to decreasing incidence in the subcutaneous group.Table 8. Venous Thromboembolism and Bleeding Events by Anticoagulation Use and by Treatment Group* Subcutaneous group Intravenous group (n=206) (n=210) Any No Any No prophylactic prophylactic prophylactic prophylactic anticoagulation anticoagulation anticoagulation anticoagulation Event — no. (%) (n=164) (n=42) (n=171) (n=39) Any venous 12 (7) 7 (17) 20 (12) 10 (26) thromboembolic event Grade 101 (2) 5 (3) 2 (5)Grade 210 (6)6 (14) 13 (8) 3 (8)Grade 3–4 2 (1) 0 2 (1) 5 (13) Grade 5 0 0 0 0 Any venous thromboembolic event leading to 0 0 0 0 death Any venous thromboembolic event leading to 0 0 0 2 (5) discontinuation of any agent Venous thromboembolic events† Pulmonary 4 (2) 2 (5) 6 (4) 3 (8) embolism Deep vein 3 (2) 2 (5) 8 (5) 3 (8) thrombosis Venous 2 (1) 1 (2) 2 (1) 1 (3) embolism Venous 3 (2) 0 1 (0.6) 2 (5) thrombosis limb Embolism 1 (0.6) 1 (2) 2 (1) 1 (3) Thrombosis 1 (0.6) 1 (2) 1 (0.6) 0 Subclavian vein 1 (0.6) 0 0 0 thrombosis Superficial vein 0 1 (2) 0 0 thrombosis Venous 0 0 2 (1) 1 (3) thrombosisPulmonary 0 0 0 1 (3) infarction Any bleeding 44 (27) 5 (12) 48 (28) 5 (13) event Grade 3–4 3 (2) 1 (2) 1 (0.6) 0 Grade 5 0 0 0 0 Any bleeding event leading to 0 0 0 0 death Any bleeding event leading to discontinuation 1 (0.6) 0 0 0 of any agent *The safety population included all the patients who had undergone randomization and received at least one dose of any trial treatment. The on prophylactic anticoagulation group included patients who had anticoagulation prior or at Cycle 1 Day 1 plus 3 days window and continued until progression, death, withdrawn from the study, occurrence of VTE or Cycle 5 Day 1. †Events in this category are listed according to decreasing incidence in the subcutaneous group. Grade 3–4 events include contusion, gingival bleeding, hemoptysis, hematemesis, and nail bed bleeding. Table 9. Venous Thromboembolism and Bleeding Events by Anticoagulation Use Across all Study Patients* Any prophylactic No prophylactic anticoagulation anticoagulation Event — no. (%) (n=335) (n=81) Any venous thromboembolic event 32 (10) 17 (21) Grade 15 (1)3 (4)Grade 223 (7)9 (11)Grade 3–4 4 (1) 5 (6) Grade 5 0 0 Any venous thromboembolic event leading to death0 0Any venous thromboembolic event leading to discontinuation of any 0 2 (2) agent Venous thromboembolic events† Deep vein thrombosis 11 (3) 5 (6) Pulmonary embolism 10 (3) 5 (6) Venous thrombosis limb 4 (1) 2 (2)Venous embolism 4 (1) 2 (2) Embolism 3 (0.9) 2 (2) Venous thrombosis 2 (0.6) 1 (1) Thrombosis 2 (0.6) 1 (1) Subclavian vein thrombosis 1 (0.3) 0 Pulmonary infarction 0 1 (1) Superficial vein thrombosis 0 1 (1) Any bleeding event 92 (27) 10 (12) Grade 3–4 4 (1) 1 (1) Grade 5 0 0 Any bleeding event leading to death 0 0 Any bleeding event leading to discontinuation of any agent1 (0.3) 0*The safety population included all the patients who had undergone randomization and received at least one dose of any trial treatment. The on prophylactic anticoagulation group included patients who had anticoagulation prior or at Cycle 1 Day 1 plus 3 days window and continued until progression, death, withdrawn from the study, occurrence of VTE or Cycle 5 Day 1. No Prophylactic Anticoagulation group included patients who never took prophylactic anticoagulation during first 4 months of amivantamab and lazertinib combination treatment. †Events in this category are listed according to decreasing incidence in the prophylactic anticoagulation group. Grade 3–4 events include contusion, gingival bleeding, hemoptysis, hematemesis, and nail bed bleeding

[0133] Adverse events leading to dose interruptions, reductions, and discontinuations of any trial agent are shown in Table 5. The most common reasons for discontinuation are presented in Table 10. Discontinuation of all agents due to treatment- related adverse events was 9% and 12% in the subcutaneous and intravenous groups, respectively. Treatment-related adverse events are shown in Table 11. Death due to adverse events occurred in 7 (3%) and 10 (5%) patients in the subcutaneous and intravenous groups, respectively. All grade 5 adverse events are listed in Table 12. Table 10. Adverse Events Leading to Treatment Interruptions, Reductions, and Discontinuations* Subcutaneous Intravenous group group (n=210) Event — no. (%) (n=206)Any event leading to interruptions of any study agent 127 (62) 127 (61) Most common events leading to interruptions of any study agent† Paronychia 27 (13) 10 (5) Dermatitis acneiform 26 (13) 15 (7) Rash 25 (12) 17 (8) Increased alanine 10 (5) 8 (4) aminotransferase COVID-19 9 (4) 12 (6) Peripheral edema 8 (4) 7 (3) Hypoalbuminemia 7 (3) 6 (3) Pyrexia 7 (3) 4 (2) Increased aspartate aminotransferase 6 (3) 6 (3) Vomiting 5 (2) 6 (3) Nausea 4 (2) 10 (5) Stomatitis 4 (2) 10 (5) Fatigue 4 (2) 9 (4) Asthenia 4 (2) 6 (3) Pneumonia 3 (2) 7 (3) Hypotension 0 6 (3) Any event leading to dose reductions of any study agent 63 (31) 52 (25) Most common events leading to dose reductions of any study agent Rash 16 (8) 8 (4) Paronychia 14 (7) 8 (4) Dermatitis acneiform 12 (6) 9 (4) Increased alanine 5 (2) 4 (2) aminotransferase Stomatitis 4 (2) 2 (1) Diarrhea 4 (2) 0 Fatigue 3 (1) 5 (2) Hypoalbuminemia 2 (1) 4 (2) Any event leading to discontinuations of any study agent 26 (13) 29 (14) Most common events leading to discontinuations of any study agentPneumonitis 7 (3) 6 (3) Dermatitis acneiform 4 (2) 1 (0.5) Infusion-related reaction 0 4 (2) *The safety population included all the patients who had undergone randomization and received at least one dose of any trial treatment. Events are listed according to decreasing incidence in the subcutaneous group. †Listed are adverse events that were reported in at least 3% of patients in any group. Listed are adverse events that were reported in at least 2% of patients in any group. Table 11. Treatment-related Adverse Events* Subcutaneous group Intravenous group Event — no. (%) (n=206) (n=210) Any event 196 (95) 206 (98) Grade ≥3 79 (38) 82 (39) Any serious event 33 (16) 34 (16) Any event resulting in death 3 (1) 4 (2) Adverse events reported in ≥15% of patients in either All Grade ≥3 All Grade ≥3 group† Paronychia 110 (53) 8 (4) 108 (51) 3 (1) Rash 90 (44) 8 (4) 91 (43) 8 (4) Hypoalbuminemia 79 (38) 5 (2) 66 (31) 7 (3) Dermatitis acneiform 64 (31) 18 (9) 69 (33) 12 (6) Stomatitis 54 (26) 1 (0.5) 67 (32) 5 (2) Peripheral edema 46 (22) 4 (2) 43 (20) 1 (0.5) Nausea 43 (21) 1 (0.5) 40 (19) 3 (1) Increased alanine aminotransferase 40 (19) 6 (3) 49 (23) 6 (3) Diarrhea 36 (17) 3 (1) 31 (15) 2 (1) Decreased appetite 37 (18) 1 (0.5) 44 (21) 2 (1) Increased aspartate aminotransferase 35 (17) 2 (1) 37 (18) 2 (1) Vomiting 33 (16) 2 (1) 29 (14) 1 (0.5) Fatigue 30 (15) 2 (1) 30 (14) 4 (2) Infusion-related reaction 27 (13) 1 (0.5) 136 (65) 8 (4) *The safety population included all the patients who had undergone randomization and received at least one dose of any trial treatment. †Events in this category are listed according to decreasing incidence in the subcutaneous group.Table 12. All Grade 5 Adverse Events* Subcutaneous group Intravenous group Event — no. (%)† (n=206) (n=210) Pneumonitis 1 (0.5) 3 (1) Respiratory failure 1 (0.5) 1 (0.5) Sudden death 1 (0.5) 1 (0.5) Respiratory disorder 1 (0.5) 0 Pneumonia 1 (0.5) 0 Pneumonia viral 1 (0.5) 0 Cardiac arrest 1 (0.5) 0 Urosepsis 0 1 (0.5) Asthenia 0 1 (0.5) Cerebral infarction 0 2 (1)§ Acute myocardial infarction 0 1 (0.5) *The safety population included all the patients who had undergone randomization and received at least one dose of any trial treatment. †Events in this category are listed according to decreasing incidence in the subcutaneous group. All events deemed related to any study treatment. §One event deemed related to any study treatment. Discussion

[0134] Subcutaneous amivantamab-lazertinib demonstrated noninferior pharmacokinetics and anti-tumor activity (objective response) compared to intravenous amivantamab-lazertinib. The geometric mean ratio was 1.15 at cycle-2-day-1 and 1.43 at cycle-4-day-1, indicating higher trough concentrations were maintained with subcutaneous versus intravenous administration, although AUCD1-D15 remained similar. Similarly to the established flat exposure-safety relationships previously reported, the 42% higher Ctrough observed here with subcutaneous amivantamab-lazertinib did not negatively impact its safety profile, as adverse event incidence was comparable between groups.

[0135] While objective response rate was noninferior for the subcutaneous versus the intravenous group, response duration was longer and there was a higher proportion of patients with stable disease in the subcutaneous group. There may be a potential clinical benefit for subcutaneous amivantamab-lazertinib in disease control. Progression-free survival was also numerically longer in the subcutaneous versus the intravenous group. The overall survival analysis showed evidence of improved survivalwith subcutaneous versus intravenous amivantamab-lazertinib (hazard ratio for death, 0.62). The potential efficacy benefit in the subcutaneous group may be driven by more sustained exposure, as indicated by higher Ctrough, or better patient compliance, as indicated by longer treatment exposure. The impact of subcutaneous administration on lymphatic absorption and immune stimulation is unknown but may also play a role. Although study follow-up is 7.0 months and further investigation is needed, this trial showed evidence of clinically relevant improvement with subcutaneous amivantamab. Furthermore, a potential progression-free survival benefit for amivantamab-lazertinib was seen in this heavily pretreated population, where docetaxel, the only available option, has demonstrated a progression-free survival of 3.5 months.

[0136] There were no unexpected toxicities from intravenous and subcutaneous amivantamab-lazertinib, consistent with previous reports. Subcutaneous amivantamab- lazertinib demonstrated an improved safety profile by reducing the rate and severity of infusion-related reactions by over 5-fold compared to intravenous amivantamab- lazertinib.

[0137] This trial is the first to prospectively evaluate the impact of prophylactic anticoagulation on the risk of VTE with amivantamab-lazertinib. The prevalence of VTE in lung cancer is 14%–30%, with values higher in patients with molecular driver alterations. It was found that prophylactic anticoagulation meaningfully reduced VTE incidence and severity, with low risk of clinically significant bleeding; this was consistent across both administration routes. The safety and efficacy of prophylactic anticoagulation seen here was comparable with prior studies of patients with similar risk profiles. Regardless of prophylactic anticoagulation, VTE rates were lower for subcutaneous amivantamab-lazertinib than the intravenous group.

[0138] Importantly, the increased tolerability and convenience of the subcutaneous formulation (e.g., median administration time was 5 minutes versus 5 hours for intravenous administration) seen in the PALOMA-3 trial may improve patient and provider experiences while maintaining efficacy. Intravenous amivantamab-based combinations are efficacious in the first- and second-line treatment of patients with advanced NSCLC harboring EGFR mutations.

[0139] In summary, subcutaneous amivantamab-lazertinib demonstrated noninferior pharmacokinetics and objective response rate versus intravenous amivantamab-lazertinib. Longer response duration, progression-free survival, and overall survival were observed in the subcutaneous group. Additionally, subcutaneousamivantamab-lazertinib led to reduced infusion-related reactions, shorter administration time, and fewer VTEs versus intravenous amivantamab-lazertinib. Prophylactic anticoagulation mitigated the risk of VTEs in both groups. Example 5: Subcutaneous Amivantamab and Lazertinib as First-line Treatment in Patients with EGFR-mutated Advanced Non-small Cell Lung Cancer (NSCLC): Interim results from the Phase 2 PALOMA-2 Study

[0140] PALOMA-2 is a global, parallel cohort, phase 2 trial evaluating the efficacy, safety, and PK of SC amivantamab (including combinations with chemotherapy and / or lazertinib) in patients with locally advanced or metastatic EGFR-mutated NSCLC. Methods

[0141] Cohorts 1 and 6 enrolled patients with treatment-naïve, EGFR Ex19del or L858R-mutated NSCLC. SC amivantamab was administered by manual injection in the abdomen at 1600 mg (or 2240 mg if ≥80 kg) weekly for the first 4 weeks and every 2 weeks thereafter. Lazertinib was administered orally at 240 mg daily. Prophylactic anticoagulation for the first 4 months of treatment was recommended in Cohort 1 and mandatory in Cohort 6. The primary endpoint was objective response rate (ORR) as assessed by the investigator per RECIST v1.1.

