Treatment methods for non-small cell lung cancer using terisotuzumab vedotin

Abstract

The present disclosure provides improved methods for treating NSCLC cancer using terisotuzumab vedotin.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 171,536, filed on April 6, 2021, and U.S. Provisional Application No. 63 / 171,571, filed on April 6, 2021, each of which is incorporated herein by reference in its entirety.

[0002] 1. Sequence Listing This application includes a sequence listing submitted electronically in ASCII format, which is incorporated herein by reference in its entirety. The ASCII copy was created on April 5, 2022, with the file name 381493_190077_SL.txt and a size of 13,581 bytes.

[0003] 2. Technical Field This application relates to an improved treatment method for non - small cell lung cancer using telisotuzumab vedotin (Teliso - V; ABBV - 399) and a method for selecting a specific patient population to be treated.

Background Art

[0004] 3. Background Art c-Met is a signaling tyrosine kinase receptor expressed on the surface of epithelial and endothelial cells. When c-Met is activated by hepatocyte growth factor (HGF), its only known ligand, it has been shown to enhance cell proliferation, angiogenesis, survival, and cell motility (Ma et al., 2003, Cancer Metastasis Rev., 22:309-325; Gherardi et al., 2012, Nat Rev Cancer., 12:89-103). Dysregulation of c-Met signaling due to receptor upregulation is thought to lead to the development of non-small cell lung cancer (NSCLC) (Ma et al., 2005, Cancer Res., 65:1479-1488; Spigel et al., 2013, J Clin Oncol., 31:4105-4114; The Cancer Genome Atlas Research Network, 2014, Nature, 511:543-550).

[0005] NSCLC accounts for 85% of all lung cancers and is the leading cause of cancer-related deaths worldwide (GLOBOCAN, 2018; American Cancer Society: Cancer Facts and Figures 2018). Abnormalities in c-Met signaling are widely observed in NSCLC, and these are thought to be caused by multiple mechanisms. Dysregulation of c-Met signaling is associated with poor prognosis (Cappuzzo et al., 2009, J Clin Oncol., 27(10):1667-1674; Vuong et al., 2018, Lung Cancer., 123:76-82; Tong et al., 2016, Clin Cancer Res., 22(12):3048-3056), tumorigenesis, resistance to chemotherapy / radiotherapy (Gu et al., 2016, J Hematol Oncol., 9:66-68), and acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) (Turke et al., 2010, Cancer Cell., 17(1):77-88).

[0006] By linking the anti-c-Met humanized monoclonal antibody ABT-700 to monomethyl auristatin E (MMAE) via a valine-citrulline linker (ABT-700-vcMMAE), the first-in-class ADC terisotuzumab vedotin (Teliso-V) was discovered. ABT-700 has been shown to deliver Teliso-V specifically and with high affinity to tumor cells expressing c-Met (Wang et al., 2016, BMC Cancer., 16:105-119; Wang et al., 2017, Clin Cancer Res., 23:992-1000). Teliso-V has demonstrated promising antitumor activity independently of MET amplification status in preclinical studies in cells overexpressing c-Met, potentially expanding the target population of this drug to patients with c-Met-expressing tumors (Wang et al., 2017, Clin Cancer Res., 23:992-1000). Therefore, we designed a phase 1 / 1b dose-escalation and expansion study in patients with solid tumors that were not initially pre-selected due to c-Met protein expression (NCT02099058). Using preliminary data from this study, we designed a phase 2 multicenter, non-randomized, single-arm, two-stage adaptive enrichment study in patients with c-Met+ locally advanced or metastatic NSCLC (NCT03539536). The first phase of this trial (i.e., Stage 1) was designed to evaluate the efficacy of Teliso-V monotherapy (1.9 mg / kg every two weeks) in five groups, divided into three c-Met+ NSCLC cohorts (based on histopathological examination and EGFR mutation status) and further divided into non-squamous cell cohorts (based on whether c-Met expression levels were moderate or high), in order to identify the population most likely to benefit from Teliso-V. The second phase of this trial (Stage 2) is designed to further evaluate the efficacy of Teliso-V in a particular group if the objective response rate (ORR) exceeds 25%. [Prior art documents] [Non-patent literature]

[0007]

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[0008] 4. Overview This application provides a method for treating a patient with NSCLC whose EGFR status is known, comprising the step of administering a therapeutically effective dose of Teliso-V to the patient if the NSCLC is positive, moderate, or has a high c-Met expression level as determined by immunohistochemical staining (IHC). The therapeutically effective dose of Teliso-V is sufficient to bring about stable disease, partial response, or confirmed response in the patient, and / or to extend the progression-free period, in accordance with RECIST version 1.1.

[0009] Furthermore, the present invention also provides a method for treating NSCLC in a subject, comprising the steps of determining whether an NSCLC sample derived from the subject contains a positive, moderate, or high c-Met expression level when determined by IHC, and treating the NSCLC by administering an effective amount of Teliso-V to the subject. In certain embodiments, if an NSCLC sample from the subject contains a negative c-Met expression level when determined by IHC, the subject is excluded from treatment.

[0010] This invention provides a method for treating NSCLC that includes the step of administering an effective amount of Teliso-V, the treatment being carried out based on c-Met overexpression in an NSCLC sample, and yielding an objective response rate of over 25%.

[0011] In the present application, a diagnostic method for determining c-Met expression in NSCLC is provided. When it is determined by IHC that positive, moderate, or high c-Met expression is shown, it is assumed that the efficacy is high when Teliso-V is administered to a subject having the NSCLC. When negative c-Met expression is detected by determination using IHC, the patient is excluded from the administration of Teliso-V.

[0012] 5. Brief Description of the Drawings This patent or application documents include at least one sheet of color drawings. Copies of this patent or patent application publication including color drawings will be provided by the authority after application and payment of the required fees.

Brief Description of the Drawings

[0013] [Figure 1A] Figures 1A - 1D show representative cytoplasmic staining intensities of c-Met on non-squamous NSCLC. SP44 OptiView IHC cytoplasmic staining intensities (20x) of IHC scores 0 (Figure 1A), 1+ (Figure 1B), 2+ (Figure 1C), and 3+ (Figure 1D) are shown. [Figure 1B] Figures 1A - 1D show representative cytoplasmic staining intensities of c-Met on non-squamous NSCLC. SP44 OptiView IHC cytoplasmic staining intensities (20x) of IHC scores 0 (Figure 1A), 1+ (Figure 1B), 2+ (Figure 1C), and 3+ (Figure 1D) are shown. [Figure 1C] Figures 1A - 1D show representative cytoplasmic staining intensities of c-Met on non-squamous NSCLC. SP44 OptiView IHC cytoplasmic staining intensities (20x) of IHC scores 0 (Figure 1A), 1+ (Figure 1B), 2+ (Figure 1C), and 3+ (Figure 1D) are shown. [Figure 1D] Figures 1A - 1D show representative cytoplasmic staining intensities of c-Met on non-squamous NSCLC. SP44 OptiView IHC cytoplasmic staining intensities (20x) of IHC scores 0 (Figure 1A), 1+ (Figure 1B), 2+ (Figure 1C), and 3+ (Figure 1D) are shown. [Figure 2A] It should be noted that there is an error in the original text where "[[ID=IO]]" should be "". This has been corrected in the translation.Figures 2A - 2D show representative membrane staining intensities of c-Met on non-squamous NSCLC. SP44 OptiView IHC membrane staining intensities (20x) with IHC scores of 0 (Figure 2A), 1+ (Figure 2B), 2+ (Figure 2C), and 3+ (Figure 2D) are shown. [Figure 2B] Figures 2A - 2D show representative membrane staining intensities of c-Met on non-squamous NSCLC. SP44 OptiView IHC membrane staining intensities (20x) with IHC scores of 0 (Figure 2A), 1+ (Figure 2B), 2+ (Figure 2C), and 3+ (Figure 2D) are shown. [Figure 2C] Figures 2A - 2D show representative membrane staining intensities of c-Met on non-squamous NSCLC. SP44 OptiView IHC membrane staining intensities (20x) with IHC scores of 0 (Figure 2A), 1+ (Figure 2B), 2+ (Figure 2C), and 3+ (Figure 2D) are shown. [Figure 2D] Figures 2A - 2D show representative membrane staining intensities of c-Met on non-squamous NSCLC. SP44 OptiView IHC membrane staining intensities (20x) with IHC scores of 0 (Figure 2A), 1+ (Figure 2B), 2+ (Figure 2C), and 3+ (Figure 2D) are shown. [Figure 3A-1] Figures 3A1 - 3C3, Figures 3B1 - 3B3, and Figures 3C1 - 3C3 show representative membrane staining intensities of c-Met on non-squamous NSCLC. SP44 OptiView IHC membrane staining intensities (20x) of c-Met negative (Figures 3A1 - 3A3), c-Met positive (Figures 3B1 - 3B3), and c-Met high (Figures 3C1 - 3C3) are shown. [Figure 3A-2] Figures 3A1 - 3C3, Figures 3B1 - 3B3, and Figures 3C1 - 3C3 show representative membrane staining intensities of c-Met on non-squamous NSCLC. SP44 OptiView IHC membrane staining intensities (20x) of c-Met negative (Figures 3A1 - 3A3), c-Met positive (Figures 3B1 - 3B3), and c-Met high (Figures 3C1 - 3C3) are shown. [Figure 3A-3]Figures 3A1-3C3, 3B1-3B3, and 3C1-3C3 show typical c-Met membrane staining intensities on non-squamous NSCLC. They show the SP44 OptiView IHC membrane staining intensities (20x) for c-Met-negative (Figures 3A1-3A3), c-Met-positive (Figures 3B1-3B3), and high c-Met (Figures 3C1-3C3). [Figure 3B-1] Figures 3A1-3C3, 3B1-3B3, and 3C1-3C3 show typical c-Met membrane staining intensities on non-squamous NSCLC. They show the SP44 OptiView IHC membrane staining intensities (20x) for c-Met-negative (Figures 3A1-3A3), c-Met-positive (Figures 3B1-3B3), and high c-Met (Figures 3C1-3C3). [Figure 3B-2] Figures 3A1-3C3, 3B1-3B3, and 3C1-3C3 show typical c-Met membrane staining intensities on non-squamous NSCLC. They show the SP44 OptiView IHC membrane staining intensities (20x) for c-Met-negative (Figures 3A1-3A3), c-Met-positive (Figures 3B1-3B3), and high c-Met (Figures 3C1-3C3). [Figure 3B-3] Figures 3A1-3C3, 3B1-3B3, and 3C1-3C3 show typical c-Met membrane staining intensities on non-squamous NSCLC. They show the SP44 OptiView IHC membrane staining intensities (20x) for c-Met-negative (Figures 3A1-3A3), c-Met-positive (Figures 3B1-3B3), and high c-Met (Figures 3C1-3C3). [Figure 3C-1] Figures 3A1-3C3, 3B1-3B3, and 3C1-3C3 show typical c-Met membrane staining intensities on non-squamous NSCLC. They show the SP44 OptiView IHC membrane staining intensities (20x) for c-Met-negative (Figures 3A1-3A3), c-Met-positive (Figures 3B1-3B3), and high c-Met (Figures 3C1-3C3). [Figure 3C-2]Figures 3A1-3C3, 3B1-3B3, and 3C1-3C3 show typical c-Met membrane staining intensities on non-squamous NSCLC. They show the SP44 OptiView IHC membrane staining intensities (20x) for c-Met-negative (Figures 3A1-3A3), c-Met-positive (Figures 3B1-3B3), and high c-Met (Figures 3C1-3C3). [Figure 3C-3] Figures 3A1-3C3, 3B1-3B3, and 3C1-3C3 show typical c-Met membrane staining intensities on non-squamous NSCLC. They show the SP44 OptiView IHC membrane staining intensities (20x) for c-Met-negative (Figures 3A1-3A3), c-Met-positive (Figures 3B1-3B3), and high c-Met (Figures 3C1-3C3). [Figure 4] The distribution of SP44 UltraView and OptiView IHC in 3+ intensity staining on a commercially available NSCLC cohort is shown. [Figure 5] The ≥25% 3+ cutoff value for SP44 OptiView indicates that it selects a similar patient population to SP44 Ultraview. The abbreviations shown in Figure 5 and the calculation methods for the values ​​in the table are as follows: PPA (Positive Agreement Rate) = Number of oV-positive uV-positives / Total number of uV-positives; NPA (Negative Agreement Rate) = Number of oV-negative uV-negatives / Total number of uV-negatives; OPA (Overall Agreement Rate) = Number of oV-positive uV-positives + Number of oV-negative uV-negatives / Total number of samples tested; PPV (Positive Predictive Value) = Number of oV-positive uV-positives / Total number of oV-positives; NPV (Negative Predictive Value) = Number of oV-negative uV-negatives / Total number of oV-negatives. %BOR represents the best overall response rate. [Figure 6] A ≥50% 3+ cutoff value for SP44 OptiView indicates that it selects a similar patient population to SP44 Ultraview. The abbreviations shown in Figure 6 and the calculation methods for the values ​​in the table are as follows: PPA (Positive Agreement Rate) = Number of oV-positive uV-positive cases / Total number of uV-positive cases; NPA (Negative Agreement Rate) = Number of oV-negative uV-negative cases / Total number of uV-negative cases; OPA (Overall Agreement Rate) = Number of oV-positive uV-positive cases + Number of oV-negative uV-negative cases / Total number of samples tested; PPV (Positive Predictive Value) = Number of oV-positive uV-positive cases / Total number of oV-positive cases; NPV (Negative Predictive Value) = Number of oV-negative uV-negative cases / Total number of oV-negative cases. %BOR represents the best overall response rate. [Figure 7]This shows the design of the Phase 2, multicenter, non-randomized, single-arm, two-stage adaptive enrichment trial (NCT03539536) in patients with c-Met+ locally advanced or metastatic NSCLC. [Figure 8A] Figures 8A and 8B summarize the overall response rate (ORR) and the probability of achieving a 25% ORR in patients with locally advanced or metastatic NSCLC with c-Met+ from the Phase 2, multicenter, non-randomized, single-arm, two-stage adaptive enrichment trial (NCT03539536). Figure 8A shows the results of grouping patients according to tumor histology, c-Met expression level, and EGFR status (WT = wild-type, MU = mutant). Figure 8B shows the results of grouping patients according to tumor histology and EGFR status. [Figure 8B] Figures 8A and 8B summarize the overall response rate (ORR) and the probability of achieving a 25% ORR in patients with locally advanced or metastatic NSCLC with c-Met+ from the Phase 2, multicenter, non-randomized, single-arm, two-stage adaptive enrichment trial (NCT03539536). Figure 8A shows the results of grouping patients according to tumor histology, c-Met expression level, and EGFR status (WT = wild-type, MU = mutant). Figure 8B shows the results of grouping patients according to tumor histology and EGFR status. [Modes for carrying out the invention]

[0014] 6. Detailed explanation 6.1. Anti-c-MetADC: Terisotuzumab vedotin As described throughout this specification, telisotuzumab vedotin (Teliso-V) is an ADC obtained by conjugating the c-Met-targeting antibody ABT-700 (PR-1266688,h224G11) via a valine-citrulline (vc) linker with the potent cytotoxic monomethyl auristatin E (MMAE). Conjugation with ABT-700 occurs via a thioether bond formed with the sulfhydryl group of the cysteine ​​residue of ABT-700. The production and bioactivity of ABT-700 are described in U.S. Patent No. 8,741,290. The production and bioactivity of telisotuzumab vedotin are described in U.S. Patent No. 10,603,389.

[0015] The terisotuzumab vedotin used in this application has the following structural formula:

[0016] [ka] This means an ADC having the formula, where n is 2 or 4, and Ab is ABT-700, and the conjugation of the drug and antibody occurs via a bond formed with the sulfhydryl group of the cysteine ​​residue of ABT-700. In one preferred embodiment, n is a numerical value of 2. In one preferred embodiment, n is a numerical value of 4. The purification and characterization of terisotuzumab vedotin with n being 2 or 4 is described in U.S. Patent No. 10,603,389.

[0017] Terisotuzumab vedotin has been used in Phase 1 clinical trials in pharmaceutical formulations with a DAR of approximately 2.4–3.6 (e.g., 3.1) (see Example 16 of U.S. Patent No. 10,603,389).

[0018] Terisotuzumab vedotin can be used in a 1:1 E2 / E4 ratio corresponding to an average DAR of 3.0 or approximately 3.0. In other words, terisotuzumab vedotin can be used as a composition containing the E2 purified fraction and the E4 purified fraction of an antibody-drug conjugate in a 1:1 ratio. In other alternative embodiments, terisotuzumab vedotin can be used in a DAR of 2.9.

[0019] As used in this application, ABT-700 refers to an arbitrarily selected antibody having the following heavy and light chain sequences. The heavy chain of ABT-700 has the following sequence:

[0020] [ka] (The constant region is shown in bold, and the CDR is shown underlined (numbering follows Kabat, and the CDR sequences are disclosed as sequence numbers 1-3 in order of appearance)) (The variable region is disclosed as Sequence ID No. 4) (The full sequence is disclosed as sequence number 5.) The light chain of ABT-700 contains the following sequence:

[0021] [ka] (The CDR sequences are disclosed as sequence numbers 6-8, respectively, in order of appearance.) (The variable region is disclosed as Sequence ID 9) (The full-length sequence is disclosed as sequence number 10.) Includes.

[0022] In one embodiment, the ABT-700 heavy chain is encoded by the following nucleotide sequence (the full-length sequence disclosed as SEQ ID NO: 11).

[0023] [ka] In the above sequences, the secretory signal peptides shown in bold capital letters include the final stop codon (TGA), the constant region is shown in bold, and the CDR is underlined (the CDR sequences are disclosed as Sequence IDs 12-14 in order of appearance).

[0024] In one embodiment, the ABT-700 light chain is encoded by the following nucleotide sequence (the full-length sequence disclosed as SEQ ID NO: 15).

[0025] [ka] In the above sequences, the secretory signal peptides shown in bold capital letters include the final stop codon (tga), the constant region is shown in bold, and the CDR is underlined (the CDR sequences are disclosed as Sequence IDs 16-18 in order of appearance).

[0026] 6.2. Composition Teliso-V is provided as an aqueous composition suitable for administration by intravenous infusion. In a given embodiment, the aqueous composition contains 20 mg / mL of Teliso-V, 10 mM histidine buffer (pH 6.0), 7% (w / v) sucrose, and 0.03% (w / v) polysorbate 80. The composition can be in the form of a lyophilized powder and, when reconstituted with 5.2 mL of sterile water or another solution suitable for injection or infusion (e.g., 0.9% physiological saline, Ringer's solution, lactated Ringer's solution, etc.), provides the aqueous composition.

[0027] 6.3.How to use The method described herein involves administering Teliso-V to patients with non-squamous NSCLC that overexpress c-Met and have a known EGFR status. NSCLC cancer may be a recurrent, refractory, recurrent-refractory, metastatic, or metastatic form of tumor overexpressing c-Met. Generally, Teliso-V is administered at a dose of 1.9 mg / kg once every two weeks (14 days). In one embodiment, Teliso-V is administered at a dose of 1.6 mg / kg once every two weeks (14 days). To demonstrate efficacy, subjects treated with Teliso-V should have an objective response rate (ORR) greater than 25%, and a median duration of response (DoR) of 6 months or more (i.e., at least 6 months, at least 8 months, and / or at least 10 months). Other efficacy endpoints include progression-free survival (PFS), overall survival (OS), and an acceptable safety and tolerability profile.

[0028] According to the results of the Stage 1 interim analysis 3 of the ongoing Phase 2 trial (NCT03539536) in c-Met-positive advanced NSCLC patients with a history of prior treatment with platinum-based chemotherapy and immune checkpoint inhibitors (or standard TKI prior treatment, second- or third-line), the clinical validity of the concept of Teliso-V in non-squamous NSCLC EGFR wild-type patients was demonstrated (see Figures 8A and 8B). In EGFR wild-type patients with c-Met-positive NSCLC, the overall response rate (ORR) was 35.1% (posterior probability of ORR >25% = 91.9%) (Figure 8B). Within the c-Met-positive EGFR cohort, the ORR was highest in the non-squamous c-Met high EGFR WT cohort, i.e., 53.8% compared to 25% in the c-Met moderate EGFR WT cohort (Figure 8A). Based on the results of Interim Analysis 3 of Stage 1, it is recommended to initiate a Stage 2 trial in patients with c-Met-positive EGFR wild-type non-squamous NSCLC. The ORR in the non-squamous NSCLC EGFR mutant cohort was 13.3% (Figure 8B), but the Stage 1 trial will likely continue until a sufficient number of patients are reached to evaluate efficacy. Based on the results of Interim Analysis 3, the use of Teliso-V to treat patients with squamous NSCLC is not recommended (Figures 8A and 8B).

[0029] In one preferred embodiment, treatment of non-squamous NSCLC patients with EGFR wild-type status achieves an ORR of over 25%, over 30%, over 35%, over 40%, over 45%, over 50%, or over 55%. In other embodiments, administration of Teliso-V results in a progression-free survival (PFS) of at least 5 months or an overall survival (OS) of at least 13 months.

[0030] In patients with non-squamous NSCLC and EGFR wild-type status, administration of Teliso-V yields a favorable safety profile, with adverse events (i.e., peripheral neuropathy, neutropenia, pneumonitis, and ocular toxicity) occurring in less than 20%, and optionally less than 15% or 10%, leading to discontinuation of Teliso-V administration. The incidence of adverse events of 3+ or higher will be less than 20%, and optionally less than 15% or 10%.

[0031] In one preferred embodiment, treatment of non-squamous NSCLC patients with EGFR mutant status achieves ORRs of over 25%, over 30%, over 35%, over 40%, over 45%, over 50%, or over 55%. In other embodiments, administration of Teliso-V results in progression-free survival (PFS) of at least 5 months or overall survival (OS) of at least 13 months.

[0032] In patients with non-squamous NSCLC who have EGFR mutant status, administration of Teliso-V yields a favorable safety profile, with adverse events (i.e., peripheral neuropathy, neutropenia, pneumonitis, and ocular toxicity) occurring in less than 20%, and optionally less than 15% or 10%, leading to discontinuation of Teliso-V administration. The percentage of patients experiencing 3+ or higher adverse events will be less than 20%, and optionally less than 15% or 10%.

[0033] IHC assays for assessing the expression levels of target proteins are known to those with ordinary skill in the art (see *Diagnostic Immunohistochemistry: Theranostic and Genomic Applications* (5th edition, 2019) by David Dabbs, and *Companion and Complementary Diagnostics: From Biomarker Discovery to Clinical Implementation* (2019) edited by JT Jorgensen). The c-Met IHC assay used in the methods of this disclosure assesses the level of c-Met overexpression in tumor tissue derived from subjects with non-squamous NSCLC. A preferred example of a method for determining the level of c-Met overexpression is the c-Met IHC assay described in detail in Example 1, which is referred to hereby as the "c-Met Teliso-V staining protocol".