[0142] As of January 6, 2024, 68 and 58 patients were enrolled in Cohorts 1 and 6, respectively (Table 13). The median follow-up was 10 months for Cohort 1 and 6.1 months for Cohort 6. Table 13. Demographics and baseline disease characteristics Characteristic, n (%) Cohort 1 Cohort 6 Total (n=68) (n=58) (n=126) Age, median (range), 58 (28–85) 62 (34–83) 59 (28–85) years Female 42 (62) 34 (59) 76 (60) Race Asian 45 (66) 40 (69) 85 (68) White 19 (28) 16 (28) 35 (28) a Other4 (5) 2 (3) 6 (5)ECOG PS score 1 48 (71) 43 (75) 91 (73) History of smoking 15 (22) 18 (31) 33 (26) Brain metastases 20 (29) 18 (31) 38 (30)b EGFR mutation type Ex19del 45 (66) 34 (59) 79 (63) L858R 24 (35) 24 (41) 48 (38) Adenocarcinoma 65 (96) 57 (98) 122 (97) histologyaOther included: Black or African-American and American Indian / Alaska Native;bPatients could be included in more than one category. ECOG PS, Eastern Cooperative Oncology Group Performance Status; EGFR, epithelial growth factor receptor; Ex19del, Exon 19 deletion. Results: Efficacy

[0143] Among all patients, investigator-assessed (INV) ORR was 77% and independent central review (ICR) ORR was 79% (Table 14). Similar ICR ORR of 86% (95% CI, 83–89) was observed with IV amivantamab + lazertinib in MARIPOSA. Among confirmed responders (n=75): - Median TTR was 1.9 months (range, 1.4–5.3) - Median DoR was not estimable in both cohorts - Best response is shown in FIG.11 - Treatment is still ongoing in 69 (92%) patients (FIG.12) Table 14. Response Cohort 1 Cohort 6 Total (n=68) (n=45) (n=113) INV ICR INV ICR INV ICR ORR, % 75 81 80 76 77 79 (95% CI) (63–85) (70–89) (65–90) (61–87) (68–84) (70–86) The median follow-up was 10.0 months for Cohort 1, 6.1 months for Cohort 6, and 8.6 months overall Results: Safety

[0144] The safety profile was consistent with what was previously reported, with no new safety signals identified (Table 15). Discontinuations of all agents due to treatment-related AEs occurred in 9% (11 / 125) of patients

[0145] Administration Related Reactions (ARRs) were reported by 15% (19 / 125) of patients. The majority of ARR events (n=18 / 20; 90%) occurred in Cycle 1 (Event onset was on or after Cycle 1 Day 1 injection start but before Cycle 1 Day 8injection start). The median time to ARR onset (calculated as the start of the ARR minus the start of the last injection prior to this event) was 2.3 hours (range, 0.3-7.2). Rates were lower compared to the rate with IV administration in MARIPOSA (63%). Table 15. Safety profile Most common Cohort 1 (n=68) Cohort 6 (n=57)1Total (n=125) treatment-emergent All Grade All Grade All Grade AEs (≥20%), n (%) grades ≥3 grades ≥3 grades ≥3 Associated with EGFR inhibition Paronychia 49 (72) 2 (3) 40 (70) 2 (4) 89 (71) 4 (3) Rash 48 (71) 9 (13) 28 (49) 3 (5) 76 (61) 12 (10) Dermatitis acneiform 31 (46) 10 (15) 18 (32) 1 (2) 49 (39) 11 (9) Pruritus 22 (32) 0 15 (26) 0 37 (30) 0 Stomatitis 20 (29) 3 (4) 31 (54) 1 (2) 51 (41) 4 (3) Diarrhea 16 (24) 0 12 (21) 1 (2) 28 (22) 1 (1) Associated with MET inhibition Hypoalbuminemia 37 (54) 3 (4) 23 (40) 0 60 (48) 3 (2) Peripheral edema 26 (38) 1 (1) 14 (25) 1 (2) 40 (32) 2 (2) Other Increased ALT 26 (38) 0 21 (37) 3 (5) 47 (38) 3 (2) Increased AST 22 (32) 1 (1) 19 (33) 2 (4) 41 (33) 3 (2) Nausea 16 (24) 0 16 (28) 0 32 (26) 0 Decreased appetite 18 (26) 0 13 (23) 0 31 (25) 0 Myalgia 18 (26) 1 (1) 12 (21) 0 30 (24) 1 (1) Constipation 18 (26) 0 14 (25) 0 32 (26) 0 Paresthesia 14 (21) 0 6 (11) 0 20 (16) 01One patient in Cohort 6 was enrolled but not treated at the time of the clinical cutoff.

[0146] A total of 71% of patients in Cohort 1 and all patients in Cohort 6 received prophylactic anticoagulation (apixaban, rivaroxaban, dalteparin, or enoxaparin (per NCCN guideline Cancer-Associated Venous Thromboembolic Disease version 1.2022) were recommended by protocol). Overall, VTE was reported in 18% (12 / 68) and 7% (4 / 57) of patients in Cohorts 1 and 6, respectively. (Table 16; 13% [16 / 125] of all patients). There were no dose reductions or discontinuations due to VTE. Grade ≥3 bleeding was reported in 2% (2 / 125) of all patients Table 16. VTE and bleeding events based on prophylactic anticoagulation use Any prophylactic No prophylactic Total Patients, n (%) anticoagulation anticoagulation (n=125) (n=105) (n=20)Any VTE 12 (11) 4 (20) 16 (13) Grade ≥30 1 (5) 1 (1)Grade 5 0 0 0 Any VTE leading to death 0 0 0 Any VTE leading to any 0 0 0 discontinuation Grade ≥3 bleeding 2 (2) 0 2 (2) VTE AEs are identified by the standardized MedDRA query for “Embolic and thrombotic events, venous (SMQ) and Preferred Term is “Thrombosis” or “Embolism.” Bleeding AE terms are identified by the standardized MedDRA query for “Hemorrhage Terms (Excl Laboratory Terms)” (narrow scope). Results: Pharmacokinetics

[0147] Consistent with historic IV levels (317 [32.0] µg / mL), mean (%CV) amivantamab concentrations on cycle 2 day 1 were: - 328 (31.8) µg / mL (n=50) in Cohort 1; and - 373 (26.9) µg / mL (n=42) in Cohort 6. Conclusions

[0148] SC amivantamab + lazertinib showed meaningful efficacy in first-line EGFR-mutated advanced NSCLC, with an ORR comparable to that of IV amivantamab + lazertinib in the MARIPOSA study. Overall, the SC amivantamab + lazertinib safety profile was similar to MARIPOSA, except for markedly low rates of ARRs (15%), which are markedly lower compared to historical IV data. Rates of VTE (13%) were similar to the rates in MARIPOSA; prophylactic anticoagulation can be safely implemented and effectively reduces the rates of VTE among patients treated with amivantamab + lazertinib. Consistent PK profiles further support the use of SC amivantamab.