[0034] In one embodiment, the treatment method includes the step of determining the level of c-Met overexpression in a non-squamous NSCLC tumor by performing c-Met immunohistochemical staining (IHC) on tumor tissue derived from the subject (i.e., tumor tissue obtained from a biopsy, excision specimen, or cytological sample, and the tumor tissue may be archived tumor tissue or fresh tumor tissue), and further includes the step of determining whether the tumor tissue exhibits a) c-Met negative expression, b) c-Met positive expression, c) c-Met moderate expression, and / or d) c-Met high expression. c-Met negative expression is defined as <25% of neoplastic cells from tumor tissue showing 3+ membrane staining or membrane + cytoplasmic staining when assessed by c-Met IHC; c-Met positive expression is defined as ≥25% of neoplastic cells from tumor tissue showing 3+ membrane staining or membrane + cytoplasmic staining when assessed by c-Met IHC; c-Met moderate expression is defined as 25% to less than 50% of neoplastic cells from tumor tissue showing 3+ membrane staining or membrane + cytoplasmic staining when assessed by c-Met IHC; and c-Met high expression is defined as ≥50% of neoplastic cells from tumor tissue showing 3+ membrane staining or membrane + cytoplasmic staining when assessed by c-Met IHC. The c-Met overexpression level of an NSCLC tumor is considered to be the overexpression level of the sample tissue as determined by c-Met IHC. In a predetermined embodiment, the c-Met IHC is performed according to the c-Met Teliso-V staining protocol.

[0035] The decision to administer Teliso-V to a subject is made based on the level of c-Met overexpression in the tumor as determined by the c-Met IHC assay. In one embodiment, subjects with EGFR wild-type tumors showing positive c-Met expression are administered Teliso-V intravenously at a dose of 1.9 mg / kg every two weeks. In another embodiment, subjects with EGFR wild-type tumors showing moderate c-Met expression are administered Teliso-V intravenously at a dose of 1.9 mg / kg every two weeks. In yet another embodiment, subjects with EGFR wild-type tumors showing high c-Met expression are administered Teliso-V intravenously at a dose of 1.9 mg / kg every two weeks. In yet another embodiment, subjects with EGFR wild-type tumors showing negative c-Met expression are excluded from intravenous administration of Teliso-V at a dose of 1.9 mg / kg every two weeks. In one embodiment, subjects with EGFR wild-type tumors exhibiting c-Met-positive expression are administered Teliso-V intravenously at a dose of 1.6 mg / kg once every two weeks. In another embodiment, subjects with EGFR wild-type tumors exhibiting moderate c-Met expression are administered Teliso-V intravenously at a dose of 1.6 mg / kg once every two weeks. In yet another embodiment, subjects with EGFR wild-type tumors exhibiting high c-Met expression are administered Teliso-V intravenously at a dose of 1.6 mg / kg once every two weeks. In yet another embodiment, subjects with EGFR wild-type tumors exhibiting c-Met-negative expression are excluded from intravenous administration of Teliso-V at a dose of 1.6 mg / kg once every two weeks.

[0036] In another embodiment, subjects with EGFR mutant tumors exhibiting c-Met-positive expression are administered Teliso-V intravenously at a dose of 1.9 mg / kg once every two weeks. In yet another embodiment, subjects with EGFR mutant tumors exhibiting moderate c-Met expression are administered Teliso-V intravenously at a dose of 1.9 mg / kg once every two weeks. In yet another embodiment, subjects with EGFR mutant tumors exhibiting high c-Met expression are administered Teliso-V intravenously at a dose of 1.9 mg / kg once every two weeks. In yet another embodiment, subjects with EGFR mutant tumors exhibiting c-Met-negative expression are excluded from intravenous administration of Teliso-V at a dose of 1.9 mg / kg once every two weeks. In yet another embodiment, subjects with EGFR mutant tumors exhibiting c-Met-positive expression are administered Teliso-V intravenously at a dose of 1.6 mg / kg once every two weeks. In another embodiment, subjects with EGFR mutants and tumors exhibiting moderate c-Met expression are administered Teliso-V intravenously at a dose of 1.6 mg / kg once every two weeks. In yet another embodiment, subjects with EGFR mutants and tumors exhibiting high c-Met expression are administered Teliso-V intravenously at a dose of 1.6 mg / kg once every two weeks. In yet another embodiment, subjects with EGFR mutants and tumors exhibiting negative c-Met expression are excluded from intravenous administration of Teliso-V at a dose of 1.6 mg / kg once every two weeks.

[0037] In one embodiment, a target population with non-squamous NSCLC tumors whose EGFR status is known is treated according to the level of c-Met overexpression in their tumor tissue as determined by c-Met IHC. Each target with a tumor that is EGFR wild-type or mutant and shows c-Met-positive expression is administered Teliso-V intravenously at a dose of 1.9 mg / kg once every two weeks, and each target with a tumor showing c-Met-negative expression is excluded from administration. In another embodiment, each target with a tumor that is EGFR wild-type or mutant and shows c-Met-positive expression is administered Teliso-V intravenously at a dose of 1.6 mg / kg once every two weeks, and each target with a tumor showing c-Met-negative expression is excluded from administration. In another embodiment, each subject in a population having tumors that are EGFR wild-type or mutant and exhibit moderate c-Met expression is intravenously administered Teliso-V at a dose of 1.9 mg / kg once every two weeks, and each subject having tumors that exhibit negative c-Met expression is excluded from administration. In another embodiment, each subject in a population having tumors that are EGFR wild-type or mutant and exhibit moderate c-Met expression is intravenously administered Teliso-V at a dose of 1.6 mg / kg once every two weeks, and each subject having tumors that exhibit negative c-Met expression is excluded from administration. In another embodiment, each subject in a population having tumors that are EGFR wild-type or mutant and exhibit high c-Met expression is intravenously administered Teliso-V at a dose of 1.9 mg / kg once every two weeks, and each subject having tumors that exhibit negative c-Met expression is excluded from administration. In another embodiment, each subject in a population having tumors that are EGFR wild-type or mutant and exhibit high c-Met expression is intravenously administered Teliso-V at a dose of 1.6 mg / kg once every two weeks, while each subject having tumors exhibiting c-Met negative expression is excluded from administration. In yet another embodiment, each subject in a population having tumors that are EGFR wild-type or mutant and exhibit high c-Met expression is intravenously administered Teliso-V at a dose of 1.9 mg / kg once every two weeks, while each subject having tumors exhibiting moderate or c-Met negative expression is excluded from administration.In another embodiment, each subject in a population with tumors exhibiting EGFR wild-type or mutant characteristics and high c-Met expression is administered Teliso-V intravenously at a dose of 1.6 mg / kg once every two weeks, while subjects with tumors exhibiting moderate or negative c-Met expression are excluded from administration.

[0038] Patients treated with Teliso-V should achieve at least one of the following clinical endpoints: an overall response rate (ORR) greater than 25%, a median duration of response (DoR) of at least 6 months, a progression-free survival (PFS) of at least 5 months, or an overall survival (OS) of at least 13 months, and should demonstrate stable disease (SD), partial response (PR), or complete response (CR) in accordance with RECIST version 1.1.

[0039] In one embodiment, Teliso-V is administered at a dose of 1.2 mg / kg to 2.4 mg / kg. In various embodiments, Teliso-V is administered at doses of 1.2 mg / kg, 1.4 mg / kg, 1.6 mg / kg, 1.8 mg / kg, 2.0 mg / kg, 2.2 mg / kg, or 2.4 mg / kg. As will be obvious to those skilled in the art, the recommended dose of Teliso-V should be adjusted to optimize patient response and maximize therapeutic effect. For example, to manage peripheral neuropathy, the dose of Teliso-V can be reduced to 1.6 mg / kg. In one embodiment, the dose for a patient weighing more than 100 kg is calculated as if the patient weighed 100 kg. In this embodiment, the maximum dose is 190 mg.

[0040] 6.4. Patient Selection Patients receiving Teliso-V have non-squamous NSCLC tumors that overexpress c-Met. Patients receiving Teliso-V are selected based on their known EGFR status, prior treatment status, and c-Met overexpression levels determined by immunohistochemical staining (c-Met IHC).

[0041] In one embodiment, the eligibility and exclusion criteria in Tables 1 and 2 below are used to determine whether a subject is eligible for treatment.

[0042] [Table 1]

[0043] [Table 2]

[0044] 6.4.1. Selection Criteria: NSCLC Tumor Type Patients selected for treatment are those with non-squamous NSCLC overexpressing c-Met. Patients are selected based on their known EGFR status, prior treatment status, and c-Met expression levels as determined by immunohistochemical staining (IHC).

[0045] In a given embodiment, patients selected for administration of Teliso-V have a non-squamous NSCLC tumor type that overexpresses c-Met and is recurrent and / or refractory, or a metastatic form of recurrent, refractory, or recurrent-refractory NSCLC. In a given embodiment, the NSCLC tumor overexpressing c-Met is locally advanced and / or metastatic NSCLC.

[0046] In a given embodiment, patients excluded from Teliso-V administration have squamous epithelial NSCLC.

[0047] The decision of whether or not to select a particular patient for Teliso-V administration requires determining whether the patient's NSCLCs have cells with mutations in the epidermal growth factor receptor gene (EGFR).

[0048] In a given embodiment, patients selected for treatment are NSCLCs that overexpress c-Met and have no mutations in the EGFR gene, e.g., EGFR wild-type (WT) NSCLCs. In a given embodiment, patients excluded from treatment are NSCLCs that overexpress c-Met and have mutations in the EGFR gene. Kinase domain mutations in EGFR are called "activating mutations" because they lead to ligand-independent activation of TK activity. In some tumors, a partially activated mutant EGFR can be made completely ligand-independent by a second mutation, and thus constitutively activated (Oncogene, 2009 Aug;28, Suppl 1:S24-S31). In one embodiment, subjects must have a known EGFR activating mutation status. In one embodiment, subjects with actionable EGFR activating mutations are excluded from Teliso-V administration. In one embodiment, subjects with actionable mutations in genes other than EGFR are eligible for Teliso-V administration.

[0049] In other embodiments, patients selected for treatment have NSCLC overexpressing c-Met with at least one EGFR mutation. In a given embodiment, the at least one EGFR mutation is selected from exon 19 deletion, exon 21 L858R mutation, and / or T790M mutation. In a given embodiment, the at least one EGFR mutation is detected by an FDA-approved test.

[0050] One example of such a study uses real-time polymerase chain reaction (PCR) to identify at least 42 mutations (including the T790M resistance mutation) in exons 18, 19, 20, and 21 of the EGFR gene. This study has been clinically validated in multiple clinical trials as a companion diagnostic (CDx) for first-line and second-line EGFR TKI treatment in patients with advanced NSCLC (Heeke, et al., (2019) Clinical Lung Cancer, 21(1):56-65).

[0051] In certain embodiments, subjects are grouped based on their c-Met expression level (i.e., negative, positive, moderate, and high c-Met expression) as determined by IHC and their EGRF status (wild-type or mutant). Treatment decisions are then made for each of the resulting groups.

[0052] 6.4.2. Selection Criteria: Prior Treatment In a predetermined embodiment, the patients selected for treatment have a history of prior treatment with two or fewer lines of systemic therapy (including one or fewer lines of systemic cytotoxic chemotherapy) for locally advanced or metastatic disease.

[0053] In other embodiments, patients selected for treatment are those undergoing (or ineligible for) systemic cytotoxic chemotherapy, undergoing immune checkpoint inhibitor therapy as monotherapy or in combination with systemic cytotoxic chemotherapy, or ineligible for immune checkpoint inhibitor therapy and, where applicable, undergoing prior anticancer therapy targeting tyrosine kinase inhibitors (TKIs).

[0054] In other embodiments, patients selected for treatment have a history of prior treatment with 1) at least one cytotoxic chemotherapeutic agent and 2) at least one immune checkpoint inhibitor or at least one tyrosine kinase inhibitor (TKI). In other embodiments, if a subject does not have a history of prior treatment with 1) at least one cytotoxic chemotherapeutic agent and 2) at least one immune checkpoint inhibitor or at least one tyrosine kinase inhibitor (TKI), the subject is not selected for treatment.

[0055] In a given embodiment, the cytotoxic chemotherapeutic agent is a platinum-based chemotherapeutic agent such as cisplatin, oxaliplatin, and carboplatin, or a combination of two platinum-based agents such as cisplatin / pemetrexed, carboplatin / pemetrexed, or carboplatin / paclitaxel.