[0149] This bridging study provides promising evidence for the efficacy and safety of subcutaneous amivantamab + lazertinib, suggesting that subcutaneous amivantamab + lazertinib could offer a valuable first-line treatment option for patients with EGFR-mutated advanced NSCLC. Example 6. Approved Drug Product LabelANNEX I SUMMARY OF PRODUCT CHARACTERISTICS1. NAME OF THE MEDICINAL PRODUCT Rybrevant 350 mg concentrate for solution for infusion. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One mL of concentrate for solution for infusion contains 50 mg amivantamab. One 7 mL vial contains 350 mg of amivantamab. 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. Excipient with known effect: One mL of solution contains 0.6 mg of polysorbate 80. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Concentrate for solution for infusion. 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 Rybrevant is indicated: ^ in combination with lazertinib for the first-line treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations. ^ 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). ^ in combination with carboplatin and pemetrexed for the first-line treatment of adult patients with advanced NSCLC with activating EGFR Exon 20 insertion mutations. ^ 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 Treatment with Rybrevant should be initiated and supervised by a physician experienced in the use of anticancer medicinal products. Rybrevant should be administered by a healthcare professional with access to appropriate medical support to manage infusion-related reactions (IRRs) if they occur. 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; testingdoes not need to be repeated once EGFR mutation status has been established (see section 5.1). Posology Premedications should be administered to reduce the risk of IRRs with Rybrevant (see below “Dose modifications” and “Recommended concomitant medicinal products”). Every 3 weeks The recommended dosages of Rybrevant, when used in combination with carboplatin and pemetrexed, is provided in Table 1 (see below “Infusion rates” and Table 5). Table 1: Recommended dosage of Rybrevant every 3 weeks Body weight Rybrevant Schedule Number of at baselineadose vials Less than 1400 mg Weekly (total of 4 doses) from Weeks 4 80 kg 1 to 4 ^ Week 1 - split infusion on Day 1 and Day 2 ^ Weeks 2 to 4 - infusion on Day 1 1750 mg Every 3 weeks starting at Week 7 5 onwards Greater than or 1750 mg Weekly (total of 4 doses) from Weeks 5 equal to 80 kg 1 to 4 ^ Week 1 - split infusion on Day 1 and Day 2 ^ Weeks 2 to 4 - infusion on Day 1 2100 mg Every 3 weeks starting at Week 7 6 onwards aDose adjustments not required for subsequent body weight changes.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 The recommended dosages of Rybrevant monotherapy or in combination with lazertinib is provided in Table 2 (see below “Infusion rates” and Table 6). Table 2: Recommended dosage of Rybrevant every 2 weeks Body weight Rybrevant Schedule Number of at baselineadose 350 mg / 7 mL Rybrevant vials Less than Weekly (total of 4 doses) from weeks 1 80 kg to 4 ^ Week 1 - split infusion on Day 1 and 1050 mg Day 2 3 ^ Weeks 2 to 4 - infusion on Day 1 Every 2 weeks starting at Week 5 onwards Greater than Weekly (total of 4 doses) from Weeks 1 or equal to to 4 80 kg ^ Week 1 - split infusion on Day 1 and 1400 mg Day 2 4 ^ Weeks 2 to 4 - infusion on Day 1 Every 2 weeks starting at Week 5 onwards aDose adjustments not required for subsequent body weight changes.When given in combination with lazertinib, it is recommended to administer Rybrevant any time after lazertinib when given on the same day. Refer to section 4.2 of the lazertinib Summary of Product Characteristics for recommended lazertinib dosing information. Duration of treatment It is recommended that patients are treated with Rybrevant until disease progression or unacceptable toxicity. Missed dose 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 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 as presented in Table 3. See also specific dose modifications for specific adverse reactions below Table 3. If used in combination with lazertinib, refer to section 4.2 of the lazertinib Summary of Product Characteristics for information about dose modifications. Table 3: Recommended dose modifications for adverse reactions Dose at which the Dose after 1stDose after 2ndDose after 3rdadverse reaction interruption for interruption for interruption for occurred adverse reaction adverse reaction adverse reaction 1050 mg 700 mg 350 mg1400 mg 1050 mg 700 mg Discontinue 1750 mg 1400 mg 1050 mgRybrevant2100 mg 1750 mg 1400 mg Infusion-related reactions 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 from 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 5 and 6). Concomitant medicinal products should be administered at the next dose (including dexamethasone (20 mg) or equivalent (see Table 4). ^ Recurrent Grade 3 or Grade 4 (life-threatening): Permanently discontinue Rybrevant. Venous thromboembolic (VTE) events with concomitant use with lazertinib At the initiation of treatment, prophylactic anticoagulants should be administered to prevent VTE events in patients receiving Rybrevant in combination with lazertinib. Consistent with clinical guidelines, patients should receive prophylactic dosing of either a direct acting oral anticoagulant (DOAC) or a low-molecular weight heparin (LMWH). Use of Vitamin K antagonists is not recommended. For VTE events associated with clinical instability (e.g., respiratory failure or cardiac dysfunction), both drugs should be withheld until the patient is clinically stable. Thereafter, both medicinal products can be resumed at the same dose. In the event of recurrence despite appropriate anticoagulation, discontinue Rybrevant. Treatment can continue with lazertinib at the same dose. Skin and nail reactions Patients should be instructed to limit sun exposure during and for 2 months after Rybrevant therapy. Alcohol-free emollient cream is recommended for dry areas. Forfurther information about prophylaxis for skin and nail reactions, see section 4.4. 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 3). 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 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 Prior to infusion (Week 1, Days 1 and 2), antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of IRRs (see Table 4). 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. Table 4: Dosing schedule of premedications Recommended dosing window prior to Premedicatio Route of Rybrevant n Dose administration administration Antihistamin Diphenhydramine (25 to Intravenous 15 to 30 minutes e*50 mg) or equivalent Oral 30 to 60 minutesParaceta Intravenous 15 to 30 minutes * mol / Acetaminophen Antipyretic (650 to 1000 mg) Oral 30 to 60 minutes Glucocorticoi Dexamethasone (20 mg) or Intravenous 60 to 120 minutes d equivalent Glucocorticoi Dexamethasone (10 mg) or Intravenous 45 to 60 minutes d+equivalent * 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 There is no relevant use of amivantamab in the paediatric population in the treatment of non-small cell lung cancer. Elderly No dose adjustments are necessary (see section 4.8, section 5.1, and section 5.2). Renal impairment 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 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 (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 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. For instructions on dilution of the medicinal product before administration, see section 6.6. Infusion rates Following dilution, the infusion should be administered intravenously at the infusion rates presented in Table 5 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 5: Infusion rates for Rybrevant every 3 weeks Body weight less than 80 kg Week Dose Initial Subsequent infusion rate infusio†(per 250 mL bag) n rate Week 1 (split dose infusion) Week 1 Day 1 350 mg 50 mL / hr 75 mL / hr Week 1 Day 2 1050 mg 33 mL / hr 50 mL / hr Week 2 1400 mg 65 mL / hr Week 3 1400 mg 85 mL / hr Week 4 1400 mg 125 mL / hr Subsequent weeks*1750 mg 125 mL / hr Body weight greater than or equal to 80 kg Week Dose Initial Subsequent i†(per 250 mL bag) nfusion rate infusion rate Week 1 (split dose infusion) Week 1 Day 1 350 mg 50 mL / hr 75 mL / hr Week 1 Day 2 1400 mg 25 mL / hr 50 mL / hr Week 2 1750 mg 65 mL / hr Week 3 1750 mg 85 mL / hr Week 4 1750 mg 125 mL / hr Subsequent weeks*2100 mg 125 mL / hr * 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.Table 6: Infusion rates for Rybrevant every 2 weeks Body weight less than 80 kg Week Dose Initial Subsequent (per 250 mL bag) infusion rate infusion rate Week 1 (split dose infusion) Week 1 Day 1 350 mg 50 mL / hr 75 mL / hr Week 1 Day 2 700 mg 50 mL / hr 75 mL / hr Week 2 1050 mg 85 mL / hr Subsequent weeks*1050 mg 125 mL / hr Body weight greater than or equal to 80 kg Week Dose Initial Subsequent (per 250 mL bag) infusion rate infusion rate Week 1 (split dose infusion) Week 1 Day 1 350 mg 50 mL / hr 75 mL / hr Week 1 Day 2 1050 mg 35 mL / hr 50 mL / hr Week 2 1400 mg 65 mL / hr Week 3 1400 mg 85 mL / hr Subsequent weeks*1400 mg 125 mL / hr * 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 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 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 Infusion-related reactions commonly occurred in patients treated with amivantamab (see section 4.8). 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. 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 recurrent Grade 3 or Grade 4 IRRs, Rybrevant should be permanently discontinued (see section 4.2). Interstitial lung disease Interstitial lung disease (ILD) or ILD-like adverse reactions (e.g., pneumonitis) have been reported in patients treated with amivantamab, including fatal events (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 adversereactions 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). Venous thromboembolic (VTE) events with concomitant use with lazertinib In patients receiving Rybrevant in combination with lazertinib, VTE events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), including fatal events, were reported (see section 4.8). Consistent with clinical guidelines, patients should receive prophylactic dosing of either a direct acting oral anticoagulant (DOAC) or a low-molecular weight heparin (LMWH). Use of Vitamin K antagonists is not recommended. Signs and symptoms of VTE events should be monitored. Patients with VTE events should be treated with anticoagulation as clinically indicated. For VTE events associated with clinical instability treatment should be withheld until the patient is clinically stable. Thereafter, both drugs can be resumed at the same dose. In the event of recurrence despite appropriate anticoagulation, Rybrevant should be discontinued. Treatment can continue with lazertinib at the same dose (see section 4.2). Skin and nail reactions 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. This includes prophylactic therapy with an oral antibiotic (e.g., doxycycline or minocycline, 100 mg twice daily) starting on Day 1 for the first 12 weeks of treatment and after completion of oral antibiotic therapy, topical antibiotic lotion to the scalp (e.g., clindamycin 1%) for the next 9 months of treatment. Non-comedogenic skin moisturiser on the face and whole body (except scalp) and chlorhexidine solution to wash hands andfeet should be considered beginning on Day 1 and continued for the first 12 months of treatment. Prescriptions for topical and / or oral antibiotics and topical corticosteroids are recommended to be available at the time of initial dosing to minimise any delay in reactive management should rash develop despite prophylactic treatment. 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). Toxic epidermal necrolysis (TEN) has been reported. Treatment with this medicinal product should be discontinued if TEN is confirmed. Eye disorders 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 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 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).Polysorbate content This medicinal product contains 0.6 mg of polysorbate 80 in each mL, which is equivalent to 4.2 mg per 7 mL vial. Polysorbates may cause hypersensitivity reactions. 4.5 Interaction with other medicinal products and other forms of interaction 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 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 Women of child-bearing potential should use effective contraception during and for 3 months after cessation of amivantamab treatment. Pregnancy 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, andabortion. 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 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 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 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 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 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 Table 7 summarises the adverse drug reactions that occurred in patients receiving amivantamab as monotherapy. 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). 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). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.Table 7: Adverse reactions in patients receiving amivantamab as monotherapy System organ class Frequency Any Grade Grade 3-4 Adverse reaction category (%) (%) Metabolism and nutrition disorders Hypoalbuminaemia* (see Very common 31 2†section 5.1) Decreased appetite 16 0.5†Hypocalcaemia 10 0.3†Hypokalaemia Common 9 2 Hypomagnesaemia 8 0 Nervous system disorders Dizziness* Very common 13 0.3†Eye disorders Visual impairment* Common 3 0 Growth of eyelashes* 1 0 Other eye disorders* 6 0 Keratitis Uncommon 0.5 0 Uveitis 0.3 0 Respiratory, thoracic and mediastinal disorders Interstitial lung disease* Common 3 0.5†Gastrointestinal disorders Diarrhoea Very common 11 2†Stomatitis* 24 0.5†Nausea 23 0.5†Constipation 23 0Vomiting 12 0.5†Abdominal pain* Common 9 0.8†Haemorrhoids 3.7 0 Hepatobiliary disorders Alanine aminotransferase increased Very common 15 2 Aspartate aminotransferase 13 1 increased Blood alkaline phosphatase 12 0.5†increased Skin and subcutaneous tissue disorders Rash* Very common 76 3†Nail toxicity* 47 2†Dry skin* 19 0 Pruritus 18 0 Toxic epidermal necrolysis Uncommon 0.3 0.3†Musculoskeletal and connective tissue disorders Myalgia Very common 11 0.3†General disorders and administration site conditions Oedema* Very common 26 0.8†Fatigue* 26 0.8†Pyrexia 11 0 Injury, poisoning and procedural complications Infusion related reaction Very common 67 2 * Grouped terms † Grade 3 events onlySummary of the safety profile 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%). Table 8 summarises the adverse drug reactions that occurred in patients receiving amivantamab in combination with chemotherapy. 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). 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).Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Table 8: Adverse reactions in patients receiving amivantamab in combination with carboplatin and pemetrexed System organ class Frequency Any Grade Grade 3-4 Adverse reaction category (%) (%) Blood and lymphatic system disorders Neutropenia Very common 57 39 Thrombocytopenia 40 12 Metabolism and nutrition disorders Decreased appetite Very common 33 1.3 Hypoalbuminaemia* 32 3.7 Hypokalaemia 20 6.6 Hypomagnesaemia 13 1.3 Hypocalcaemia 12 1.0 Nervous system disorders Dizziness* Common 10 0.3 Vascular disorders Venous thromboembolism* Very common 14 3.0 Eye disorders Other eye disorders* Common 7.3 0 Visual impairment* 3.0 0 Growth of eyelashes Uncommon 0.3 0 Keratitis 0.3 0 Uveitis 0.3 0Respiratory, thoracic and mediastinal disorders Interstitial lung disease* Common 2.3 1.7 Gastrointestinal disorders Nausea Very common 43 1.0 Constipation 40 0.3 Stomatitis* 39 3.0 Vomiting 22 2.0 Diarrhoea 19 2.3 Abdominal pain* Common 11 0.3 Haemorrhoids 9.3 0.7 Hepatobiliary disorders Alanine aminotransferase increased Very common 26 4.3 Aspartate aminotransferase 23 0.7 increased Blood alkaline phosphatase Common 10 0.3 increased Skin and subcutaneous tissue disorders Rash* Very common 83 14 Nail toxicity* 53 4.3 Dry skin* 16 0 Pruritus 10 0 Musculoskeletal and connective tissue disorders Myalgia Common 5.0 0.7 General disorders and administration site conditions Fatigue* Very common 43 4.7 Oedema* 40 1.3Pyrexia 14 0 Injury, poisoning and procedural complications Infusion related reaction Very common 51 3.0 * Grouped terms Summary of the safety profile In the dataset of amivantamab in combination with lazertinib (N=421), the most frequent adverse reactions in all grades were rash (89%), nail toxicity (71%), infusion-related reactions (63%), hypoalbuminaemia (48%), hepatotoxicity (47%), oedema (47%), stomatitis (43%), venous thromboembolism (37%), paraesthesia (lazertinib) (34%), fatigue (32%), diarrhoea (29%), constipation (29%), dry skin (26%), pruritis (24%), decreased appetite (24%), hypocalcaemia (21%), nausea (21%) and other eye disorders (21%). The most frequent serious adverse reactions included venous thromboembolism (11%), pneumonia (4.0%), rash (3.1%), ILD / pneumonitis (2.9%), hepatotoxicity (2.4%), COVID-19 (2.4%), and IRR and pleural effusion (2.1%). Twenty-three percent of patients discontinued Rybrevant due to adverse reactions. The most frequent adverse reactions leading to Rybrevant discontinuation were rash (5.5%), infusion related reactions (4.5%), nail toxicity (3.6%), ILD (2.9%) and VTE (2.9%). Table 9 summarises the adverse drug reactions that occurred in patients receiving amivantamab in combination with lazertinib. The data reflects exposure to amivantamab in combination with lazertinib in 421 patients with locally advanced or metastatic non-small cell lung cancer. Patients received amivantamab 1050 mg (for patients < 80 kg) or 1400 mg (for patients ≥ 80 kg) once weekly for 4 weeks, then every 2 weeks thereafter. The median exposure to study treatment in the amivantamab and lazertinib combination group was 18.5 months (range: 0.2 to 31.4 months).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). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Table 9: Amivantamab adverse reactions in patients receiving amivantamab in combination with lazertinib System organ class Frequency Any Grade Grade 3-4 Adverse reaction category (%) (%) Metabolism and nutrition disorders Hypoalbuminaemia*Very 48 5 Decreased appetite common 24 1.0 Hypocalcaemia 21 2.1 Hypokalaemia 14 3.1 Hypomagnesaemia Common 5.0 0 Nervous system disorders Paraesthesia*Very 34 1.7 Dizziness*common 13 0 Vascular disorders Venous thromboembolism*Very 37 11 commonEye disorders Other eye disorders*Very 21 0.5 common Visual impairment*Common 4.5 0 Keratitis 2.6 0.5 Growth of eyelashes*1.9 0 Respiratory, thoracic and mediastinal disorders Interstitial lung disease / Pneumonitis*Common 3.1 1.2 Gastrointestinal disorders Stomatitis*Very 43 2.4 Diarrhoea common 29 2.1 Constipation 29 0 Nausea 21 1.2 Vomiting 12 0.5 Abdominal pain*11 0 Haemorrhoids Common 10 0.2 Hepatobiliary disorders Hepatotoxicity†Very 47 9 common Skin and subcutaneous tissue disorders Rash*Very 89 27 Nail toxicity*common 71 11 Dry skin*26 1.0 Pruritus 24 0.5 Palmar-plantar erythrodysaesthesia Common 6 0.2 syndromeUrticaria 1.2 0 Musculoskeletal and connective tissue disorders Muscle spasms Very 17 0.5 Myalgia common 13 0.7 General disorders and administration site conditions Oedema*Very 47 2.9 Fatigue*common 32 3.8 Pyrexia 12 0 Injury, poisoning and procedural complications Infusion related reaction Very 63 6 common *Grouped termsAssessed as ADR for lazertinib only.†The most common events included increased ALT (36%), increased AST (29%) and increase blood alkalinephosphatase (12%). Description of selected adverse reactions Infusion-related reactions 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). In patients treated with amivantamab in combination with carboplatin and pemetrexed, infusion-related reactions occurred in 50% of patients. Greater than 94% of IRRs wereGrade 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. In patients treated with amivantamab in combination with lazertinib, infusion-related reactions occurred in 63% of patients. Ninety-four percent of IRRs were Grade 1-2. A majority of IRRs occurred at the first infusion with a median time to onset of 1 hour, 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) Occasionally an IRR can occur at re-initiation of amivantamab after prolonged dose interruptions of more than 6 weeks. Interstitial lung disease or ILD-like adverse reactions have been reported with the use ofas as with other EGFR inhibitors. Interstitial lung disease or pneumonitis was reported in 2.6% of patients treated with amivantamab monotherapy, 2.3 % of patients treated with amivantamab in combination with carboplatin and pemetrexed and 3.1% of patients treated with amivantamab in combination with lazertinib, including 1 (0.2%) fatal case. 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). Venous thromboembolic (VTE) events with concomitant use with lazertinib When Rybrevant is used in combination with lazertinib, VTE events, including deep venous thrombosis (DVT) and pulmonary embolism (PE), were reported in 37% of the 421 patients receiving Rybrevant in combination with lazertinib. Most cases were Grade 1 or 2, with Grade 3-4 events occurring in 11% of patients receiving Rybrevant in combination with lazertinib and deaths occurring in 0.5% of patients receivingRybrevant in combination with lazertinib. For information on prophylactic anticoagulants and management of VTE events, see sections 4.2 and 4.4. In patients receiving Rybrevant in combination with lazertinib, the median time to first onset of a VTE event was 84 days. VTE events led to Rybrevant treatment discontinuation in 2.9% of patients. Skin and nail reactions Rash (including dermatitis acneiform), pruritus, and dry skin occurred in 76% 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. 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 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). Rash (including dermatitis acneiform), occurred in 89% of patients treated with amivantamab in combination with lazertinib. Most cases were Grade 1 or 2, with Grade 3 rash events occurring in 27% of patients. Rash leading to amivantamab discontinuation occurred in 5.5% 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 lazertinib. Most events were Grade 1 or 2, with Grade 3 nail toxicity occurring in 11% of patients (see section 4.4).Eye disorders 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. 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). Eye disorders, including keratitis (2.6%) occurred in patients treated with amivantamab in combination with lazertinib. Other reported adverse reactions included growth of eyelashes, visual impairment, and other eye disorders. Most events were Grade 1-2 (see section 4.4). Special populations Elderly 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 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 1862 (0.2%) participants who were treated with Rybrevant and evaluable for the presence of anti-drug antibodies (ADA), tested positive fortreatment-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 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 via the national reporting system listed in Appendix V.4.9 Overdose 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 Amivantamab is a low-fucose, fully-human IgG1-based EGFR-MET bispecific antibody with immune cell-directing activity that targets tumours with activating EGFR mutationssuch as Exon 19 deletions, Exon 21 L858R substitution, and Exon 20 insertion mutations. Amivantamab binds to the extracellular domains of EGFR and MET. 