[0056] In a given embodiment, the at least one immune checkpoint inhibitor is selected from antibodies targeting PD-1 (e.g., pembrolizumab, nivolumab, and pizilizumab), PD-L1 (e.g., durvalumab, atezolizumab, avelumab, MEDI4736, MSB0010718C, and MPDL3280A), and CTLA4 (cytotoxic lymphocyte antigen 4, e.g., ipilimumab, tremelimumab).

[0057] In a given embodiment, the at least one tyrosine kinase inhibitor (TKI) is selected from osimertinib, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, afatinib, axitinib, crizotinib, erlotinib, gefitinib, lapatinib, nilotinib, pazopanib, regorafenib, sorafenib, sunitinib, toceranib, batalanib, or radotinib.

[0058] In a predetermined embodiment, the subjects selected for treatment have no prior history of systemic therapy for locally advanced or metastatic disease.

[0059] 6.4.3. Selection Criteria: c-Met expression by IHC Intravascular health testing (IHC) is used to evaluate candidate patients to be selected for Teliso-V administration based on the c-Met overexpression levels observed in non-squamous NSCLC tumor tissue. In a given embodiment, c-Met IHC is performed on at least one non-squamous NSCLC tumor tissue derived from the subject, the at least one tumor tissue being selected from archived tumor tissue and / or fresh tumor tissue.

[0060] In one embodiment, c-Met immunohistochemical staining (c-Met IHC) is performed on neoplastic cells from tumor tissue derived from the subject, and the level of c-Met overexpression in non-squamous NSCLC tumors is determined by determining whether the neoplastic cells exhibit i) c-Met negative expression, ii) c-Met positive expression, iii) moderate c-Met expression, or iv) high c-Met expression based on the results of the c-Met IHC assay. In one embodiment, the c-Met IHC is performed according to the c-Met Teliso-V staining protocol described herein.

[0061] c-Met negative expression is defined as <25% of neoplastic cells from tumor tissue having 3+ membrane staining or membrane+ cytoplasmic staining when assessed by c-Met IHC.

[0062] c-Met positivity is defined as ≥25% of neoplastic cells from tumor tissue exhibiting 3+ membrane staining or membrane + cytoplasmic staining when assessed by c-Met IHC.

[0063] Moderate c-Met expression is defined as having 25% to less than 50% of neoplastic cells from tumor tissue exhibiting 3+ membrane staining or membrane + cytoplasmic staining, as assessed by c-Met IHC.

[0064] High c-Met expression is defined as ≥50% of neoplastic cells from tumor tissue exhibiting 3+ membrane staining or membrane+ cytoplasmic staining, as assessed by c-Met IHC.

[0065] In certain embodiments, subjects with non-squamous NSCLC exhibiting c-Met-negative expression are excluded from Teliso-V administration.

[0066] In a predetermined embodiment, patients selected for administration of Teliso-V have non-squamous NSCLC exhibiting c-Met-positive expression.

[0067] In a predetermined embodiment, patients selected for administration of Teliso-V have non-squamous NSCLC exhibiting moderate c-Met expression.

[0068] In a predetermined embodiment, patients selected for administration of Teliso-V have non-squamous NSCLC exhibiting high c-Met expression.

[0069] 6.4.3.1. IHC determination of c-Met expression To determine c-Met overexpression in NSCLC in candidate patients for Teliso-V administration, c-Met-specific immunohistochemical staining (c-Met IHC) is envisioned. For this purpose, IHC scores of 0, 1+, 2+, and 3+ are used. 0 orders, no dyeing 1+=weak staining 2+ = moderate staining 3+ = Strong staining This represents the visual c-Met staining intensity of individual neoplastic cells from tumor tissue.

[0070] Generally, approximately 100 human NSCLC cells are present in a 20x fixed field of view. In this application, IHC scoring refers to the intensity of membrane c-Met staining or the intensity of membrane + cytoplasmic c-Met staining.

[0071] In a predetermined embodiment, patients with NSCLC selected for Teliso-V administration exhibit c-Met overexpression as determined by IHC, and the IHC is 1) A step of staining the membrane or membrane and cytoplasm of neoplasms of NSCLC with a diagnostic reagent specific to c-Met, 2) The process includes performing IHC scoring using numerical values ​​set to correspond to a score of 0, a score of 1+, a score of 2+, and / or a score of 3+, and scoring the intensity of membrane staining or membrane + cytoplasmic staining, A score of 0 corresponds to the lowest visible membrane staining or membrane + cytoplasmic staining intensity of the negative control or near it; a score of 3+ corresponds to the maximum visible membrane staining or membrane + cytoplasmic staining intensity of the positive control or near it; and scores of 1+ and 2+ correspond to approximately 1 / 3 or near it and approximately 2 / 3 or near it of the maximum visible membrane staining or membrane + cytoplasmic staining intensity of the positive control, respectively.

[0072] Details regarding the visualization and determination method of c-Met overexpression levels are described in the following text and in Example 1. In the spirit of this application, including the claims, the specific assay used in Example 1 is referred to as the “c-Met Teliso-V staining protocol.” Briefly, the aim is to develop a c-Met IHC staining assay for c-Met overexpression using the Ventana c-Met CONFIRM (SP44) kit (catalog no. 790-4430) for use in selecting patients for Teliso-V administration. In this assay, tissue samples are stained with Ventana anti-c-Met antibody and then scored by determining the percentage of neoplastic cells in tumor tissue stained at predetermined intensity levels from weak / low to strong / high (i.e., 0, 1+, 2+, 3+). This assay produces staining of the c-Met protein in both the cytoplasm and cell membrane, and membrane staining or membrane + cytoplasmic staining is used for IHC score determination.

[0073] If different IHC methods yield different c-Met IHC scoring results, the c-Met IHC scoring results determined by the method described in Example 1 are used to determine whether a particular embodiment falls within the scope of the embodiment. For example, the "c-Met Teliso-V staining protocol" is used to evaluate c-Met protein expression. If the reagents used in this protocol are no longer available, another FDA-approved protocol for assessing c-Met expression levels by IHC may be used.

[0074] IHC detection of c-Met c-Met IHC detection is a diagnostic technique that visualizes the c-Met antigen after identifying its localization with a primary anti-c-Met antibody. In a given embodiment, the primary anti-c-Met antibody is selected from mouse IgG, mouse IgM, or rabbit antibody. In a given embodiment, IHC detection includes direct visualization of the primary anti-cMet antibody. In a given embodiment, IHC detection includes indirect visualization of the primary anti-cMet antibody. In a given embodiment, indirect visualization includes a secondary antibody specific to the primary anti-cMet antibody species. In a given embodiment, indirect visualization further includes a tertiary antibody conjugated to the secondary antibody, the tertiary antibody conjugated to at least one enzyme. In a given embodiment, indirect visualization further includes a chromogen having a substrate specific to the at least one enzyme of the tertiary antibody. In a given embodiment, it is preferable that the chromogen produces a detectable precipitate, the precipitate being detectable by visualization and / or colorimetric change. In certain embodiments, the substrate is hydrogen peroxide. In certain embodiments, the pigment source is 3,3'-diaminobenzidine tetrahydrochloride (DAB).

[0075] In a given embodiment, c-Met expression is determined using the OptiView DAB IHC detection kit (Ventana catalog number 760-700). The OptiView kit uses an indirect method to visualize specific mouse and rabbit primary antibodies bound to the antigen by depositing a brown precipitate.

[0076] Preparation of tissue samples for IHC detection In a given embodiment, IHC detection of c-Met expression includes staining frozen, formalin-fixed, and / or paraffin-embedded tumor tissue. In a given embodiment, tumor tissue membrane staining is performed by a slide staining apparatus. As expected, such a slide staining apparatus automates the slide staining process (e.g., washing the slide after the antibody incubation process to remove unbound material and / or attaching a coverslip to the slide). In a given embodiment, the slide staining apparatus is a VENTANA(R) slide staining apparatus. In a given embodiment, the slide staining apparatus is a VENTANA(R) benchmark series instrument (i.e., a benchmark ULTRA IHC / ISH system).

[0077] For use with the OptiView DAB IHC detection kit and VENTANA(R) benchmark series instruments, formalin-fixed paraffin-embedded tissue is suitable. In a given embodiment, the preparation of tumor tissue for IHC detection includes the step of contacting the tumor tissue with a fixative. In a given embodiment, a formalin-based fixative (e.g., 10% neutral buffered formalin (NBF)) is used.

[0078] To minimize variations in visualization results, the thickness of tumor tissue sections, fixation type, and time can be optimized. In a given embodiment, the tumor tissue sections are approximately 2 μm to 6 μm thick. In a given embodiment, the tumor tissue sections are approximately 2 μm, 3 μm, 4 μm, 5 μm, or 6 μm thick. Slide heating is envisioned to dry the tumor tissue sections after slide mounting or to enhance tissue adhesion to the microscope glass slide. In a given embodiment, it is preferable to heat and bake the slide containing the tumor tissue sections. In a given embodiment, the slide is heated at 60°C ± 5°C for 2 to 24 hours. Avoid overheating the tumor tissue, as this may reduce its antigen availability. In a given embodiment, the slide is brought into contact with cold acetone (i.e., 4 to 8°C) for 10 minutes. In a given embodiment, after contacting the slide with cold acetone, it is air-dried for at least 30 minutes, preferably overnight.

[0079] contrast The c-Met IHC staining method is intended to test a positive tissue control. This positive tissue control may be, for example, tumor tissue or non-neoplastic gallbladder tissue. Some or all of the positive tissue control will show strong staining. The positive tissue control may include both positive and negative staining and may function as both a positive and negative control tissue. Unstained cellular components are thought to demonstrate the absence of specific staining and provide an indicator of background staining. In a given embodiment, the same tissue used for the positive tissue control is used as the negative tissue control. In a given embodiment, the positive or negative control tissues are prepared in the same way as the test tissues.

[0080] A negative control is useful for interpreting the c-Met IHC score. In a given embodiment, a negative reagent control is used instead of the primary anti-c-Met antibody to evaluate nonspecific staining. In a given embodiment, the negative control reagent is a diluent alone. In a preferred embodiment, the incubation time for the negative reagent control is equal to the incubation time for the primary antibody.

[0081] Before using the primary anti-cMet antibody for the first time in the treatment method described in this application, it is necessary to verify the specificity of the antibody by testing its performance in a series of tissues in which the immunohistochemical staining performance characteristics of c-Met expression are known for positive and negative tissues.

[0082] Interpretation of results The OptiView DAB IHC detection kit (Ventana catalog number 760-700) envisioned in this invention precipitates a brown reaction product at or near the c-Met antigen site whose localization has been identified by a primary anti-c-Met antibody.

[0083] In a given embodiment, detection of c-Met expression by IHC is performed by a qualified pathologist skilled in immunohistochemical staining. In a given embodiment, detection of c-Met expression is performed after the step of evaluating positive and negative controls. The staining of the negative reagent control is recorded, and these results are compared with the stained material to verify that the observed visualization is not due to nonspecific interactions. The positive tissue control is tested to verify that the reagent is functioning correctly. If the positive tissue control does not show positive staining, the results of these test specimens should be considered invalid for the purposes of the therapeutic method disclosed herein. Negative tissue controls must be tested after positive tissue controls to verify the specific labeling of the target antigen by the primary antibody. If no specific staining occurs in the negative tissue control, it is confirmed that there is no binding of the anti-c-Met primary antibody. If specific staining occurs in the negative tissue control, the results of these test specimens should be considered invalid for the purposes of the therapeutic method disclosed herein. Nonspecific staining may result in a diffuse appearance. Sparse, light staining may indicate excessive formalin fixation of cells. Necrotic or degenerated cells may stain nonspecifically.