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 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-untreated NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations (MARIPOSA) NSC3003 (MARIPOSA) is a randomised, open-label, active-controlled, multicenter phase 3 study assessing the efficacy and safety of Rybrevant in combination with lazertinib as compared to osimertinib monotherapy as first-line treatment in patients with EGFR-mutated locally advanced or metastatic NSCLC not amenable to curative therapy. Patient samples were required to have one of the two common EGFR mutations (Exon 19 deletion or Exon 21 L858R substitution mutation), as identified by local testing. Tumour tissue (94%) and / or plasma (6%) samples for all patients were tested locally to determine EGFR Exon 19 deletion and / or Exon 21 L858R substitutionmutation status using polymerase chain reaction (PCR) in 65% and next generation sequencing (NGS) in 35% of patients. A total of 1074 patients were randomised (2:2:1) to receive Rybrevant in combination with lazertinib, osimertinib monotherapy, or lazertinib monotherapy until disease progression or unacceptable toxicity. 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 thereafter starting at week 5. Lazertinib was administered at 240 mg orally once daily. Osimertinib was administered at a dose of 80 mg orally once daily. Randomisation was stratified by EGFR mutation type (Exon 19 deletion or Exon 21 L858R), race (Asian or non-Asian), and history of brain metastasis (yes or no). Baseline demographics and disease characteristics were balanced across the treatment arms. The median age was 63 (range: 25–88) years with 45% of patients ≥ 65 years; 62% were female; and 59% were Asian, and 38% were White. Baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 (34%) or 1 (66%); 69% never smoked; 41% had prior brain metastases; and 90% had Stage IV cancer at initial diagnosis. With regard to EGFR mutation status, 60% were Exon 19 deletions and 40% were Exon 21 L858R substitution mutations. Rybrevant in combination with lazertinib demonstrated a statistically significant improvement in progression-free survival (PFS) by BICR assessment. With a median follow up of approximately 31 months, the updated OS HR was 0.77; (95% CI: 0.61, 0.96; p=0.0185). This was not statistically significant as compared to a 2-sided significance level of 0.00001.Table 10: Efficacy results in MARIPOSA Rybrevant + lazertinib Osimertinib (N=429) (N=429) Progression-free survival (PFS)aNumber of events 192 (45%) 252 (59%) Median, months (95% CI) 23.7 (19.1, 27.7) 16.6 (14.8, 18.5) Hazard Ratio (95% CI); p-value 0.70 (0.58, 0.85); p=0.0002 Overall survival (OS) Number of events 142 (33%) 177 (41%) Median, months (95% CI) NE (NE, NE) 37.3 (32.5, NE) Hazard Ratio (95% CI); 0.77 (0.61, 0.96); p=0.0185 p-valuebObjective response rate (ORR)a,cORR % (95% CI) 80% (76%, 84%) 77% (72%, 81%) Duration of response (DOR)a,cMedian (95% CI), months 25.8 (20.3, 33.9) 18.1 (14.8, 20.1) BICR = blinded independent central review; CI = confidence interval; NE = not estimable PFS results are from data cut-off 11 August 2023 with a median follow-up of 22.0 months. OS, DOR and ORR results are from data cut-off 13 May 2024 with a median follow-up of 31.3 months.aBICR by RECIST v1.1.bThe p-value is compared to a 2-sided significance level of 0.00001. Thus the OS results are not statisticallysignificant as of the latest interim analysis.cBased on confirmed responders.Figure 1: Kaplan-Meier curve of PFS in previously untreated NSCLC patients by BICR assessmentFigure 2: Kaplan-Meier curve of OS in previously untreated NSCLC patientsIntracranial ORR and DOR by BICR were pre-specified endpoints in MARIPOSA. In the subset of patients with intracranial lesions at baseline, the combination of Rybrevant and lazertinib, demonstrated similar intracranial ORR to the control. Per protocol, all patients in MARIPOSA had serial brain MRIs to assess intracranial response and duration. Results are summarised in Table 11.Table 11: Intracranial ORR and DOR by BICR assessment in subjects with intracranial lesions at baseline - MARIPOSA Rybrevant + lazertinib Osimertinib (N=180) (N=186) Intracranial Tumour Response Assessment Intracranial ORR (CR+PR), % 77% 77% (95% CI) (70%, 83%) (70%, 82%) Complete response 63% 59% Intracranial DOR Number of responders 139 144 Median, months (95% CI) NE (21.4, NE) 24.4 (22.1, 31.2) CI = confidence interval NE = not estimable Intracranial ORR and DOR results are from data cut-off 13 May 2024 with a median follow-up of 31.3 months. Previously treated NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations (MARIPOSA-2) 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 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, 263 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. 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). 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. 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).Efficacy results are summarised in Table 12. Table 12: Efficacy results in MARIPOSA-2 Rybrevant+ carboplatin+ carboplatin+ pemetrexed pemetrexed (N=131) (N=263) Progression-free survival (PFS)aNumber of events (%) 74 (57) 171 (65) Median, months (95% CI) 6.3 (5.6, 8.4) 4.2 (4.0, 4.4) HR (95% CI); p-value 0.48 (0.36, 0.64); p<0.0001 Overall survival (OS) Number of events (%) 65 (50) 143 (54) Median, months (95% CI) 17.7 (16.0, 22.4) 15.3 (13.7, 16.8) HR (95% CI); p-valueb0.73 (0.54, 0.99); p=0.0386 Objective response rateaORR, % (95% CI) 64% (55%, 72%) 36% (30%, 42%) Odds Ratio (95% CI); p-value 3.10 (2.00, 4.80); p<0.0001 Duration of response (DOR)aMedian (95% CI), months 6.90 (5.52, NE) 5.55 (4.17, 9.56) Patients with DOR ≥ 6 months 31.9% 20.0%CI = Confidence Interval NE = not estimable PFS, DOR 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. aBICR-assessedbThe p-value is compared to a 2-sided significance level of 0.0142. Thus the OS results are not significant as ofthe second interim analysis. Figure 3: Kaplan-Meier curve of PFS in previously treated NSCLC patients by BICR assessmentThe 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.Figure 4: Kaplan-Meier curve of OS in previously treated NSCLC patientsIntracranial metastases efficacy data 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. Previously-untreated non-small cell lung cancer (NSCLC) with Exon 20 insertion mutations (PAPILLON) 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 todetermine 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. 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. 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. 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. The primary endpoint for PAPILLON was PFS, as assessed by BICR. The median follow-up was14.9 months (range: 0.3 to 27.0).Efficacy results are summarised in Table 13. Table 13: Efficacy results in PAPILLON Rybrevant + carboplatin+ carboplatin+ pemetrexed pemetrexed (N=153) (N=155) Progression-free survival (PFS)aNumber of events 84 (55%) 132 (85%) Median, months (95% CI) 11.4 (9.8, 13.7) 6.7 (5.6, 7.3) HR (95% CI); p-value 0.395 (0.29, 0.52); p<0.0001 Objective response ratea, bORR, % (95% CI) 73% (65%, 80%) 47% (39%, 56%) Odds ratio (95% CI); p-value 3.0 (1.8, 4.8); p<0.0001 Complete response 3.9% 0.7% Partial response 69% 47% Overall survival (OS)cNumber of events 40 52 Median OS, months (95% CI) NE (28.3, NE) 28.6 (24.4, NE) HR (95% CI); p-value 0.756 (0.50, 1.14); p=0.1825 CI = confidence interval NE = not estimable aBlinded Independent Central Review by RECIST v1.1bBased on Kaplan-Meier estimate.cBased on the results of an updated OS with median follow-up of 20.9 months. The OS analysis was not adjustedfor the potentially confounding effects of crossover (78 [50.3%] patients on the carboplatin + pemetrexed arm who received subsequent Rybrevant monotherapy treatment).Figure 5: Kaplan-Meier curve of PFS in previously untreated NSCLC patients by BICR assessmentThe 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).Figure 6: Kaplan-Meier curve of OS in previously untreated NSCLC patients by BICR assessmentPreviously-treated non-small cell lung cancer(NSCLC) with Exon 20 insertion mutations (CHRYSALIS) 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 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 wasinvestigator-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%). Efficacy results are summarised in Table 14. Table 14: Efficacy results in CHRYSALIS Investigator assessment (N=114) Overall response ratea, b(95% CI) 37% (28%, 46%) Complete response 0% Partial response 37% Duration of response Medianc(95% CI), months 12.5 (6.5, 16.1) Patients with DOR ≥ 6 months 64%CI = Confidence Interval aConfirmed responsebORR 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%.cBased on Kaplan-Meier estimate.Anti-tumour activity was observed across studied mutation subtypes. Elderly No overall differences in effectiveness were observed between patients ≥ 65 years of age and patients < 65 years of age. Paediatric population 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 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. Based on simulations from the population pharmacokinetic model, AUC1 week 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-stateconcentrations 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 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 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 No clinically meaningful differences in the pharmacokinetics of amivantamab were observed based on age (21-88 years). Renal impairment No clinically meaningful effect on the pharmacokinetics of amivantamab was observed in patients with mild (60 ≤ creatinine clearance [CrCl] < 90 mL / min), moderate (29 ≤ CrCl < 60 mL / min) or severe (15 ≤ CrCl < 29 mL / min) renal impairment. Data in patients with severe renal impairment are limited (n=1), but there is no evidence to suggest that dose adjustment is required in these patients. The effect of end-stage renal disease (CrCl < 15 mL / min) on amivantamab pharmacokinetics is unknown.Hepatic impairment 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. No clinically meaningful effect in the pharmacokinetics of amivantamab was observed based on mild [(total bilirubin ≤ ULN and AST > ULN) or (ULN < total bilirubin ≤ 1.5 x ULN)] or moderate (1.5×ULN < total bilirubin ≤ 3×ULN and any AST) hepatic impairment. Data in patients with moderate hepatic impairment are limited (n=1), but there is no evidence to suggest that dose adjustment is required in these patients. The effect of severe (total bilirubin > 3 times ULN) hepatic impairment on amivantamab pharmacokinetics is unknown. Paediatric population The pharmacokinetics of Rybrevant in paediatric patients have not been investigated. 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity. Carcinogenicity and mutagenicity 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 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. 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 injections6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. 6.3 Shelf life Unopened vial 3 years After dilution 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 Store in a refrigerator (2°C to 8°C). Do not freeze. Store in the original package in order to protect from light. For storage conditions after dilution of the medicinal product, see section 6.3.6.5 Nature and contents of container 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 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, lowprotein-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. ^ 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 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)9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION Date of first authorisation: 09 December 2021 Date of latest renewal: 11 September 2023 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency https: / / www.ema.europa.eu.1. NAME OF THE MEDICINAL PRODUCT Rybrevant 1600 mg solution for injection Rybrevant 2240 mg solution for injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Rybrevant 1600 mg solution for injection One mL of solution for injection contains 160 mg amivantamab. One 10 mL vial of solution for injection contains 1600 mg of amivantamab. Rybrevant 2240 mg solution for injection One mL of solution for injection contains 160 mg amivantamab. One 14 mL vial of solution for injection contains 2240 mg of amivantamab. 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. Excipient with known effect: One mL of solution contains 0.6 mg of polysorbate 80. For the full list of excipients, see section 6.1.3. PHARMACEUTICAL FORM Solution for injection. The solution is colourless to pale yellow. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Rybrevant subcutaneous formulation is indicated: ^ in combination with lazertinib for the first-line treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations. ^ 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 Treatment with Rybrevant subcutaneous formulation should be initiated and supervised by a physician experienced in the use of anticancer medicinal products. Before initiation of Rybrevant subcutaneous formulation, 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. Once EGFR mutation status has been established, testing does not need to be repeated (see section 5.1).Rybrevant subcutaneous formulation should be administered by a healthcare professional with access to appropriate medical support to manage administration-related reactions if they occur. Posology Premedications should be administered to reduce the risk of administration-related reactions with Rybrevant subcutaneous formulation (see below “Dose modifications” and “Recommended concomitant medicinal products”). The recommended dosages of Rybrevant subcutaneous formulation in combination with lazertinib or as monotherapy based on baseline body weight, are provided in Table 1. Table 1: Recommended dosage of Rybrevant subcutaneous formulation Body weight at Recommended Dosing schedule baseline* dose Less than 80 kg 1600 mg^ Weekly (total of 4 doses) fromWeeks 1 to 4 ^ Every 2 weeks starting at Week 5 onwards Greater than or equal2240 mg^ Weekly (total of 4 doses) fromto 80 kg Weeks 1 to 4 ^ Every 2 weeks starting at Week 5 onwards * Dose adjustments not required for subsequent body weight changes. When given in combination with lazertinib, it is recommended to administer Rybrevant subcutaneous formulation any time after lazertinib when given on the same day. Refer to section 4.2 of the lazertinib Summary of Product Characteristics for recommended lazertinib dosing information.Duration of treatment It is recommended that patients are treated with Rybrevant subcutaneous formulation until disease progression or unacceptable toxicity. Missed dose If a dose of Rybrevant subcutaneous formulation is missed between Weeks 1 to 4, it should be administered within 24 hours. If a dose of Rybrevant subcutaneous formulation is missed from Week 5 onward, it should be administered within 7 days. Otherwise, the missed dose should not be administered and the next dose should be administered per the usual dosing schedule. Dose modifications 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 as presented in Table 2. See also specific dose modifications for specific adverse reactions below Table 2. If used in combination with lazertinib, refer to section 4.2 of the lazertinib Summary of Product Characteristics for information about dose modifications. Table 2: Recommended dose modifications for adverse reactions Dose*Dose after 1stDose after 2ndDose after 3rdinterruption for interruption for interruption for adverse reaction adverse reaction adverse reaction 1600 mg 1050 mg 700 mg2240 mg 1600 mg 1050 mg Discontinue Rybrevant subcutaneous formulation * Dose at which the adverse reaction occurred Administration-related reactions Premedications should be administered to reduce the risk of administration-related reactions with Rybrevant subcutaneous formulation (see “Recommended concomitant medicinal products”). Injections should be interrupted at the first sign of administration-related reactions. 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 Rybrevant subcutaneous formulation injections. Concomitant medicinal products should be administered at the next dose, including dexamethasone (20 mg) or equivalent (see Table 3). ^ Recurrent Grade 3 or Grade 4 (life-threatening): Permanently discontinue Rybrevant. Venous thromboembolic (VTE) events with concomitant use with lazertinib At the initiation of treatment, prophylactic anticoagulants should be administered to prevent VTE events in patients receiving Rybrevant subcutaneous formulation in combination with lazertinib. Consistent with clinical guidelines, patients should receive prophylactic dosing of either a direct acting oral anticoagulant (DOAC) or a low‑molecular weight heparin (LMWH). Use of Vitamin K antagonists is not recommended. For VTE events associated with clinical instability (e.g., respiratory failure or cardiac dysfunction), both drugs should be withheld until the patient is clinically stable. Thereafter, both medicinal products can be resumed at the same dose. In the event of recurrence despite appropriate anticoagulation, discontinue Rybrevant. Treatment can continue with lazertinib at the same dose (see section 4.4).Skin and nail reactions Patients should be instructed to limit sun exposure during and for 2 months after Rybrevant therapy. Alcohol‑free emollient cream is recommended for dry areas. For further information about prophylaxis for skin and nail reactions, see section 4.4. 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 2). If the patient develops a Grade 3 skin or nail reaction, supportive care should be initiated, and interruption of Rybrevant subcutaneous formulation should be considered until the adverse reaction improves. Upon recovery of the skin or nail reaction to ≤ Grade 2, Rybrevant subcutaneous formulation 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 Rybrevant subcutaneous formulation 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 Prior to the initial dose (Week 1, Day 1), antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of administration-related reactions (see Table 3). 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.Table 3: Dosing schedule of premedications Premedication Dose Route of Recommended administration dosing window prior to Rybrevant subcutaneous formulation administration Antihistamine*Diphenhydramine (25 to Intravenous 15 to 30 minutes 50 mg) or equivalent Oral 30 to 60 minutes Antipyretic*Paracetamol / Acetaminophen Intravenous 15 to 30 minutes (650 to 1000 mg) or Oral 30 to 60 minutes equivalent Glucocorticoid†Dexamethasone (20 mg) or Intravenous 45 to 60 minutes equivalent Oral At least 60 minutes Glucocorticoid Dexamethasone (10 mg) or Intravenous 45 to 60 minutes equivalent Oral 60 to 90 minutes * Required at all doses. † Required at initial dose (Week 1, Day 1) or at the next subsequent dose in the event of an administration-related reaction. Optional for subsequent doses.Special populations Paediatric population There is no relevant use of amivantamab in the paediatric population in the treatment of NSCLC.Elderly No dose adjustments are necessary (see section 4.8, section 5.1, and section 5.2). Renal impairment 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 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 (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 Rybrevant solution for injection is for subcutaneous use only. Rybrevant subcutaneous formulation is not intended for intravenous administration and should be given by subcutaneous injection only, using the doses specified. See section 6.6 for instructions on handling of the medicinal product before administration.Inject the required volume of Rybrevant subcutaneous formulation into the subcutaneous tissue of the abdomen over approximately 5 minutes. Do not administer at other sites of the body as no data are available. Pause or slow delivery rate if the patient experiences pain. In the event pain is not alleviated by pausing or slowing down delivery rate, a second injection site may be chosen on the opposite side of the abdomen to deliver the remainder of the dose. If administering with a subcutaneous infusion set, ensure that the full dose is delivered through the infusion set. Sodium chloride 9 mg / mL (0.9%) solution may be utilised to flush remaining medicinal product through the line. Do not inject into tattoos or scars or areas where the skin is red, bruised, tender, hard, not intact or within 5 cm around the periumbilical area. Injection sites should be rotated for successive injections. 4.3 Contraindications 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 In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.Administration-related reactions Administration-related reactions occurred in patients treated with Rybrevant subcutaneous formulation (see section 4.8). Prior to the initial injection (Week 1 Day 1), antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of administration-related reactions. For subsequent doses, antihistamines and antipyretics should be administered. Patients should be treated in a setting with appropriate medical support to treat administration-related reactions. At the first sign of administration-related reactions of any severity, injections should be interrupted, if ongoing, and post-injection medicinal products should be administered as clinically indicated. Upon resolution of symptoms, the injection should be resumed. For Grade 4 or recurrent Grade 3 administration-related reactions, Rybrevant should be permanently discontinued (see section 4.2). Interstitial lung disease Interstitial lung disease (ILD) or ILD-like adverse reactions (e.g., pneumonitis) have been reported in patients treated with amivantamab, including fatal events (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). Venous thromboembolic (VTE) events with concomitant use with lazertinib In patients receiving amivantamab in combination with lazertinib, VTE events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), were reported (see section 4.8). Fatal events were observed with amivantamab intravenous formulation.Consistent with clinical guidelines, patients should receive prophylactic dosing of either a direct acting oral anticoagulant (DOAC) or a low molecular weight heparin (LMWH). Use of Vitamin K antagonists is not recommended. Signs and symptoms of VTE events should be monitored. Patients with VTE events should be treated with anticoagulation as clinically indicated. For VTE events associated with clinical instability, treatment should be withheld until the patient is clinically stable. Thereafter, both drugs can be resumed at the same dose. In the event of recurrence despite appropriate anticoagulation, Rybrevant should be discontinued. Treatment can continue with lazertinib at the same dose (see section 4.2). Skin and nail reactions 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. This includes prophylactic therapy with an oral antibiotic (e.g., doxycycline or minocycline, 100 mg twice daily) starting on Day 1 for the first 12 weeks of treatment and after completion of oral antibiotic therapy, topical antibiotic lotion to the scalp (e.g., clindamycin 1%) for the next 9 months of treatment. Non‑comedogenic skin moisturiser on the face and whole body (except scalp) and chlorhexidine solution to wash hands and feet should be considered beginning on Day 1 and continued for the first 12 months of treatment. Prescriptions for topical and / or oral antibiotics and topical corticosteroids are recommended to be available at the time of initial dosing to minimise any delay in reactive management should rash develop despite prophylactic treatment. 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 anatypical 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). Toxic epidermal necrolysis (TEN) has been reported. Treatment with this medicinal product should be discontinued if TEN is confirmed. Eye disorders 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 This medicinal product contains less than 1 mmol (23 mg) sodium per dose, that is to say essentially “sodium-free” (see section 6.6). Polysorbate content This medicinal product contains 0.6 mg of polysorbate 80 in each mL, which is equivalent to 6 mg per 10 mL vial, or 8.4 mg per 14 mL vial. Polysorbates may cause hypersensitivity reactions. 4.5 Interaction with other medicinal products and other forms of interaction 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 highaffinity to a unique epitope on EGFR and MET, amivantamab is not anticipated to alter drug-metabolising enzymes. Vaccines 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 Women of child-bearing potential should use effective contraception during and for 3 months after cessation of amivantamab treatment. Pregnancy 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 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 tolow 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 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 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 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 Rybrevant as monotherapy In the dataset of Rybrevant intravenous formulation 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 patientsdiscontinued 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 Table 4 summarises the adverse drug reactions that occurred in patients receiving Rybrevant as monotherapy. The data reflects exposure to Rybrevant intravenous formulation 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). 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). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.Table 4: Adverse reactions in patients receiving Rybrevant as monotherapy (N=380) System organ class Frequency Any grade Grade 3-4 Adverse reaction category (%) (%) Metabolism and nutrition disorders Hypoalbuminaemia* (see Very common 31 2†section 5.1) Decreased appetite 16 0.5†Hypocalcaemia 10 0.3†Hypokalaemia Common 9 2 Hypomagnesaemia 8 0 Nervous system disorders Dizziness* Very common 13 0.3†Eye disorders Visual impairment* Common 3 0 Growth of eyelashes* 1 0 Other eye disorders* 6 0 Keratitis Uncommon 0.5 0 Uveitis 0.3 0 Respiratory, thoracic and mediastinal disorders Interstitial lung disease* Common 3 0.5†Gastrointestinal disorders Diarrhoea Very common 11 2†Stomatitis* 24 0.5†Nausea 23 0.5†Constipation 23 0Vomiting 12 0.5†Abdominal pain* Common 9 0.8†Haemorrhoids 3.7 0 Hepatobiliary disorders Alanine aminotransferase increased Very common 15 2 Aspartate aminotransferase 13 1 increased Blood alkaline phosphatase 12 0.5†increased Skin and subcutaneous tissue disorders Rash* Very common 76 3†Nail toxicity* 47 2†Dry skin* 19 0 Pruritus 18 0 Toxic epidermal necrolysis Uncommon 0.3 0.3†Musculoskeletal and connective tissue disorders Myalgia Very common 11 0.3†General disorders and administration site conditions Oedema* Very common 26 0.8†Fatigue* 26 0.8†Pyrexia 11 0 Injury, poisoning and procedural complications Infusion-related reaction Very common 67 2 * Grouped terms † Grade 3 events onlyRybrevant in combination with lazertinib Overall, the safety profile of Rybrevant subcutaneous formulation was consistent with the established safety profile of Rybrevant intravenous formulation, with a lower incidence of administration-related reactions and VTEs observed with the subcutaneous formulation compared to the intravenous formulation. In the dataset of Rybrevant (either intravenous or subcutaneous formulations) in combination with lazertinib (N=752), the most frequent adverse reactions of any grade (≥ 20% patients) were rash (87%), nail toxicity (67%), hypoalbuminaemia (48%), hepatotoxicity (43%), stomatitis (43%), oedema (42%), fatigue (35%), paraesthesia (29%), constipation (26%), diarrhoea (26%), dry skin (25%), decreased appetite (24%), nausea (24%), and pruritus (23%). Clinically relevant differences between the intravenous and subcutaneous formulations, when given in combination with lazertinib, were observed for administration-related reactions (63% for intravenous vs.14% for subcutaneous) and VTE (37% for intravenous vs.11% for subcutaneous). Serious adverse reactions were reported in 14% of patients who received Rybrevant subcutaneous formulation in combination with lazertinib, including ILD (4.2%), VTE (2.7%), hepatotoxicity (2.1%), and fatigue (1.5%). Seven percent of patients discontinued Rybrevant subcutaneous formulation due to adverse reactions. In patients treated with Rybrevant subcutaneous formulation in combination with lazertinib, the most frequent adverse reactions of any grade (≥ 1% patients) leading to discontinuation of Rybrevant subcutaneous formulation were ILD (3.6%) and rash (1.5%). Tabulated list of adverse reactions The adverse reactions for Rybrevant (either intravenous or subcutaneous formulation) when received in combination with lazertinib are summarised in Table 5.The safety data below reflect exposure to Rybrevant (either intravenous or subcutaneous formulation) in combination with lazertinib in 752 patients with locally advanced or metastatic NSCLC, including 421 patients in MARIPOSA, 125 patients in PALOMA-2 cohorts 1 and 6, and 206 patients in PALOMA-3 subcutaneous arm. Patients received Rybrevant (either intravenous or subcutaneous formulation) until disease progression or unacceptable toxicity. The median duration of treatment with amivantamab overall for both intravenous and subcutaneous formulations was 9.9 months (range: 0.1 to 31.4 months). Median duration on treatment for the subcutaneous formulation was 5.7 months (range: 0.1 to 13.2 months) while median duration on treatment for the intravenous formulation was 18.5 months (range: 0.2 to 31.4 months). 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). Table 5: Adverse reactions for Rybrevant (either intravenous or subcutaneous formulation) when received in combination with lazertinib (N=752) System Organ Class Frequency Any grade Grade 3-4 Adverse Reaction category (%) (%) Metabolism and nutrition disorders Hypoalbuminaemia* Very common 48 4.5 Decreased appetite 24 0.8 Hypocalcaemia 19 1.2 Hypokalaemia 13 2.7 Hypomagnesaemia Common 6 0 Nervous system disorders Paraesthesia*, aVery common 29 1.3Dizziness* 12 0 Eye disorders Other eye disorders* Very common 19 0.5 Visual impairment* Common 3.6 0 Keratitis 1.7 0.3 Growth of eyelashes* 1.7 0 Vascular disorders Venous thromboembolism Amivantamab intravenous*, bVery common 37 11 Amivantamab subcutaneous*, cVery common 11 0.9 Respiratory, thoracic, and mediastinal disorders Interstitial lung disease* Common 3.6 1.7 Gastrointestinal disorders Stomatitis* Very common 43 2.0 Constipation 26 0 Diarrhoea 26 1.7 Nausea 24 0.8 Vomiting 15 0.5 Abdominal pain* 10 0.1 Haemorrhoids Common 8 0.1 Hepatobiliary disorders Hepatotoxicity* Very common 43 7 Skin and subcutaneous tissue disorders Rash* Very common 87 23 Nail toxicity* 67 8Dry skin* 25 0.7 Pruritus 23 0.3 Palmar-plantar erythrodysaesthesia Common 3.9 0.1 syndrome Urticaria 1.6 0 Musculoskeletal and connective tissue disorders Myalgia Very common 15 0.5 Muscle spasms 13 0.4 General disorders and administration site conditions Oedema* Very common 42 2.7 Fatigue* 35 3.5 Pyrexia 11 0 Injection site reactions*, c, dCommon 8 0 Injury, poisoning, and procedural complications Infusion- / Administration-related reactions Amivantamab intravenousb, eVery common 63 6 Amivantamab subcutaneousc, fVery common 14 0.3 * Grouped terms.aApplicable only to lazertinib.bFrequency based on amivantamab intravenous study only (MARIPOSA [N=421]).cFrequency based on amivantamab subcutaneous studies only (PALOMA-2 cohorts 1 and 6 [N=125] andPALOMA-3 subcutaneous arm [N=206]).dInjection site reactions are local signs and symptoms associated with subcutaneous mode of administration.eInfusion-related reactions are systemic signs and symptoms associated with infusion of amivantamabintravenous.fAdministration-related reactions are systemic signs and symptoms associated with administration ofamivantamab subcutaneous.Description of selected adverse reactions Administration-related reactions Overall, administration-related reactions occurred in 14% of patients treated with Rybrevant subcutaneous formulation in combination with lazertinib. In PALOMA-3, administration-related reactions were reported in 13% of patients treated with Rybrevant subcutaneous formulation in combination with lazertinib compared to 66% when treated with Rybrevant intravenous formulation in combination with lazertinib. The most frequent signs and symptoms of administration-related reactions include dyspnoea, flushing, fever, chills, nausea, and chest discomfort. Median time to onset of first administration-related reactions was 2.1 hours (range: 0.0 to 176.5 hours). Most administration-related reactions (98%) were Grades 1 or 2 in severity. Injection site reactions Overall, injection site reactions occurred in 8% of patients treated with Rybrevant subcutaneous formulation in combination with lazertinib. All injection site reactions were Grade 1 or 2 in severity. The most frequent symptom of injection site reactions was erythema. Interstitial lung disease(ILD) or ILD-like adverse reactions have been reported with the use of amivantamab as well as with other EGFR inhibitors. ILD was reported in 3.6% of patients treated with Rybrevant (either intravenous or subcutaneous formulation) in combination with lazertinib, including 2 (0.3%) patients with a fatal reaction. Patients with a medical history of ILD, including drug-induced ILD or radiation pneumonitis, were excluded from PALOMA-2 and PALOMA-3.Venous thromboembolic (VTE) events with concomitant use with lazertinib VTE events, including deep venous thrombosis (DVT) and pulmonary embolism (PE), were reported in 11% of patients receiving Rybrevant subcutaneous formulation in combination with lazertinib in PALOMA-2 and PALOMA-3. Most cases were Grade 1 or 2, with Grade 3 events occurring in 3 (0.9%) patients. Additionally, 269 (81%) of these 331 patients receiving Rybrevant subcutaneous formulation took prophylactic anticoagulants with a direct oral anticoagulant or low molecular weight heparin within the first four months of study treatment. In PALOMA-3, the incidence of VTE reactions was 9% for patients treated with Rybrevant subcutaneous formulation in combination with lazertinib, compared to 13% when treated with Rybrevant intravenous formulation in combination with lazertinib, with similar rates of prophylactic anticoagulant use in both treatment arms (80% in the subcutaneous arm vs.81% in the intravenous arm). For patients who did not receive prophylactic anticoagulants, the overall incidence of VTE was 17% for patients treated with Rybrevant subcutaneous formulation in combination with lazertinib with all VTE reactions reported as Grade 1-2 and serious VTE reactions reported in 4.8% of these patients, compared to an overall incidence of 23% for patients treated with Rybrevant intravenous formulation in combination with lazertinib with Grade 3 VTE reactions reported in 10% and serious VTE reactions reported in 8% of these patients. Skin and nail reactions Rash (including dermatitis acneiform), pruritus, and dry skin have occurred in patients treated with Rybrevant (either intravenous or subcutaneous formulation) in combination with lazertinib. Rash occurred in 87% of patients, leading to discontinuation of Rybrevant in 0.7% of patients. Most cases were Grade 1 or 2, with Grade 3 and Grade 4 reactions occurring in 23% and 0.1% of patients, respectively. Eye disorders Eye disorders, including keratitis (1.7%), occurred in patients treated with Rybrevant (either intravenous or subcutaneous formulation). Other reported adverse reactions included growth of eyelashes, visual impairment, and other eye disorders.Special populations Elderly 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. Reporting of suspected adverse reactions 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 via the national reporting system listed in Appendix V.4.9 Overdose There is no information on overdose with Rybrevant subcutaneous formulation and no known specific antidote for 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.Rybrevant subcutaneous formulation contains recombinant human hyaluronidase (rHuPH20). rHuPH20 works locally and transiently to degrade hyaluronan ((HA), a naturally occurring glycoaminoglycan found throughout the body) in the extracellular matrix of the subcutaneous space by cleaving the linkage between the two sugars (N-acetylglucosamine and glucuronic acid), which comprise HA. Mechanism of action 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, Exon 21 L858R substitution and Exon 20 insertion mutations. Amivantamab binds to the extracellular domains of EGFR and MET. 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 After the first full dose of Rybrevant subcutaneous formulation, mean serum EGFR and MET concentrations decreased substantially and remained suppressed for the duration of treatment for all studied doses.Albumin Rybrevant subcutaneous formulation 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 experience of Rybrevant subcutaneous formulation The efficacy of Rybrevant subcutaneous formulation in patients with EGFR-mutated locally advanced or metastatic NSCLC is based on achieving non-inferior PK exposure to intravenous amivantamab in the non-inferiority study PALOMA-3 (see section 5.2). The study demonstrated non-inferior efficacy of subcutaneous to intravenous amivantamab given in combination with lazertinib in patients with EGFR-mutated locally advanced or metastatic NSCLC whose disease has progressed on or after treatment with osimertinib and platinum-based chemotherapy. Clinical experience of Rybrevant intravenous formulation Previously-untreated NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations (MARIPOSA) NSC3003 (MARIPOSA) is a randomised, open-label, active-controlled, multicentre phase 3 study assessing the efficacy and safety of Rybrevant intravenous formulation in combination with lazertinib as compared to osimertinib monotherapy as first-line treatment in patients with EGFR-mutated locally advanced or metastatic NSCLC not amenable to curative therapy. Patient samples were required to have one of the two common EGFR mutations (Exon 19 deletion or Exon 21 L858R substitution mutation), as identified by local testing. Tumour tissue (94%) and / or plasma (6%) samples for all patients were tested locally to determine EGFR Exon 19 deletion and / or Exon 21 L858Rsubstitution mutation status using polymerase chain reaction (PCR) in 65% and next generation sequencing (NGS) in 35% of patients. A total of 1074 patients were randomised (2:2:1) to receive Rybrevant intravenous formulation in combination with lazertinib, osimertinib monotherapy, or lazertinib monotherapy until disease progression or unacceptable toxicity. Rybrevant intravenous formulation 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 thereafter starting at week 5. Lazertinib was administered at 240 mg orally once daily. Osimertinib was administered at a dose of 80 mg orally once daily. Randomisation was stratified by EGFR mutation type (Exon 19 deletion or Exon 21 L858R), race (Asian or non-Asian), and history of brain metastasis (yes or no). Baseline demographics and disease characteristics were balanced across the treatment arms. The median age was 63 (range: 25–88) years with 45% of patients ≥ 65 years; 62% were female; and 59% were Asian, and 38% were White. Baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 (34%) or 1 (66%); 69% never smoked; 41% had prior brain metastases; and 90% had Stage IV cancer at initial diagnosis. With regard to EGFR mutation status, 60% were Exon 19 deletions and 40% were Exon 21 L858R substitution mutations. Rybrevant intravenous formulation in combination with lazertinib demonstrated a statistically significant improvement in progression-free survival (PFS) by BICR assessment. With a median follow up of approximately 31 months, the updated OS HR was 0.77; (95% CI: 0.61, 0.96; p=0.0185). This was not statistically significant as compared to a 2-sided significance level of 0.00001.Table 6: Efficacy results in MARIPOSA Rybrevant intravenous formulation + lazertinib Osimertinib (N=429) (N=429) Progression-free survival (PFS)aNumber of events 192 (45%) 252 (59%) Median, months (95% CI) 23.7 (19.1, 27.7) 16.6 (14.8, 18.5) Hazard Ratio (95% CI); p-value 0.70 (0.58, 0.85); p=0.0002 Overall survival (OS) Number of events 142 (33%) 177 (41%) Median, months (95% CI) NE (NE, NE) 37.3 (32.5, NE) Hazard Ratio (95% CI); 0.77 (0.61, 0.96); p=0.0185 p-valuebObjective response rate (ORR)a, cORR % (95% CI) 80% (76%, 84%) 77% (72%, 81%) Duration of response (DOR)a, cMedian (95% CI), months 25.8 (20.3, 33.9) 18.1 (14.8, 20.1) BICR = blinded independent central review; CI = confidence interval; NE = not estimable PFS results are from data cut-off 11 August 2023 with a median follow-up of 22.0 months. OS, DOR and ORR results are from data cut-off 13 May 2024 with a median follow-up of 31.3 months.aBICR by RECIST v1.1.bThe p-value is compared to a 2-sided significance level of 0.00001. Thus the OS results are not statisticallysignificant as of the latest interim analysis.cBased on confirmed responders.Figure 1: Kaplan-Meier curve of PFS in previously untreated NSCLC patients by BICR assessmentFigure 2: Kaplan-Meier curve of OS in previously untreated NSCLC patientsIntracranial ORR and DOR by BICR were pre-specified endpoints in MARIPOSA. In the subset of patients with intracranial lesions at baseline, the combination of Rybrevant intravenous formulation and lazertinib, demonstrated similar intracranial ORR to the control. Per protocol, all patients in MARIPOSA had serial brain MRIs to assess intracranial response and duration. Results are summarised in Table 7.Table 7: Intracranial ORR and DOR by BICR assessment in subjects with intracranial lesions at baseline - MARIPOSA Rybrevant intravenous formulation + lazertinib Osimertinib (N=180) (N=186) Intracranial tumour response assessment Intracranial ORR (CR+PR), % 77% 77% (95% CI) (70%, 83%) (70%, 82%) Complete response 63% 59% Intracranial DOR Number of responders 139 144 Median, months (95% CI) NE (21.4, NE) 24.4 (22.1, 31.2) CI = confidence interval NE = not estimable Intracranial ORR and DOR results are from data cut-off 13 May 2024 with a median follow-up of 31.3 months. Previously-treated non-small cell lung cancer (NSCLC) with Exon 20 insertion mutations (CHRYSALIS) CHRYSALIS is a multicentre, open-label, multi-cohort study conducted to assess the safety and efficacy of Rybrevant intravenous formulation 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 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 intravenous formulation 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 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%). Efficacy results are summarised in Table 8. Table 8: Efficacy results in CHRYSALIS Investigator assessment (N=114) Overall response ratea, b(95% CI) 37% (28%, 46%) Complete response 0% Partial response 37% Duration of response Medianc(95% CI), months 12.5 (6.5, 16.1)Patients with DOR ≥ 6 months 64% CI = Confidence interval aConfirmed responsebORR 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%. cBased on Kaplan-Meier estimate.Anti-tumour activity was observed across studied mutation subtypes. Immunogenicity Anti-drug antibodies (ADA) were uncommonly detected after treatment with Rybrevant subcutaneous formulation. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed. Among the 389 participants who received Rybrevant subcutaneous formulation as monotherapy or as part of combination therapy, 37 participants (10%) were positive for treatment-emergent antibodies to rHuPH20. The immunogenicity to rHuPH20 observed in these participants did not impact the pharmacokinetics of amivantamab. Elderly No overall differences in effectiveness were observed between patients ≥ 65 years of age and patients < 65 years of age. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Rybrevant in all subsets of the paediatric population in NSCLC (see section 4.2 for information on paediatric use).5.2 Pharmacokinetic properties Absorption Following subcutaneous administration, the geometric mean (%CV) of amivantamab bioavailability is 66.6% (14.9%) with a median time to reach maximum concentration of 3 days, based on the individual amivantamab PK parameter estimates for participants receiving subcutaneous administration in the population PK analysis. For the every 2-week subcutaneous dosing regimen, the geometric mean (%CV) maximum trough concentration of amivantamab after the 4thweekly dose was 335 µg / mL (32.7%). The mean AUC1week increased 3.5-fold from the first dose to Cycle 2 Day 1. Maximum trough concentration of amivantamab after subcutaneous administration as monotherapy and in combination with lazertinib is typically observed at the end of the weekly dosing (Cycle 2 Day 1). Amivantamab steady-state concentration is reached by approximately Week 13. The geometric mean (%CV) steady-state trough concentration of amivantamab at Cycle 4 Day 1 was 206 µg / mL (39.1%). Table 9 lists the observed geometric mean (%CV) maximum trough concentrations (Cycle 2 Day 1 Ctrough) and Cycle 2 area under the concentration time curve (AUCDay 1-15) following the recommended doses of amivantamab administered subcutaneously and intravenously in patients with NSCLC. These PK endpoints were the basis for the demonstration of non-inferiority that supports the intravenous to subcutaneous bridging.Table 9: Summary of serum pharmacokinetics parameters of amivantamab in patients with NSCLC (PALOMA-3 Study) Parameter Rybrevant subcutaneous Rybrevant intravenous formulation formulation 1600 mg 1050 mg (2240 mg for body weight (1400 mg for body weight ≥ 80 kg) ≥ 80 kg) Geometric mean (%CV) Cycle 2 Day 1 335 (32.7%) 293 (31.7%) Ctrough (µg / mL) Cycle 2 AUC(Day1-135861 (30.7%) 131704 (24.0%) 15) (µg / mL) Distribution Based on the individual amivantamab PK parameter estimates for participants receiving subcutaneous administration in the population PK analysis, the geometric mean (%CV) total volume of distribution for amivantamab administered subcutaneously is 5.69 L (23.8%). Elimination Based on the individual amivantamab PK parameter estimates for participants receiving subcutaneous administration in the population PK analysis, the estimated geometric mean (% CV) linear CL and associated-terminal half-life is 0.224 L / day (26.0%) and 18.8 days (34.3%), respectively.Special populations Elderly No clinically meaningful differences in the pharmacokinetics of amivantamab were observed based on age (21-88 years). Renal impairment No clinically meaningful effect on the pharmacokinetics of amivantamab was observed in patients with mild (60 ≤ creatinine clearance [CrCl] < 90 mL / min), moderate (29 ≤ CrCl < 60 mL / min) or severe (15 ≤ CrCl < 29 mL / min) renal impairment. Data in patients with severe renal impairment are limited (n=1), but there is no evidence to suggest that dose adjustment is required in these patients. The effect of end-stage renal disease (15 ≤ CrCl < 29 mL / min) on amivantamab pharmacokinetics is unknown. Hepatic impairment 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. No clinically meaningful effect in the pharmacokinetics of amivantamab was observed based on mild [(total bilirubin ≤ ULN and AST > ULN) or (ULN < total bilirubin ≤ 1.5 x ULN)] or moderate (1.5×ULN < total bilirubin ≤ 3×ULN and any AST) hepatic impairment. Data in patients with moderate hepatic impairment are limited (n=1), but there is no evidence to suggest that dose adjustment is required in these patients. The effect of severe (total bilirubin > 3 times ULN) hepatic impairment on amivantamab pharmacokinetics is unknown. Paediatric population The PK of amivantamab in paediatric patients have not been investigated.5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity. Carcinogenicity and mutagenicity 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 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 signalling 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.6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Recombinant human hyaluronidase (rHuPH20) EDTA disodium salt dihydrate Glacial acetic acid L-methionine Polysorbate 80 (E433) Sodium acetate trihydrate Sucrose Water for injections 6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. 6.3 Shelf life Unopened vial 18 months Prepared syringe Chemical and physical in-use stability has been demonstrated up to 24 hours at 2°C to 8°C followed by up to 24 hours at 15°C to 30°C. From a microbiological point of view, unless the method of dose preparation precludes the risk of microbial contamination, theproduct 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 Store in a refrigerator (2°C to 8°C). Do not freeze. Store in the original package in order to protect from light. For storage conditions after preparing the syringe, see section 6.3. 