[0084] In a prescribed embodiment of the treatment method with Teliso-V, intact cells of NSCLC tissue are assayed for c-Met expression by IHC. Following controls, patient tissue biopsies, excised specimens, or cytological specimens are tested as described in this application using staining intensity assessed within the context of optional, nonspecific background staining of controls (i.e., negative tissue controls and negative reagent controls). The morphology of cells in the NSCLC tissue specimens should also be examined by a qualified pathologist skilled in immunohistochemical staining. In a prescribed embodiment, the NSCLC tissue specimens are contacted with hematoxylin or eosin dye.

[0085] Automated slide staining In a predetermined embodiment, patients with NSCLC selected for Teliso-V administration exhibit c-Met overexpression when tumor tissue is assessed by a c-Met IHC assay, the c-Met IHC assay being a c-Met Teliso-V staining protocol. In a predetermined embodiment, the c-Met IHC assay is performed using an automated slide staining device. In a given embodiment, the c-Met IHC assay includes the steps of: 1) preparing a barcode label printed with a barcode corresponding to one or more automated IHC protocols to be performed by an automated slide staining device, and attaching it to a slide containing tumor tissue; 2) setting a primary anti-c-Met antibody, at least one negative reagent control, and / or one or more detection reagents in the automated slide staining device; 3) setting at least one slide containing tumor tissue in the automated slide staining device; 4) staining the c-Met tumor tissue on the slide by operating the automated slide staining device according to one or more automated IHC protocols; and 5) detecting and scoring the c-Met IHC stain of the slide. In a given embodiment, the automated slide staining device is a Ventana Benchmark series instrument, and optionally a Ventana Benchmark Ultra automated staining device. In a given embodiment, the barcode corresponds to the SP44 IHC protocol. In a given embodiment, the SP44 IHC protocol is selected from a deparaffinization protocol, a cell conditioning protocol (i.e., Ventana catalog number 950-224), an antibody protocol (i.e., Ventana catalog number 790-4430 for SP44, or Ventana catalog number 790-4795 for rabbit monoclonal negative control Ig), a detection protocol (i.e., Ventana catalog number 760-700 for the OptiView DAB IHC detection kit), or a counterstaining protocol (i.e., Ventana catalog number 790-2208 for hematoxylin II, or catalog number 760-2037 for a bluing agent). In a given embodiment, the primary anti-cMet antibody is the SP44 antibody.In a given embodiment, the one or more negative reagent controls are negative control immunoglobulins. In a given embodiment, the one or more detection reagents are components of the OptiView detection kit and are optionally selected from reaction buffer (Ventana catalog no. 950-300), Ultra Liquid Coverslip (Ventana catalog no. 650-210), or EZ Prep (Ventana catalog no. 950-102). [Examples]

[0086] 7. Examples The following examples are provided for illustrative purposes, focusing on the specific features and characteristics of representative embodiments of the antibody and binding fragment described in this application.

[0087] 7.1. Example 1: c-Met Teliso-V staining protocol To determine the suitability of candidate patients with NSCLC for Teliso V administration, the following assays were developed. An IHC staining assay was developed to determine c-Met overexpression using the Ventana c-Met CONFIRM (SP44) kit and the c-Met SP44 OptiView IHC staining assay.

[0088] The details of this assay and protocol are suitable for pre-screening patients with NSCLC, either as candidates for terisotuzumab vedotin administration or for administration of biosimilarities to terisotuzumab vedotin.

[0089] 7.1.1. Materials and Methods Specimen preparation Tumor tissue was processed according to standard procedures, fixed with formalin, and embedded in paraffin. It was then sectioned to approximately 4 microns and suspended on positively charged glass slides. The tissue was fixed using 10% neutral buffered formalin. To avoid time-dependent decrease in antigenicity, the slides were stained immediately after sectioning.

[0090] Immunohistochemical staining procedure Immunohistochemical staining (IHC) for c-Met was performed using the Ventana Benchmark Ultra automated staining platform. The primary antibody used was anti-c-Met clone SP44. The OptiView DAB IHC detection kit was used for indirect visualization of the primary antibody to determine c-Met expression.

[0091] The staining procedure using the Ventana benchmark instrument is as follows: 1) The process of attaching a barcode label corresponding to the SP44 IHC protocol to be implemented (Table 3) to the slide; 2) The SP44 antibody, rabbit monoclonal negative control Ig, and OptiView detection kit dispenser are placed in the reagent tray, and the auxiliary reagents (Table 4) are optionally prepared and the waste tank is empty; 3) The process of setting the slide to be tested into an automatic slide staining device; 4) The process includes the step of initiating the staining run using a Ventana instrument.

[0092] After the Ventana instrument run was complete, the slides were removed and soaked in mild detergent to remove the oil coverslip. The slides were thoroughly rinsed with distilled water and then dehydrated using a stepwise alcohol series. The slides were punctured with xylene and the coverslips were attached using permanent mounting medium.

[0093] [Table 3]

[0094] [Table 4]

[0095] 7.1.2. Results and Analysis Slide evaluation and interpretation The positivity of neoplastic cells stained with the c-MET SP44 OptiView IHC assay was visually evaluated based on the intensity of the diaminobenzidine (DAB) signal. The IHC signal may be uniformly distributed throughout the neoplasm, or it may be heterogeneously distributed, resulting in fewer positively stained cells.

[0096] c-MET(SP44) IHC staining in NSCLCs revealed that membrane staining often accompanied cytoplasmic staining (i.e., both cytoplasmic and membrane staining were present). When membrane staining was observed, it could be circumferential (broadly distributed) or partial (i.e., basal and lateral staining in adenocarcinoma). Both membrane and cytoplasmic staining showed intensity ranging from no staining (IHC score 0) to strong staining (IHC score 3+). Cytoplasmic staining was generally less intense than membrane staining. In some cases, cytoplasmic staining showed intensity comparable to membrane staining (i.e., especially moderate or high intensity), requiring careful differentiation of membrane staining from cytoplasmic staining.

[0097] Normal lung cells, bronchial epithelial cells, lung cells, and alveolar macrophages generally did not show strong levels of c-Met overexpression. However, bronchial epithelial cells and lung cells stained with IHC scores of 2+ to 3+ in the basal and lateral patterns. Staining of normal cellular components appears to be suitable as an internal control of the method. Representative staining intensity guidelines for cytoplasmic and membrane staining are shown in Tables 5 and 6, respectively.

[0098] [Table 5]

[0099] [Table 6]

[0100] Scoring algorithm c-Met stained tumor tissue IHC slides were evaluated for membrane staining on neoplastic cells. Non-squamous NSCLC samples with <25% 3+ membrane staining were considered c-Met negative. Non-squamous NSCLC samples where ≥25% of viable tumor cells showed 3+ membrane staining were considered c-Met positive. Non-squamous NSCLC samples where ≥25% to <50% of viable tumor cells showed 3+ membrane staining were considered moderately c-Met. Non-squamous NSCLC samples where ≥50% of viable tumor cells showed 3+ membrane staining were considered highly c-Met. Table 7 shows the various membrane staining intensities and positive / negative statuses based on the scoring algorithm.

[0101] [Table 7]

[0102] 7.1.3. Verification of the IHC Platform Comparison of the c-Met IHC assays SP44 "Ultraview" and SP44 "Optiview" A comparison of the analysis methods of SP44 Ultraview and SP44 OptiView was conducted in a large cohort of commercially available NSCLC tissue (Figure 4). These results showed that the SP44 OptiView IHC assay selected a similar patient population to SP44 Ultraview with a ≥25% 3+ membrane staining cutoff value. The overall agreement rate at this cutoff value between the two assays was 93%. In the human Phase I clinical trial, patients with an H-score of 150 were initially enrolled using the SP44 UltraView assay. Re-scoring of the slides revealed that the optimal cutoff value using the SP44 Ultraview IHC assay was ≥25% 3+, with a best overall response rate of 56%. Statistical modeling showed that the best overall response rate for the OptiView IHC assay using Phase I data was 52% (Figure 5).

[0103] Similarly, the SP44 OptiView IHC assay showed a 99% overall agreement with the SP44 Ultraview IHC assay at a ≥50% 3+ membrane staining cutoff value (Figure 6). In the human Phase I clinical trial, patients with an H score of 150 were initially enrolled using the SP44 UltraView assay. Upon rescoring the slides, the SP44 Ultraview IHC assay showed a best overall response rate of 67% at a ≥50% 3+ membrane staining cutoff value. Statistical modeling using Phase I data showed that the best overall response rate for the OptiView IHC assay was 63% (Figure 6).

[0104] 7.2. Example 2: Phase 2 open-label safety and efficacy study of terisotuzumab vedotin (ABBV-399) in patients with previously treated c-Met+ non-small cell lung cancer. 7.2.1. Overview An ongoing Phase 2 open-label trial (clinicaltrials.gov identifier NCT03539536, as incorporated herein) is evaluating the safety and efficacy of terisotuzumab vedotin in patients with previously treated c-Met+ non-small cell lung cancer. This is a Phase 2 multicenter, non-randomized, single-arm adaptive trial evaluating the efficacy, safety, pharmacokinetics, and pharmacodynamic properties of terisotuzumab vedotin in patients with c-Met+ locally advanced or metastatic NSCLC exhibiting c-Met overexpression according to designated IHC laboratory assay specifications, using a pre-defined c-Met-positive cutoff value. The trial is designed in two stages: Stage 1 identifies the optimal c-Met-overexpressing target NSCLC population for second-line or third-line terisotuzumab vedotin treatment, and Stage 2 expands the group to further evaluate efficacy in the selected population. The trial design is shown in Figure 7. The data presented in this application correspond to Interim Analysis 3 of Stage 1 and show favorable results for terisotuzumab vedotin in a validated clinical setting in a selected patient cohort.

[0105] Participants were required to have a known EGFR status and to have c-Met+NSCLC assessed by a designated IHC laboratory. Participants were also required to submit an archive or fresh tumor material for assessment of c-Met overexpression during the pre-screening period.

[0106] In Stage 1, approximately 150 patients with evaluable c-Met+NSCLC will be divided into three cohorts and treated with terisotuzumab vedotin monotherapy. The primary efficacy analysis will include a subset of patients with measurable disease as determined by independent central review (ICR). • Non-squamous EGFR wild-type NSCLC (N=approximately 60) • Non-squamous EGFR mutant NSCLC (N=approximately 60) • Squamous epithelial NSCLC (N=up to approximately 30).

[0107] For the enrollment of non-squamous epithelial cell cohorts, c-Met+ was defined as ≥25% of neoplastic cells from tumor tissue exhibiting a 3+ intensity membrane staining by immunohistochemical (IHC). Each c-Met+ non-squamous epithelial cell cohort was further subdivided into a moderate c-Met group (defined as ≥25% to <50% of neoplastic cells from tumor tissue exhibiting a 3+ intensity membrane staining by IHC) and a high c-Met group (defined as ≥50% of neoplastic cells from tumor tissue exhibiting a 3+ intensity membrane staining by IHC). The c-Met+ cutoff value for squamous epithelial cell cohorts was set as ≥75% of neoplastic cells from tumor tissue exhibiting any intensity (i.e., ≥1+) of membrane staining by IHC.

[0108] To evaluate efficacy in Stage 1 of the trial, NSCLC patients will be divided into five groups, consisting of a non-squamous cell cohort and a squamous cell cohort, with a maximum of 30 patients per group, and will be treated with terisotuzumab vedotin monotherapy. ·Non-squamous EGFR wild type NSCLC c-Met high (up to N=approximately 30) ·Non-squamous EGFR wild type NSCLC c-Met moderate (N=up to approximately 30) • Non-squamous epithelial EGFR mutant NSCLC with high c-Met (N=approximately 30) • Non-squamous EGFR mutant NSCLC with moderate c-Met (N=approximately 30) • Squamous epithelial NSCLC c-Met+ (N=approximately 30).

[0109] In Stage 2, the efficacy of terisotuzumab vedotin as monotherapy will be further evaluated in a specific group that showed promising results during Stage 1, and then further evaluated in a single-arm expanded cohort.

[0110] All subjects will receive terisotuzumab vedotin monotherapy until disease progression or the criteria for discontinuation of the study are met.

[0111] In Stage 1, approximately 30 additional subjects with measurable diseases by ICR and evaluable for c-Met+ efficacy will be enrolled. After following up these enrolled cohorts / groups for at least 12 weeks, an interim analysis will be conducted to formally evaluate efficacy. The number of subjects to begin the interim analysis can be adjusted as needed depending on whether the cohort / group progresses to Stage 2, completes the study, or reaches the maximum enrollment limit for the group.

[0112] A hierarchical Bayesian model is used to further assess the ORR of each group, enabling information borrowing between groups, with the degree of borrowing depending on the similarity of effectiveness observed between groups. This model takes into account the influence of disease histology and c-Met expression levels. By comparing the estimated posterior probability of success with upper and lower decision thresholds, a decision is made to stop group enrollment to Stage 1 due to futility or to move the group to an expanded Stage 2 cohort. The posterior probability of success is defined as the posterior probability of an ORR greater than 25%. The lower decision threshold is defined as 10%, and the upper decision threshold is defined as 70%. The above analysis is also performed at the cohort level.

[0113] In each interim analysis, decision-making begins with at least 10 efficacy evaluable subjects enrolled in one group or at least 15 efficacy evaluable subjects enrolled in one cohort (i.e., non-squamous EGFR wild-type, non-squamous EGFR mutants). If the posterior probability of success above 25% in a particular group is less than 0.10, it is considered useless. On the other hand, if the same posterior probability estimate is high (above 0.70), the group can be expanded, i.e., it can "move on" to a Stage 2 expansion. Even if the posterior probability of success for this group is intermediate, if the posterior probability of success for the cohort to which this group belongs meets the expansion criteria, this group can also be expanded. In all other scenarios, group enrollment continues until the upper sample size limit of approximately 30 is reached. Thus, multiple groups can "move on" from Stage 1 at various intermediate points and move to a single Stage 2 expansion to confirm efficacy. One example of a possible scenario for a group in Stage 1 is when enrollment has reached the upper limit and the evidence is useless or uncertain regarding expansion (uncertain and upper limit). A fourth possibility is that the registration limit has not been reached after a reasonable amount of time (i.e., a reasonable number of interim assessments), and that several groups are less certain than others.

[0114] In Stage 2, the efficacy of terisotuzumab vedotin as monotherapy will be further evaluated in a specific group that showed promising results during Stage 1, and the evaluation will be conducted in an expanded single-arm cohort until the total number of enrolled patients reaches approximately 160.

[0115] 7.2.2. Purpose The objective of this study was to evaluate the safety and efficacy of terisotuzumab vedotin in a cohort (based on histopathological examination and epidermal growth factor receptor [EGFR] mutations) and subgroups (based on c-Met expression) of patients with previously treated locally advanced or metastatic non-small cell lung cancer (NSCLC) and c-Met protein overexpression (c-Met+).

[0116] The primary objective was to determine the overall response rate (ORR) of terisotuzumab vedotin by independent central review (ICR) in patients with c-Met+NSCLC who had been followed up for 12 weeks or more.

[0117] Secondary purposes include the following: • Duration of response (DoR) • Disease control rate (DCR) • Progression-free survival (PFS) ·Overall survival (OS) • Safety and tolerability The goal was to obtain that.

[0118] 7.2.3. Patient Selection: Primary Eligibility / Exclusion Criteria Here are some of the key eligibility criteria for the terisotuzumab vedotin Phase 2 non-randomized single-arm adaptive trial. • Participants must be 18 years of age or older. • Participants must have locally advanced or metastatic NSCLC, and their disease must be measurable according to the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. • The subject must have c-Met+NSCLC as assessed by a designated IHC testing facility. Subjects with non-squamous NSCLC or squamous NSCLC with recorded histological findings and known EGFR status (wild-type or mutant). • Patients with a history of prior treatment with two or fewer lines of systemic therapy for locally advanced or metastatic disease, including cytotoxic chemotherapy (1 line), immunotherapy, and (if applicable) therapy targeting driver gene mutations. • The target group is those with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0119] Here are some of the main exclusion criteria. • Patients must not have a history of prior treatment with c-Met-targeted antibody therapy, nor a history of a major immune response to IgG-containing agents. • The subjects must not have adenosquamous carcinoma as determined by histological examination. • The subjects must not have a history of interstitial lung disease or pneumonitis requiring systemic steroid treatment. • Uncontrolled central nervous system metastases (except when the patient is receiving curative treatment, is asymptomatic, or has discontinued systemic steroids and anticonvulsants at least two weeks prior to the first dose of terisotuzumab vedotin). • Patients must not have undergone major surgery within 21 days prior to the first dose of ABBV-399. • Patients must not have any unresolved clinically significant adverse events of grade 2 or higher resulting from prior anticancer treatment other than alopecia or anemia. • The subjects must not have evidence of pulmonary fibrosis or pneumonitis, or a history of interstitial lung disease requiring systemic steroid therapy within 3 months of the planned initial dose of terisotuzumab vedotin. • Participants must not have received a live vaccine within 30 days of the first dose of the investigational drug. Patients who are currently undergoing systemic cytotoxic therapy (or are ineligible for systemic cytotoxic chemotherapy), currently undergoing immune checkpoint inhibitor therapy (or are ineligible for immune checkpoint inhibitor therapy) (either as monotherapy or in combination with systemic cytotoxic chemotherapy), and who have a history of prior anti-cancer therapy targeting driver gene mutations (where applicable). Patients must not have received pulmonary radiation therapy <6 months prior to the first dose of terisotuzumab vedotin. • Patients must have a history of prior treatment with two or fewer lines of systemic therapy (including one or fewer lines of systemic cytotoxic chemotherapy) for locally advanced or metastatic disease. Multiple lines of TKIs targeting the same TK count as the one line of therapy targeted by this eligibility criterion. • Before the first dose of terisotuzumab vedotin, exclude any of the following therapies within the specified period. Within 4 weeks (28 days): Systemic cytotoxic chemotherapy; small molecule targeted drugs with a half-life of 7 days or more; monoclonal antibodies, antibody-drug conjugates, radioactive immune complexes, or T-cell or other cell therapies. Within 1 week (7 days): Herbal medicine or a potent cytochrome P450 3A4 (CYP3A4) inhibitor. Within 2 weeks (14 days): Low-molecular-weight targeted drugs with a half-life of less than 7 days; radiotherapy that does not affect the pleural cavity. None of the following therapies require a drug-free period. Symptomatic radiotherapy of 10 fractions or less for bone, skin, or subcutaneous metastases; see below for CNS metastases. Patients currently receiving EGFR TKIs. Patients with metastases to the central nervous system (CNS) are only eligible if they have undergone curative treatment (such as surgery or radiation therapy) and meet the following conditions: ...There is no evidence of progression of CNS metastasis at least 4 weeks after curative treatment. ...The patient is asymptomatic and has discontinued systemic steroids and anticonvulsants for at least two weeks prior to the first dose of terisotuzumab vedotin. The subject must not have a history of other malignant tumors, except in the following cases: Malignant tumors that are being treated for curative purposes, have no known active disease for at least two years prior to the first dose of the investigational drug, and are perceived by the investigator as having a low risk of recurrence. • Skin cancer other than melanoma or malignant lentigo that is properly treated and for which there is no evidence of disease. Carcinoma in situ that is appropriately treated and currently lacks evidence of disease. The subjects must not have a clinically significant medical condition, and are not limited to the following: Edema or lymphedema of grade ≥ 2. Ascites or pleural effusion of grade ≥ 2. • A history of neuropathy of grade ≥ 2 or grade ≥ 3. Uncontrolled bacterial or viral infection. Congestive heart failure, ≥III according to the New York Heart Association Classification. Unstable angina or cardiac arrhythmia.

[0120] 7.2.4. Dosage regimen The subjects were administered terisotuzumab vedotin every 14 days (once per cycle) at a dose of 1.9 mg / kg over 30 ± 10 minutes via intravenous (IV) infusion.

[0121] 7.2.5.Grading In the pre-screening for c-Met, eligibility criteria, medical history, and cancer history were thoroughly examined. c-Met overexpression was determined by a c-Met IHC assay (Ventana; Tucson, AZ) at the central facility. If ≥25% of neoplastic cells from tumor tissue showed 3+ intensity c-Met staining, they were considered non-squamous epithelium; if 25% to less than 50% showed 3+ intensity staining, they were considered moderate c-Met; if ≥50% showed 3+ intensity staining, they were considered high c-Met; and if ≥75% of neoplastic cells from tumor tissue showed 1+ intensity c-Met staining, they were considered squamous epithelium (i.e., the c-Met Teliso-V staining protocol as described in Example 1).

[0122] Study visits and evaluations were conducted during pre-screening, screening, on days 1 and 8 of cycle 1, and on day 1 of each subsequent cycle. Assessments included limited physical examinations, blood tests, urine tests, and chemical tests performed before administration of all investigational drugs and at the final visit. ECG and ECOG performance status were obtained at screening, on day 1 of cycle 1, day 1 of cycle 2, and at the final visit. Adverse events, laboratory values, and vital signs were assessed throughout the entire study period.

[0123] Baseline radiographic tumor assessments were obtained by CT (or MRI) of the head, chest, abdomen, and pelvis within 28 days prior to day 1 of cycle 1. CT scans (or MRI) were repeated approximately every 6 weeks after the start of treatment to assess the degree of tumor burden. Radiographic tumor assessments continued until disease progression was demonstrated by imaging, until new anticancer therapy was initiated, or until death or withdrawal of consent. Response evaluation was performed according to RECIST version 1.1. Evidence of clinical disease progression was assessed at each hospital visit.

[0124] 7.2.6. Evaluation Criteria The criteria and statistical methods for evaluating efficacy and safety are shown in Table 8 below.

[0125] [Table 8]

[0126] Effectiveness The overall efficacy analysis was performed primarily by clinical examination. Clinical efficacy endpoints included objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), as determined using RECIST version 1.1.

[0127] Objective response rate Objective response rate (ORR) was defined as the proportion of patients who achieved a confirmed complete response (CR) or confirmed partial response (PR), in accordance with RECIST v1.1. Tumor assessments were performed at baseline and every 6 weeks, in accordance with RECIST v1.1. The ORR for each treatment cohort was estimated for all pooled sites.

[0128] An interim analysis was conducted using a hierarchical Bayesian model to assess the objective response rate (ORR) for each group, and a threshold for advancing to stage 2 was defined as a posterior probability of at least 70% where the true ORR was >25%. Patients who experienced clinical progression or death before the first tumor assessment after baseline were considered non-responders.

[0129] Total duration of efficacy For confirmed responders, DoR was defined as the period from the initial response (CR or PR) to the first radiographic progression confirmed by independent central review or death from any cause. For responders who did not experience progression or death, the DoR period was censored at the time of the final tumor assessment.

[0130] Disease control rate DCR was defined as the percentage of patients demonstrating the best overall response rate (CR), including confirmed complete response (CR), confirmed partial response (PR), or stable disease (SD), within at least 12 weeks (two planned tumor assessments) after the first dose of terisotuzumab vedotin, in accordance with RECIST version 1.1.

[0131] Progression-free survival PFS was defined as the time from the first administration of the investigational drug to the first radiographic progression confirmed by independent central review or death from any cause. PFS for subjects who did not experience progression or death was censored at the time of final tumor assessment.

[0132] overall survival Overall survival (OS) was defined as the time from the first dose of the investigational drug to death from any cause. Subjects who did not die were terminated on the last known day they were alive.

[0133] Quality of Life Quality of life was assessed using various electronic PRO models (EORTC QLQ-C15-PAL, EORTC QLQ-LC13, EORTC QLQCIPN20, EQ-5D-5L).