6.5 Nature and contents of container 10 mL solution in a Type 1 glass vial with an elastomeric closure and aluminium seal with a flip-off cap containing 1600 mg amivantamab. Pack size of 1 vial. 14 mL solution in a Type 1 glass vial with an elastomeric closure and an aluminium seal with a flip-off cap containing 2240 mg amivantamab. Pack size of 1 vial. 6.6 Special precautions for disposal and other handling Rybrevant subcutaneous formulation is for single use only and is ready to use. The solution for injection should be prepared using aseptic technique as follows:Preparation ^ Determine the dose required and the appropriate Rybrevant subcutaneous formulation vial needed based on the patient’s baseline weight (see section 4.2). ^ Patients < 80 kg receive 1600 mg and for patients ≥ 80 kg, 2240 mg weekly from Weeks 1 to 4 and then every 2 weeks starting at Week 5 onwards. ^ Remove the appropriate Rybrevant subcutaneous formulation vial from refrigerated storage (2°C to 8°C). ^ Check that the Rybrevant solution is colourless to pale yellow. Do not use if opaque particles, discolouration or other foreign particles are present. ^ Equilibrate Rybrevant subcutaneous formulation to room temperature (15°C to 30°C) for at least 15 minutes. Do not warm Rybrevant subcutaneous formulation in any other way. Do not shake. ^ Withdraw the required injection volume of Rybrevant subcutaneous formulation from the vial into an appropriately sized syringe using a transfer needle. Smaller syringes require less force during preparation and administration. ^ Rybrevant subcutaneous formulation is compatible with stainless steel injection needles, polypropolene and polycarbonate syringes, and polyethylene, polyurethane, and polyvinylchloride subcutaneous infusion sets. A sodium chloride 9 mg / mL (0.9%) solution may also be used to flush an infusion set if needed. ^ Replace the transfer needle with the approriate ancillaries for transport or administration. Use of a 21G to 23G needle or infusion set is recommended to ensure ease of administration. Storage of prepared syringe The prepared syringe should be administered immediately. If immediate administration is not possible, store the prepared syringe refrigerated at 2°C to 8°C for up to 24 hours followed by at room temperature of 15°C to 30°C for up to 24 hours. The prepared syringe should be discarded if stored for more than 24 hours refrigerated or more than 24 hours at room temperature. If stored in the refrigerator, the solution should come up to room temperature before administration. Disposal This medicinal product is for single use only. Any unused medicinal product or waste material 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) 9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION Date of first authorisation: 09 December 2021 Date of latest renewal: 11 September 2023 10. DATE OF REVISION OF THE TEXTANNEX 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 PRODUCTA. 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 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) 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. 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. The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 6 months following authorisation. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT ^ Risk management plan (RMP) 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. 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 / riskprofile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.ANNEX III LABELLING AND PACKAGE LEAFLETA. LABELLINGPARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Rybrevant 350 mg concentrate for solution for infusion amivantamab 2. STATEMENT OF ACTIVE SUBSTANCE(S) One vial of 7 mL contains 350 mg of amivantamab (50 mg / mL). 3. LIST OF EXCIPIENTS Excipients: ethylenediaminetetraacetic acid (EDTA), L-histidine, L-histidine hydrochloride monohydrate, L-methionine, polysorbate 80, sucrose, and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Concentrate for solution for infusion1 vial 5. METHOD AND ROUTE(S) OF ADMINISTRATION For intravenous use after dilution. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Do not shake. 8. EXPIRY DATE EXP9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Store in the original package in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium 12. MARKETING AUTHORISATION NUMBER(S) EU / 1 / 21 / 1594 / 00113. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted. 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included.18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NNMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION Rybrevant 350 mg sterile concentrate amivantamab IV 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER LotCONTENTS BY WEIGHT, BY VOLUME OR BY UNIT mL OTHERPARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Rybrevant 1600 mg solution for injection amivantamab 2. STATEMENT OF ACTIVE SUBSTANCE(S) One vial of 10 mL contains 1600 mg of amivantamab (160 mg / mL). 3. LIST OF EXCIPIENTS Excipients: recombinant human hyaluronidase (rHuPH20), EDTA disodium salt dihydrate, glacial acetic acid, L-methionine, polysorbate 80, sodium acetate trihydrate, sucrose, and water for injections. See leaflet for further information.4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 1600 mg / 10 mL 1 vial 5. METHOD AND ROUTE(S) OF ADMINISTRATION For subcutaneous use only. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Do not shake.8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Store in the original package in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium12. MARKETING AUTHORISATION NUMBER(S) EU / 1 / 21 / 1594 / XXX 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted.17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NNMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION Rybrevant 1600 mg solution for injection amivantamab Subcutaneous use SC 2. METHOD OF ADMINISTRATION For subcutaneous use only. 3. EXPIRY DATE EXP4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 1600 mg / 10 mL 6. OTHERPARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Rybrevant 2240 mg solution for injection amivantamab 2. STATEMENT OF ACTIVE SUBSTANCE(S) One vial of 14 mL contains 2240 mg of amivantamab (160 mg / mL). 3. LIST OF EXCIPIENTS Excipients: recombinant human hyaluronidase (rHuPH20), EDTA disodium salt dihydrate, glacial acetic acid, L-methionine, polysorbate 80, sodium acetate trihydrate, sucrose, and water for injections. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection2240 mg / 14 mL 1 vial 5. METHOD AND ROUTE(S) OF ADMINISTRATION For subcutaneous use only. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Do not shake. 8. EXPIRY DATE EXP9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Store in the original package in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium 12. MARKETING AUTHORISATION NUMBER(S)13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted. 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PCSN NNMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION Rybrevant 2240 mg solution for injection amivantamab Subcutaneous use SC 2. METHOD OF ADMINISTRATION For subcutaneous use only. 3. EXPIRY DATE EXP4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 2240 mg / 14 mL 6. OTHERB. PACKAGE LEAFLETPackage leaflet: Information for the patient Rybrevant 350 mg concentrate for solution for infusion amivantamab 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 information1. What Rybrevant is and what it is used for What Rybrevant is 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 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: ^ as the first medicine you receive for your cancer in combination with lazertinib. ^ 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. How Rybrevant works The active substance in Rybrevant, amivantamab, targets two proteins found on cancer cells: ^ epidermal growth factor receptor (EGFR), and ^ mesenchymal-epithelial transition factor (MET). 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. 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). 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 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. The condition may be life-threatening, therefore healthcare professionals will monitor you for potential symptoms. ^ When used with another drug called lazertinib; life-threatening side effects (due to blood clots in the veins) may occur. Your doctor will give you additional medication to help prevent blood clots during the course of your treatment and will monitor you for potential symptoms. ^ 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. Your doctor may recommend that you start a medicine(s) to prevent skin problems, may treat you with a medicine(s), or send you to see a skin specialist (dermatologist) if you get skin reactions during 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 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.Other medicines and Rybrevant 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 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 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 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 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 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 treated with Rybrevant once every 2 or 3 weeks according to the treatment your doctor decides for you. 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. 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 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. 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. In the first week, your doctor will give you the Rybrevant dose split over two days. Medicines given during treatment with Rybrevant 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). You may also be given additional medicines based on any symptoms you may experience. If you are given more Rybrevant than you should 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. If you forget your appointment to have Rybrevant It is very important to go to all your appointments. If you miss an appointment, make another one as soon as possible. If you have any further questions on the use of this medicine, ask your doctor or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them.Serious side effects 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. ^ When given together with another medicine called ‘lazertinib’, a blood clot in the veins, especially in the lungs or legs can occur. Signs may include sharp chest pain, shortness of breath, rapid breathing, leg pain, and swelling of your arms or legs. ^ 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). The following side effects have been reported in clinical studies with Rybrevant in combination with lazertinib: Other side effects Tell your doctor if you notice any of the following side effects:Very common (may affect more than 1 in 10 people): ^ nail problems ^ low level of the protein ‘albumin’ in the blood ^ swelling caused by fluid build up in the body ^ sores in the mouth ^ increase levels of liver enzymes in the blood ^ nerve damage that may cause tingling, numbness, pain or loss of pain sensation ^ feeling very tired ^ constipation ^ diarrhoea ^ decreased appetitie ^ low level of calcium in the blood ^ feeling sick (nausea) ^ muscle spasms ^ low level of potassium in the blood ^ feeling dizzy ^ muscle aches ^ vomiting ^ fever ^ stomach pain Common (may affect up to 1 in 10 people) ^ haemorrhoids ^ redness, swelling, peeling or tenderness, mainly on the hands or feet (palmar- plantar erythrodysesthesia syndrome) ^ low level of magnesium in the blood ^ itchy rash (hives) The following side effects have been reported in clinical studies with Rybrevant when given alone: Other side effects 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 The following side effects have been reported in clinical studies with Rybrevant in combination with chemotherapy: Other side effects 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 ^ 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 If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine. 5. How to store Rybrevant Rybrevant will be stored at the hospital or clinic. Keep this medicine out of the sight and reach of children. 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. 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. Store in a refrigerator (2°C to 8°C). Do not freeze. Store in the original package in order to protect from light. 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 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 30B-2340 Beerse Belgium Manufacturer Janssen Biologics B.V. Einsteinweg 101 2333 CB Leiden The Netherlands For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: This leaflet was last revised in.The following information is intended for healthcare professionals only: This medicinal product must not be mixed with other medicinal products except those mentioned below. 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. Each vial of Rybrevant 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. ^ 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. Disposal 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.Package leaflet: Information for the patient Rybrevant 1600 mg solution for injection Rybrevant 2240 mg solution for injection amivantamab 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 information1. What Rybrevant is and what it is used for What Rybrevant is 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 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: ^ as the first medicine you receive for your cancer in combination with lazertinib, or ^ when chemotherapy is no longer working against your cancer. How Rybrevant works The active substance in Rybrevant, amivantamab, targets two proteins found on cancer cells: ^ epidermal growth factor receptor (EGFR), and ^ mesenchymal-epithelial transition factor (MET). 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. 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). 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 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 injected. ^ Sudden difficulty in breathing, cough, or fever that may suggest inflammation of the lungs. The condition may be life‑threatening; therefore healthcare professionals will monitor you for potential symptoms. ^ When used with another drug called lazertinib; life‑threatening side effects (due to blood clots in the veins) may occur. Your doctor will give you additional medication to help prevent blood clots during the course of your treatment and will monitor you for potential symptoms. ^ 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. Your doctor may recommend that you start a medicine(s) to prevent skin problems, may treat you with a medicine(s), or send you to see a skin specialist (dermatologist) if you get skin reactions during 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 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.Other medicines and Rybrevant 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 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 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 This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’. Rybrevant contains polysorbateThis medicine contains 0.6 mg of polysorbate 80 in each mL, which is equivalent to 6 mg per 10 mL vial, or 8.4 mg per 14 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 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. The recommended dose of Rybrevant is: ^ 1600 mg if you weigh less than 80 kg. ^ 2240 mg if you weigh more than or equal to 80 kg. How the medicine is given Rybrevant will be given to you by a doctor or nurse as an injection under your skin (subcutaneous injection) over approximately 5 minutes. It is given in the stomach area (abdomen), not in other sites of the body, and not into areas of the abdomen where the skin is red, bruised, tender, hard or where there are tattoos or scars. If you experience pain during the injection, the doctor or nurse may interrupt the injection and give you the remaining injection in another area of your abdomen. Rybrevant is given as follows: ^ once a week for the first 4 weeks ^ then once every 2 weeks starting at week 5, for as long as you keep getting benefit from the treatment.Medicines given during treatment with Rybrevant Before each injection of Rybrevant, you will be given medicines which help lower the chance of administration-related reactions. These may include: ^ medicines for an allergic reaction (antihistamines) ^ medicines for inflammation (corticosteroids) ^ medicines for fever (such as paracetamol). You may also be given additional medicines based on any symptoms you may experience. If you are given more Rybrevant than you should 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. If you forget your appointment to have Rybrevant It is very important to go to all your appointments. If you miss an appointment, make another one as soon as possible. If you have any further questions on the use of this medicine, ask your doctor or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Serious side effects 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 injection - such as chills, feeling short of breath, feeling sick (nausea), flushing, chest discomfort, and fever. This can happen especially with the first dose. Your doctor may give you other medicines, or the injection may need to be 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. ^ When given together with another medicine called ‘lazertinib’, a blood clot in the veins, especially in the lungs or legs can occur. Signs may include sharp chest pain, shortness of breath, rapid breathing, leg pain, and swelling of your arms or legs. ^ Eye problems - such as dry eye, swollen eyelid, and itchy eyes. Common (may affect up to 1 in 10 people): ^ 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. ^ Eye problems - such as problems with vision and growth of eyelashes. ^ Inflamed cornea (front part of the eye). The following side effects have been reported in clinical studies with Rybrevant when given alone as an infusion into a vein: Other side effects 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 ^ nausea ^ vomiting ^ constipation or diarrhoea ^ decreased appetite ^ increased level of the liver enzymes ‘alanine aminotransferase’ and ‘aspartate aminotransferase’ in the blood ^ 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. The following side effects have been reported in clinical studies with Rybrevant (either as an infusion into a vein or as an injection under the skin) in combination with lazertinib: Other side effects 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 ^ sores in the mouth ^ liver toxicity ^ swelling caused by fluid build up in the body ^ feeling very tired ^ unusual feeling in the skin (such as tingling or a crawling feeling) ^ constipation ^ diarrhoea ^ decreased appetite ^ nausea ^ low level of calcium in the blood ^ vomiting ^ muscle aches ^ low level of potassium in the blood ^ muscle spasms ^ feeling dizzy ^ fever ^ stomach pain.Common (may affect up to 1 in 10 people): ^ haemorrhoids ^ irritation or pain where the injection is given ^ low level of magnesium in the blood ^ redness, swelling, peeling or tenderness, mainly on the hands or feet (palmar-plantar erythrodysaesthesia syndrome) ^ itchy rash (hives). Reporting of side effects If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine. 5. How to store Rybrevant Rybrevant will be stored at the hospital or clinic. Keep this medicine out of the sight and reach of children. 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. Store in a refrigerator (2°C to 8°C). Do not freeze. Store in the original package in order to protect from light. Chemical and physical in-use stability of the prepared syringe has been demonstrated up to 24 hours at 2°C to 8°C followed by up to 24 hours at 15°C to 30°C. From amicrobiological point of view, unless the method of dose preparation 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. 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 solution contains 160 mg of amivantamab. One vial of 10 mL of solution for injection contains 1600 mg of amivantamab. One vial of 14 mL of solution for injection contains 2240 mg of amivantamab. ^ The other ingredients are recombinant human hyaluronidase (rHuPH20), EDTA disodium salt dihydrate, glacial acetic acid, L-methionine, polysorbate 80 (E433), sodium acetate trihydrate, sucrose, and water for injections (see “Rybrevant contains sodium” and “Rybrevant contains polysorbate” in section 2). What Rybrevant looks like and contents of the pack Rybrevant solution for injection is a colourless to pale yellow liquid. This medicine is available in a carton pack containing 1 glass vial of 10 mL of solution or 1 glass vial of 14 mL of solution. Marketing Authorisation Holder Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse BelgiumManufacturer Janssen Biologics B.V. Einsteinweg 101 2333 CB Leiden The Netherlands This leaflet was last revised in.The following information is intended for healthcare professionals only: Rybrevant subcutaneous formulation should be administered by a healthcare professional. To prevent medication errors, it is important to check the vial labels to ensure that the appropriate formulation (intravenous or subcutaneous formulation) and dose is being given to the patient as prescribed. Rybrevant subcutaneous formulation should be given by subcutaneous injection only, using the dose specified. Rybrevant subcutaneous formulation is not intended for intravenous administration. This medicinal product must not be mixed with other medicinal products except those mentioned below. Prepare the solution for subcutaneous injection using aseptic technique as follows: Preparation ^ Determine the dose required and the appropriate Rybrevant subcutaneous formulation vial needed based on patient’s baseline weight. ^ Patients < 80kg receive 1600 mg and patients ≥ 80 kg receive 2240 mg weekly from Weeks 1 to 4 and then every 2 weeks starting at Week 5 onward. ^ Remove the appropriate Rybrevant subcutaneous formulation vial from refrigerated storage (2°C to 8°C). ^ Check that the solution is colourless to pale yellow. Do not use if opaque particles, discolouration or other foreign particles are present. ^ Equilibrate Rybrevant subcutaneous formulation to room temperature (15°C to 30°C) for at least 15 minutes. Do not warm Rybrevant subcutaneous formulation in any other way. Do not shake. ^ Withdraw the required injection volume of Rybrevant subcutaneous formulation from the vial into an appropriately sized syringe using a transfer needle. Smaller syringes require less force during preparation and administration. ^ Rybrevant subcutaneous formulation is compatible with stainless steel injection needles, polypropolene and polycarbonate syringes, and polyethylene, polyurethan, and polyvinylchloride subcutaneous infusion sets. A sodium chloride 9 mg / mL (0.9%) solution may also be used to flush an infusion set if needed. ^ Replace the transfer needle with the appropriate ancillaries for transport or administration. Use of a 21G to 23G needle or infusion set is recommended to ensure ease of administration.Storage of prepared syringe The prepared syringe should be administered immediately. If immediate administration is not possible, store the prepared syringe refrigerated at 2°C to 8°C for up to 24 hours followed by at room temperature of 15°C to 30°C for up to 24 hours. The prepared syringe should be discarded if stored for more than 24 hours refrigerated or more than 24 hours at room temperature. If stored in the refrigerator, allow the solution to come to room temperature before administration. Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Disposal This medicinal product is for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Example 7. Summary of results and conclusions from PALOMA-3 study.