[0134] safety Safety and tolerability were assessed throughout the entire study period by evaluating adverse events (AEs) and changes in laboratory values ​​and vital signs. AE severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). TEAEs (Teased Adverse Events) were defined as AEs that occurred during or within 30 days after administration of terisotuzumab vedotin.

[0135] The safety analysis included all patients who received one or more doses of terisotuzumab vedotin. The efficacy analysis included patients who were enrolled at least 12 weeks prior to the data cutoff date, received one or more doses of terisotuzumab vedotin, and underwent at least one post-baseline tumor assessment (or had clinical evidence of disease progression or had died prior to the post-baseline assessment).

[0136] Pharmacokinetic and pharmacodynamic properties Pharmacokinetic samples were collected upon hospital visit and evaluation. Serum samples for terisotuzumab vedotin conjugate and whole ABT-700 assays, and plasma samples for free MMAE concentration measurement were collected at designated times. Serum samples for anti-drug antibody (ADA) and neutralizing anti-drug antibody (nAb) assays were also collected at designated times. If data was guaranteed, the non-compartment method was used to determine PK parameters for terisotuzumab vedotin conjugate, whole ABT-700, and MMAE, including maximum observed blood concentration (Cmax), time to Cmax (peak time, Tmax), and area under the concentration-time curve (AUC).

[0137] Using a nonlinear mixed-effects modeling approach, we estimated population PK parameters such as clearance (CL) and volume (V) for the terisotuzumab vedotin conjugate and MMAE.

[0138] c-Met biomarker The c-Met IHC assay was used to predictively screen subjects for c-Met protein overexpression in archived or fresh tumor tissue and determine their eligibility (Example 1 shows an IHC assay suitable for pre-screening patients).

[0139] Throughout the entire study period, biological samples (plasma, tumor material, whole blood) were collected at designated points in time, and known and / or novel disease-related or terisotuzumab vedotin-related biomarkers were evaluated in circulation or in tumor tissue.

[0140] RECIST (version 1.1) criteria for tumor response The response criteria were assessed using RECIST (version 1.1). Changes in measurable lesions between treatment cycles were evaluated using the following criteria.

[0141] a. Eligibility Subjects with measurable disease at baseline can demonstrate an objective tumor response when evaluated according to RECIST criteria. Measurable disease is defined by the presence of at least one measurable lesion. If measurable disease is limited to isolated lesions, the nature of the neoplasm should be confirmed by cytology / histochemistry, if possible.

[0142] b.Measurability

[0143] [Table 9]

[0144] All measurements should be taken and recorded in the metric system, and calipers should be used for clinical assessment. The entire baseline assessment should be performed within four weeks prior to the start of treatment, as close to the start of treatment as possible.

[0145] To characterize each lesion identified and reported at baseline and during follow-up, the same assessment methods and techniques should be used.

[0146] Clinical lesions are considered measurable only if they are superficial (e.g., cutaneous nodules and palpable lymph nodes) and have a diameter of ≥10 mm as assessed using calipers. For cutaneous lesions, color photographs with rulers to estimate lesion size are recommended.

[0147] c.Measurement method For sections with a continuous slice thickness of 5 mm or less, conventional CT should be performed. This applies to tumors of the chest and abdomen. A scale bar should be added to all X-ray images.

[0148] In rare cases, cytology and histology can be used to distinguish between partial response (PR) and complete response (CR) when necessary.

[0149] d. Baseline documentation of "targeted" and "non-targeted" lesions Up to two measurable lesions per organ corresponding to all affected organs, and a total of five measurable lesions, were identified as target lesions and recorded and measured at baseline. Tumor lesions located in areas previously irradiated or receiving other local treatments were not typically considered measurable unless progression of the lesion was demonstrated.

[0150] Lymph nodes are noteworthy because they are normal anatomical structures that can be seen on imaging even if they are not affected by tumors. Pathological lymph nodes, defined as measurable and identifiable as target lesions, must meet the criterion of a short axis ≥ 15 mm on a CT scan. Only the short axes of these lymph nodes will be included in the baseline diameter sum. The short axis of a lymph node is the diameter commonly used by radiologists to determine whether a lymph node is affected by a solid tumor. Lymph node size is generally reported as two dimensions within the plane in which the image is acquired (in a CT scan, this is almost always the axial plane). The smaller of these measurements is the short axis. For example, an abdominal lymph node reported as 20 mm × 30 mm has a short axis of 20 mm and is considered a measurable malignant lymph node. In this example, 20 mm should be reported as the lymph node measurement. All other pathological lymph nodes (with a short axis between 10 mm and 15 mm) should be considered non-target lesions. Lymph nodes with a short axis of <10 mm should be considered non-pathological and should not be recorded or followed up.

[0151] The sum of the diameters of all target lesions was calculated and reported as the baseline sum of diameters. When lymph nodes were included in the sum of diameters, only the short axis was added, as described above. The baseline sum of diameters was used as a criterion to characterize objective tumor response.

[0152] All other lesions (or disease sites), including pathological lymph nodes, should be identified as non-target lesions and should also be recorded at baseline. Measurement of these lesions is not necessary, but their presence (stable, increasing, or decreasing) or absence should be recorded throughout the entire follow-up period.

[0153] e. Evaluation of target lesions Complete response (CR): The absence of all target lesions. All pathological lymph nodes (whether target or non-target) must have shrunk to <10 mm in their short axis.

[0154] Partial response (PR): A reduction of at least 30% in the sum of target lesion diameters compared to the baseline sum.

[0155] Disease progression (PD): An increase of at least 20% in the sum of diameters of target lesions compared to the minimum sum of diameters recorded since the start of treatment or since the appearance of one or more new lesions (from baseline). In addition to a 20% relative increase, the sum of diameters must also show an absolute increase of at least 5 mm.

[0156] Disease Stability (SD): (Since baseline) Compared to the sum of minimum diameters since the start of treatment, there is neither a reduction sufficient to be considered a partial response (PR) nor a significant increase sufficient to be considered a progressive state (PD).

[0157] Assessment of target lesions: Lymph nodes identified as target lesions should always have actual short-axis recorded measurements (measured in the same anatomical plane as the baseline study), even if they regress to less than 10 mm during the study. In other words, since a normal lymph node is defined as having a short axis of <10 mm, when a lymph node is included as a target lesion, the "sum of diameters" of the lesions does not need to be zero, even if the criteria for complete response are met. For PR, SD, and PD, the actual short-axis measurements of the lymph nodes should be included in the sum of diameters of the target lesions.

[0158] All lesions (lymph node and non-lymph node) recorded at baseline should have actual measurements recorded in each subsequent assessment, even if they are very small (<5 mm). However, target lesions or lymph nodes may be too small to measure. If the radiologist believes the lesion has disappeared, the measurement should be recorded as 0 mm. If a lesion is thought to be present but too small to measure, a default value of 5 mm (based on a 5 mm CT slice thickness) should be assigned. Since the measurements of these lesions are potentially non-reproducible, setting this default value will prevent false responses or false progression due to measurement errors.

[0159] f. Evaluation of non-target lesions Complete response (CR): Remission of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be of non-pathological size (short axis <10 mm).

[0160] Non-CR / Non-PD: Persistence of one or more non-target lesions and / or persistent tumor marker levels above the normal limit.

[0161] Disease progression (PD): Clear progression of existing non-target lesions.

[0162] In this setting, for "clear progression" to be reached based on the non-target disease, there must be substantial progression at a total level in the non-target disease to the extent that the total tumor burden has increased sufficiently to warrant discontinuation of treatment, even if SD or PR exists in the target disease. A moderate "increase" in the size of one or more non-target lesions is usually not sufficient to be considered a clear progression status. Therefore, it would be extremely rare to designate overall progression based solely on changes in the non-target disease while the target disease is SD or PR.

[0163] Note: If a patient discontinues treatment due to worsening symptoms, all efforts should be made to objectively record the progression of the condition even after treatment has been discontinued.

[0164] New lesions The appearance of new malignant lesions signifies disease progression. While there are no specific criteria for identifying new radiographic lesions, findings of new lesions should be clear and not attributable to differences in scanning technique, timing of scans, contrast agent administration phase, changes in imaging methods, or findings that appear to represent something other than a tumor (for example, a “new” bone lesion could simply be a healing or recurrence of an existing lesion). Lesions identified during follow-up studies in anatomical locations not scanned at baseline would be considered new lesions and would be judged as disease progression. This particular case involved a patient with visceral disease at baseline who was instructed to undergo brain CT or MRI during the study, resulting in the discovery of metastases. Even if brain imaging had not been performed at baseline, the patient’s brain metastases would be considered evidence of disease progression.

[0165] If a new lesion is ambiguous (i.e., too small to measure), treatment and follow-up evaluations should be continued to determine whether it is truly a new disease. If repeated scans confirm the presence of a new lesion, progression should be declared based on the date of the initial scan.

[0166] 7.2.7.Results As of December 2020, 841 patients were screened, and evaluable c-Met IHC data were obtained (Table 10). The c-Met+ rate was generally lower in the EGFR WT (25%) group than in the EGFR MU (37%) group in the non-squamous cell cohort. In the squamous cell cohort, 39% of patients had c-Met+ tumors. Figures 8A and 8B summarize the observed overall response rates (ORR). Figure 8A shows the results of grouping according to both c-Met expression level and EGFR status (WT = wild-type, MU = mutant), while Figure 8B shows the results of grouping according to EGFR status only.

[0167] [Table 10]

[0168] 113 patients with c-Met+NSCLC were enrolled in Stage 1, and 90 patients who met the criteria for efficacy evaluation were followed up for ≥12 weeks (Table 11). Based on the H score, c-Met expression was generally lower in the squamous cell cohort compared to the non-squamous cell cohort. In the non-squamous cell cohort, moderate c-Met expression was more frequent in patients with wild-type EGFR, and high c-Met expression was more frequent in patients with mutant EGFR.

[0169] Patients in the non-squamous EGFR mutant cohort had a longer median duration of prior systemic cancer therapy than the other two cohort groups.

[0170] Prior treatment with platinum-based therapy was the most common across all cohorts (>80%). The majority of patients in the non-squamous EGFR wild-type cohort and the squamous cell cohort (73% and 91%, respectively) had a history of prior treatment with immune checkpoint inhibitors, while all patients in the non-squamous EGFR mutant cohort (100%) had a history of prior treatment with EGFR TKIs.

[0171] [Table 11] TIFF0007905040000017.tif71161

[0172] Effectiveness The ORR was 35.1% in the non-squamous EGFR wild-type cohort (53.8% in the high c-Met group and 25.0% in the moderate c-Met group; Table 12), but lower in the non-squamous EGFR mutant cohort and the squamous epithelium cohort.

[0173] At the time of this interim analysis, no patients had achieved a complete response, 26 out of 88 patients (30%) achieved a partial response, and 9 out of 88 patients (10%) experienced disease progression.

[0174] [Table 12]

[0175] The median progression-free survival (PFS) was 7.0 months (95% CI: 3.0 months, 8.3 months) for non-squamous epithelium with high EGFR WT c-Met, 3.9 months (95% CI: 2.6 months, 5.3 months) for non-squamous epithelium with moderate EGFR WT c-Met, 4.1 months (95% CI: 2.6 months, --) for non-squamous epithelium with high EGFR MU c-Met, 3.0 months (95% CI: 1.2 months, --) for non-squamous epithelium with moderate EGFR MU c-Met, and 3.1 months (95% CI: 1.6 months, 5.7 months) for squamous epithelium.

[0176] safety In total, 96% of patients experienced adverse events (TEAEs) during administration of the investigational drug, as assessed by investigators, and 72% experienced TEAEs related to Teliso-v. Table 13 summarizes the TEAEs (all grades) that occurred in ≥10% of the total patients. 50 patients (44%) experienced TEAEs of grade ≥3. The most frequent was progression of malignant neoplasm, which occurred in 6% of patients. The most common serious TEAEs were pneumonia (n=6, 5%), progression of malignant neoplasm (n=4, 4%), and pneumonitis (n=4, 4%). Three patients died as a result of TEAEs that investigators considered potentially related to teliso-v (sudden death, dyspnea, and pneumonitis, n=1 each).