[0150] A total of 416 participants (206 participants in amivantamab SC+lazertinib and 210 participants in amivantamab IV+lazertinib) received at least 1 dose of study treatment. Two participants (0.9%) who were randomized to amivantamab IV+lazertinib did not receive any dose of study treatment due to withdrawal of consent (1 participant) and investigator decision (1 participant) following prolonged hospitalization prior to the start of treatment. Overall, 202 participants (48.3%) had completed the study and 216 participants (51.7%) had discontinued the study, mostly because of transferring to the LTE phase (195 participants [46.7%]). Other reasons for discontinuation from the study were withdrawal by the participant (17 participants [4.1%]) and lost to follow-up (4 participants [1.0%]).

[0151] Demographic and Other Baseline Characteristics: Demographics and baseline characteristics were well balanced between the two treatment arms. The median age was 61 (range: 29-82) years, with 39.5% of the participants ≥ 65 years old and 9.6% ≥ 75 years old. A total of 66.7% of participants were female, 61.0% were Asian, and 37.1% were White. Overall, 88.0% of participants had weight <80 kg and 68.4% had never smoked. Baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 (28.5%) or 1

[0152] (71.5%). The disease characteristics reflect the target population of the study. The majority of participants (411 [98.3%]) were diagnosed with adenocarcinoma and at screening 415 (99.3%) had stage IV disease. The most common sites of metastases at screening were lung in 288 participants (68.9%), lymph node in 243 participants (58.1%), and bone in 240 participants (57.4%). A total of 142 participant (34.0%) had a history of brain metastasis. The median time since metastatic disease diagnosis was 31.24 months (range: 0.56; 168.97) months.

[0153] Exposure: At the time of the CCO (10 December 2024), the median duration of treatment in the amivantamab SC+lazertinib arm was 5.6 months (5.3 months [range: 0; 23] for amivantamab SC and 5.5 months [range: 0; 23] for lazertinib). The median duration of treatment in the amivantamab IV+lazertinib was 5.0 months (4.6 months [range: 0; 22] for amivantamab IV and 4.7 months [range: 0; 22] for lazertinib). The mean (SD) relative dose intensity, which is a ratio of actual versus prescribed doses (prescribed dose includes planned interruptions), was 91.7% (12.24) for amivantamab SC and 84.5% (16.50) for lazertinib in the amivantamab SC+lazertinib arm. In the amivantamab IV+lazertinib arm, the mean relative dose intensity was 89.0% (18.42) for amivantamab IV and 82.2% (20.33) for lazertinib.

[0154] Pharmacokinetic Results: The analysis of the primary and secondary PK endpoints was performed after the last participant completed the Cycle 4 Day 1 pre- dose sample requirement and the results were provided in the Primary Analysis CSR.

[0155] At primary analysis, the study met its co-primary endpoints and demonstrated PK non-inferiority of amivantamab SC versus amivantamab IV in participants with EGFR-mutated locally advanced or metastatic NSCLC who have progressed on or after treatment with osimertinib (or another approved 3rdgeneration EGFR TKI) and platinum-based chemotherapy. In the current CSR, results of the other PK evaluations (serum amivantamab and plasma lazertinib concentrations) are presented with a cutoff date of 10 October 2024. JNJ-61186372 (amivantamab) and JNJ-73841937(lazertinib) Clinical Study Report 61186372NSC3004. Overall, amivantamab serum concentrations were substantially overlapping between the two treatment arms, with the exception of higher concentrations observed on the first day after IV administration compared to SC administration.

[0156] Efficacy Results: At the time of the CCO (10 December 2024), non- inferiority of amivantamab SC versus amivantamab IV was further confirmed for the key secondary endpoint of ORR. Consistently comparable results between the treatment arms were also observed for the secondary endpoints of PFS, DOR, and TTR, and for the exploratory endpoint of OS. These findings continue to demonstrate a similar clinical benefit for amivantamab SC and amivantamab IV in participants with EGFR-mutated NSCLC who progressed on osimertinib (or another approved 3rd generation TKI) and platinum-based chemotherapy.

[0157] Key efficacy findings included the following (see Table 19):

[0158] A similar response rate was achieved for amivantamab SC and amivantamab IV with an ORR of 34.5% and 34.4%, respectively, yielding a relative risk of 1.00 (95% CI: 0.77, 1.30). The lower bound of the 95% CI (0.77) indicated at least 77% retention of ORR exceeding the 60% retention assumed for determining non- inferiority pertaining to this key secondary endpoint. The proportion of participants exhibiting stable disease was 40.8% in amivantamab SC+lazertinib arm and 36.3% in the amivantamab IV+lazertinib arm. Across all prespecified clinically relevant subgroups such as, race, sex, age groups, and ECOG status, ORR was consistently non-inferior for amivantamab SC.

[0159] Median PFS was consistent across the two treatment arms (5.82 months [95% CI: 4.99, 6.97] in the amivantamab SC+lazertinib arm and 5.36 months [95% CI: 4.17, 6.83] in the amivantamab IV+lazertinib arm).

[0160] Median DOR was consistent across the two treatment arms (9.66 months [95% CI: 6.93, 10.38] in the amivantamab SC+lazertinib arm and 8.18 months [95% CI: 5.59, 11.07] in ...

Claims

What is claimed 1. A method of improving the safety and efficacy of a therapy comprising a bispecific epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody for the treatment of locally advanced or metastatic EGFR-mutated non- small cell lung cancer (NSCLC) in a subject or a population of subjects, the method comprising: administering to the subject or the population of subjects a therapeutically effective amount of a subcutaneous composition comprising hyaluronidase and a bispecific EGFR / c-Met antibody, the antibody comprising: a first heavy chain (HC1) comprising a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a first light chain (LC1) comprising a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6, a second heavy chain (HC2) comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, and a second light chain (LC2) comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 12, wherein the improvement in safety and efficacy comprises an improvement in median duration of response (DoR), an improvement in median progression free survival (PFS), an improvement in overall survival (OS), a reduction in rate of venous thromboembolism (VTE), or any combination thereof, and wherein the improvement in safety and efficacy is relative to the safety and efficacy of a reference therapy comprising a bispecific EGFR / c-Met antibody administered to a reference subject or a reference population of subjects, the reference subject or reference population having been administered a therapeuticallyeffective amount of an intravenous composition comprising the bispecific EGFR / c- Met antibody without hyaluronidase, instead of the subcutaneous composition.

2. The method of claim 1, wherein the improvement comprises an improvement in median duration of response (DoR).

3. The method of claim 1, wherein the improvement comprises an improvement in median progression free survival (PFS).

4. The method of claim 1, wherein the improvement comprises an improvement in overall survival (OS).

5. The method of claim 1, wherein the improvement comprises a reduction in rate of VTE.

6. The method of any of the previous claims, wherein the population of subjects has locally advanced or metastatic EGFR-mutated NSCLC that is positive for an EGFR L858R mutation or an EGFR Exon 19 deletion (Ex19del).

7. The method of any of the previous claims, wherein the population of subjects has progressed on or after treatment with osimertinib and platinum-based chemotherapy.

8. The method of any of the previous claims, wherein the method comprises administering to the population of subjects a combination therapy comprising (i) the therapeutically effective amount of the subcutaneous composition and (ii) a therapeutically effective amount of an oral composition comprising lazertinib, the reference population of subjects having been administered a combination therapy comprising (i) the therapeutically effective amount of the intravenous composition and (ii) a therapeutically effective amount of the oral composition comprising lazertinib.

9. The method of claim 8, wherein the oral composition comprises 240 mg of the lazertinib and is administered once daily.

10. The method of any of the previous claims, wherein the subcutaneous composition comprises about 2,000 Units / mL of hyaluronidase and about 160 mg / mL of the bispecific antibody.

11. The method of claim 10, wherein for subjects with a body weight of less than 80 kg, the subcutaneous composition comprises about 1,600 mg of the bispecific antibody and about 20,000 units of the hyaluronidase.

12. The method of claim 10, wherein for subjects with a body weight greater than or equal to 80 kg, the subcutaneous composition comprises about 2,240 mg of the bispecific antibody and about 28,000 units of the hyaluronidase.

13. The method of any one of the previous claims, comprising administering the subcutaneous composition weekly for the first four weeks and every two weeks thereafter.

14. The method of claim 13, comprising administering the subcutaneous composition on days 1, 8, 15, and 22 of a first treatment cycle.

15. The method of claim 13 or 14, comprising, after the administering during the first treatment cycle, administering the subcutaneous composition on days 1 and 15 of each 28-day period during the second treatment cycle 16. The method of any of claims 1-12, comprising: administering the subcutaneous composition weekly, for a total of 5 doses, from Weeks 1 to 5; administering no dose of the subcutaneous composition during Week 6; and administering the subcutaneous composition every two weeks starting at Week 7 onwards.

17. The method of any of the previous claims, wherein the intravenous composition is administered to the reference population at a dose of 1050 mg for subjects with a body weight of less than 80 kg, or 1400 mg for subjects with a body weight of ≥80 kg, weekly for the first four weeks and every two weeks thereafter, with the first dose split over 2 days (350 mg on Day 1, the remainder on Day 2).

18. The method of any one of the previous claims, wherein the method provides an improvement in median DoR, an improvement in median PFS, an improvement in OS, a reduction in rate of VTE, or a combination thereof, as compared to a subject receiving about 240 mg of lazertinib administered orally once daily and the intravenous composition comprising about 1,050 mg to about 1,400 mg of the bispecific antibody without hyaluronidase administered intravenously as a split dose on days 1-2, and on days 8, 15, and 22 during the first cycle and on days 1 and 15 of each subsequent 28 day period during a second cycle.

19. The method of any one of the previous claims, wherein the method provides a median DoR of about 11 months or more.

20. The method of any one of the previous claims, wherein the method provides a median PFS of about 6 months or more.

21. The method of any one of the previous claims, wherein the method provides an OS of about 12 months or more.

22. The method of any one of the previous claims, wherein the method provides a reduction in rate of VTE of about 10% or less.

23. The method of any one of the previous claims, wherein: the HC1 of the bispecific antibody comprises a variable region 1 (VH1) comprising the amino acid sequence of SEQ ID NO: 13; the LC1 of the bispecific antibody comprises a variable region 1 (VL1) comprising the amino acid sequence of SEQ ID NO: 14; the HC2 of the bispecific antibody comprises a variable region 2 (VH2) comprising the amino acid sequence of SEQ ID NO: 15; and the LC2 of the bispecific antibody comprises a variable region 2 (VL2) comprising the amino acid sequence of SEQ ID NO:

16.

24. The method of any one of the previous claims, wherein: the HC1 of the bispecific antibody comprises the amino acid sequence of SEQ ID NO: 17;the LC1 of the bispecific antibody comprises the amino acid sequence of SEQ ID NO: 18; the HC2 of the bispecific antibody comprises the amino acid sequence of SEQ ID NO: 19; and the LC2 of the bispecific antibody comprises the amino acid sequence of SEQ ID NO:

20.

25. The method of any one of the previous claims, wherein the bispecific antibody is amivantamab.

26. The method of any one of the previous claims, wherein the hyaluronidase is a soluble human PH20 (rHuPH20) comprising the amino acid sequence of SEQ ID NO:

21.

27. The method of any one of the previous claims, wherein the composition comprises: about 144 mg / mL to about 176 mg / mL of the bispecific antibody; about 10 mM to about 50 mM of acetate and / or a pharmaceutically acceptable acetate salt; about 6.8% (w / v) to about 10.2% (w / v) of sucrose; about 0.036% (w / v) to about 0.084% (w / v) of polysorbate 80 (PS80); about to 0.8 mg / mL to about 1.2 mg / mL of methionine; about 16 μg / mL to about 24 μg / mL of ethylenediaminetetraacetic acid (EDTA); and about 2,000 U / mL of the hyaluronidase, wherein the composition has a pH from about 5.2 to about 6.

2.

28. The method of claim 27, wherein the composition comprises about 160 mg / mL of the bispecific antibody.

29. The method of claim 27 or 28, wherein the composition comprises about 30 mM of the acetate and / or the pharmaceutically acceptable acetate salt.

30. The method of any one of claims 27-29, wherein the acetate comprises glacial acetic acid.

31. The method of any one of claims 27-29, wherein the pharmaceutically acceptable acetate salt comprises sodium acetate trihydrate.

32. The method of any one of claims 27-31, wherein the composition comprises about 8.5% (w / v) sucrose.

33. The method of any one of claims 27-32, wherein the composition comprises about 0.06% (w / v) PS80.

34. The method of any one of claims 27-33, wherein the methionine comprises L- methionine.

35. The method of claim 34, wherein the composition comprises about 1 mg / mL of L-methionine.

36. The method of any one of claims 27-35, wherein the composition comprises about 20 µg / mL of EDTA.

37. The method of any one of claims 27-36, wherein the composition has a pH of about 5.

7.

38. The method of any one of the previous claims, wherein the composition comprises: about 160 mg / mL of the bispecific antibody, about 30 mM acetate and / or pharmaceutically acceptable acetate salt, about 8.5% sucrose, about 1 mg / mL L-methionine polysorbate 80 to a final concentration of about 0.06% (w / v) EDTA to a final concentration of about 20 µg / mL, rHuPH20 to a final concentration of about 2,000 U / mL, a pH of about 5.7, andwherein the HC1 of the bispecific antibody comprises the amino acid sequence of SEQ ID NO: 17, the LC1 of the bispecific antibody comprises the amino acid sequence of SEQ ID NO: 18, the HC2 of the bispecific antibody comprises the amino acid sequence of SEQ ID NO: 19, and the LC2 of the bispecific antibody comprises the amino acid sequence of SEQ ID NO:

20.

39. The method of any one of the previous claims, further comprising administering an anticoagulant to the population of subjects.

40. The method of claim 39, comprising administering the anticoagulant to the population of subjects for the first four months.

41. A method of improving the safety and efficacy of a therapy comprising a bispecific epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody for the treatment of locally advanced or metastatic EGFR-mutated non- small cell lung cancer (NSCLC) in a subject, the method comprising: administering to the subject a therapeutically effective amount of a subcutaneous composition comprising hyaluronidase and a bispecific EGFR / c-Met antibody, the antibody comprising: a first heavy chain (HC1) comprising a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a first light chain (LC1) comprising a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6, a second heavy chain (HC2) comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, and a second light chain (LC2) comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LCDR2 comprising the amino acid sequenceof SEQ ID NO: 11, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 12, wherein the improvement in safety and efficacy comprises an improvement in overall survival (OS), a reduction in rate of venous thromboembolism (VTE), or a combination thereof, and wherein the improvement in safety and efficacy is relative to the safety and efficacy of a reference therapy comprising a bispecific EGFR / c-Met antibody administered to a reference subject or a reference population of subjects, the reference subject or reference population having been administered a therapeutically effective amount of an intravenous composition comprising the bispecific EGFR / c- Met antibody without hyaluronidase, instead of the subcutaneous composition.

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