[0177] [Table 13] TIFF0007905040000020.tif49161

[0178] 7.3. Discussion In a non-squamous EGFR-weighted non-squamous endothelial cell carcinoma (NSLC) cohort, administration of Teliso-V at a dose of 1.9 mg / kg every two weeks demonstrated a promising overall response rate (ORR) and an acceptable safety profile. Based on pre-specified criteria, this cohort was expanded and enrolled in Stage 2. The ORR was highest in the high c-Met group, but was also clinically significant in the moderate c-Met group.

[0179] Based on pre-specified criteria, enrollment in the squamous cell cohort will be suspended, and enrollment in the EGFR MU cohort will continue until the next designated interim analysis.

[0180] 8. Typical Embodiment The above describes various specific embodiments, some of which are illustrated below. Naturally, various modifications can be made as long as they do not deviate from the spirit and scope of the present invention. 1. A method for treating non-squamous non-small cell lung cancer ("NSCLC") tumors expressing c-Met, comprising the step of administering a pharmaceutical composition containing Teliso-V, an anti-c-Met antibody-drug conjugate ("ADC"), to a human subject having the NSCLC tumor, wherein the drug of the conjugate is monomethyl auristatin E ("MMAE"), and the ADC has the following structure:

[0181] [ka] The formula contains an IgG antibody in which Ab is composed of a heavy chain consisting of the amino acid sequence of SEQ ID NO: 5 and a light chain consisting of the amino acid sequence of SEQ ID NO: 10, n is a numerical value of 2 or 4, and binding to Ab occurs via a thioether bond formed with the sulfhydryl group of a cysteine ​​residue. A method wherein, when evaluated by c-Met immunohistochemical staining (IHC), ≥25% of neoplastic cells from non-squamous NSCLC tumor tissue expressing c-Met derived from the subject exhibit 3+ membrane staining or membrane + cytoplasmic staining. 2. The method according to Embodiment 1, wherein the non-squamous NSCLC tumor does not possess a mutated EGFR gene. 3. The method according to Embodiment 1, wherein the non-squamous NSCLC tumor possesses a mutated EGFR gene. 4. The method according to any one of Embodiments 1 to 3, wherein, when assessed by c-Met IHC, 25% to less than 50% of neoplastic cells from non-squamous NSCLC tumor tissue expressing c-Met derived from the subject have 3+ membrane staining or membrane + cytoplasmic staining. 5. The method according to any one of Embodiments 1 to 3, wherein, when assessed by c-Met IHC, ≥50% of neoplastic cells from non-squamous NSCLC tumor tissue expressing c-Met derived from the subject have 3+ membrane staining or membrane + cytoplasmic staining. 6. The method according to any one of Embodiments 1 to 5, wherein administration of Teliso-V achieves an objective response rate (ORR) of more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, or more than 55% in the subjects. 7. The method according to Embodiment 6, wherein the ORR has a posterior probability of at least 70%. 8. The method according to any one of Embodiments 1 to 7, wherein administration of Teliso-V achieves a median duration of response (DoR) of at least 6 months, at least 8 months, or at least 10 months in the subjects. 9. The method according to any one of Embodiments 1 to 8, wherein administration of Teliso-V achieves a progression-free survival (PFS) of at least 5 months, or at least 5.5 months, in the subjects. 10. The method according to any one of Embodiments 1 to 8, wherein administration of Teliso-V achieves an overall survival (OS) of at least 13 months or at least 14 months in the subject. 11. The method according to any one of Embodiments 1 to 8, wherein administration of Teliso-V achieves a partial response (PR) in the subject. 12. The method according to any one of Embodiments 1 to 8, wherein administration of Teliso-V achieves a complete response (CR) in the subject. 13. The method according to Embodiment 1, wherein the non-squamous NSCLC tumors do not possess a mutated EGFR gene, administration of Teliso-V achieves an objective response rate (ORR) of more than 25%, preferably more than 30%, preferably more than 35%, and preferably more than 40% in the subjects, the ORR has a posterior probability of at least 70%, and optionally, administration of Teliso-V achieves a median duration of response (DoR) of at least 6 months, at least 8 months, or at least 10 months in the subjects. 14. The method according to Embodiment 4, wherein the non-squamous NSCLC tumor does not possess a mutated EGFR gene, and administration of Teliso-V achieves an objective response rate (ORR) of more than 25% in the subjects. 15. The method according to Embodiment 5, wherein the non-squamous NSCLC tumors do not possess a mutated EGFR gene, administration of Teliso-V achieves an objective response rate (ORR) of more than 25%, preferably more than 50%, in the subjects, the ORR has a posterior probability of at least 70%, preferably at least 95%, and optionally, administration of Teliso-V achieves a median duration of response (DoR) of at least 6 months in the subjects. 16. The method according to any one of Embodiments 1 to 15, wherein the pharmaceutical composition comprising Teliso-V has an E2 to E4 ratio of about 1:1. 17. The method according to any one of Embodiments 1 to 16, wherein the pharmaceutical composition comprising Teliso-V has a drug-antibody ratio ("DAR") of about 2.6 to about 3.4, or about 2.9 to about 3.1. The method according to any one of Embodiments 1 to 17, wherein 18.1.9 mg / kg of Teliso-V is administered intravenously once every two weeks. 19. The method according to any one of Embodiments 1 to 18, wherein 1.9 mg / kg of Teliso-V is administered intravenously once every two weeks to subjects weighing 100 kg or less, and 190 mg is administered intravenously to subjects weighing more than 100 kg. 20. The method according to any one of Embodiments 1 to 19, wherein the tumor tissue is collected from the subject before the administration of the first dose of Teliso-V. 21. The method according to any one of Embodiments 1 to 20, wherein the subject has a history of prior treatment with systemic therapy for locally advanced or metastatic disease. 22. The method according to any one of Embodiments 1 to 20, wherein the subject has no prior history of systemic therapy for locally advanced or metastatic disease. 23. The method according to any one of Embodiments 1 to 22, wherein the c-Met IHC is performed according to the c-Met Teliso-V staining protocol. 24. A method for treating non-squamous non-small cell lung cancer ("NSCLC") tumors that express c-Met in human subjects, (a) A step of determining whether the tumor exhibits i) c-Met negative expression, ii) c-Met positive expression, iii) moderate c-Met expression, or iv) high c-Met expression, where, i) c-Met negative expression is defined as <25% of neoplastic cells from the tumor tissue of the non-squamous NSCLC having 3+ membrane staining or membrane+ cytoplasmic staining, as assessed by IHC; ii) c-Met positive expression is defined as ≥25% of neoplastic cells from the tumor tissue of the non-squamous NSCLC having 3+ membrane staining or membrane + cytoplasmic staining, as assessed by IHC; iii) Moderate c-Met expression is defined as having 25% to less than 50% of neoplastic cells from the tumor tissue of the non-squamous NSCLC having 3+ membrane staining or membrane + cytoplasmic staining, as assessed by IHC. iv) High c-Met expression is defined as having ≥50% of neoplastic cells from the tumor tissue of non-squamous NSCLC having 3+ membrane staining or membrane + cytoplasmic staining, as assessed by IHC. (b) If the tumor tissue shows c-Met positive expression, administer to the subject having the non-squamous NSCLC tumor a pharmaceutical composition containing Teliso-V, which is an anti-c-Met antibody drug conjugate ("ADC"), wherein the drug of the conjugate is monomethyl auristatin E ("MMAE"), and the ADC has the following structure:

[0182] [ka] The formula contains an IgG antibody in which Ab is composed of a heavy chain consisting of the amino acid sequence of SEQ ID NO: 5 and a light chain consisting of the amino acid sequence of SEQ ID NO: 10, n is a numerical value of 2 or 4, and binding to Ab occurs via a thioether bond formed with the sulfhydryl group of a cysteine ​​residue. Methods that include... 25. The method according to Embodiment 24, wherein the non-squamous NSCLC tumor does not possess a mutated EGFR gene. 26. The method according to Embodiment 25, wherein the non-squamous NSCLC tumor possesses a mutated EGFR gene. 27. The method according to any one of Embodiments 24 to 26, wherein administration of Teliso-V achieves an objective response rate (ORR) of more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, or more than 55% in the subjects. 28. The method according to Embodiment 27, wherein the ORR has a posterior probability of at least 70%. 29. The method according to any one of Embodiments 24 to 28, wherein administration of Teliso-V achieves a median duration of response (DoR) of at least 6 months, at least 8 months, or at least 10 months in the subjects. 30. The method according to any one of Embodiments 24 to 29, wherein administration of Teliso-V achieves a progression-free survival (PFS) of at least 5 months or at least 5.5 months in the subject. 31. The method according to any one of embodiments 24 to 29, wherein administration of Teliso-V achieves an overall survival (OS) of at least 13 months or at least 14 months in the subject. 32. The method according to any one of Embodiments 24 to 29, wherein administration of Teliso-V achieves a partial response (PR) in the subject. 33. The method according to any one of Embodiments 24 to 29, wherein administration of Teliso-V achieves a complete response (CR) in the subject. 34. The method according to embodiment 24, wherein the non-squamous NSCLC tumor does not carry a mutant EGFR gene, administration of Teliso-V achieves an objective response rate (ORR) of more than 25%, preferably more than 35% in the subject, the ORR has a posterior probability of at least 70%, and optionally, administration of Teliso-V achieves a median duration of response (DoR) of at least 6 months in the subject. 35. The method according to any one of embodiments 24 to 34, wherein the pharmaceutical composition comprising Teliso-V has a ratio of E2 to E4 of about 1:1. 36. The method according to any one of embodiments 24 to 35, wherein the pharmaceutical composition comprising Teliso-V has a drug-to-antibody ratio ( "DAR") of about 2.4 to about 3.6, or about 2.9 to about 3.1. 37. The method according to any one of embodiments 24 to 36, wherein 1.9 mg / kg of Teliso-V is administered intravenously once every two weeks. 38. The method according to any one of embodiments 24 to 37, wherein 1.9 mg / kg of Teliso-V is administered intravenously once every two weeks to a subject weighing 100 kg or less, and 190 mg is administered intravenously to a subject weighing more than 100 kg. 39. The method according to any one of embodiments 24 to 38, wherein the tumor tissue is collected from the subject before administration of the first dose of Teliso-V. 40. The method according to any one of embodiments 24 to 39, wherein the subject has a prior treatment history with systemic therapy in a locally advanced or metastatic setting. 41. The method according to any one of embodiments 24 to 39, wherein the subject has no prior treatment history with systemic therapy in a locally advanced or metastatic setting. 42. The method according to any one of embodiments 24 to 41, wherein the c-Met IHC is performed according to the c-Met Teliso-V staining protocol. 43. A method for treating a non-squamous non-small cell lung cancer ( "NSCLC") tumor that expresses c-Met in a human subject, (a) determining whether the tumor exhibits any one of i) c-Met negative expression, ii) c-Met positive expression, iii) c-Met moderate expression, or iv) c-Met high expression, wherein i) c-Met negative expression is defined as <25% of neoplastic cells from the tumor tissue of the non-squamous NSCLC having 3+ membrane staining or membrane + cytoplasmic staining when evaluated by IHC; ii) c-Met positive expression is defined as ≧25% of neoplastic cells from the tumor tissue of the non-squamous NSCLC having 3+ membrane staining or membrane + cytoplasmic staining when evaluated by IHC; iii) c-Met moderate expression is defined as 25% or more and less than 50% of neoplastic cells from the tumor tissue of the non-squamous NSCLC having 3+ membrane staining or membrane + cytoplasmic staining when evaluated by IHC, iv) c-Met high expression is defined as ≧50% of neoplastic cells from the tumor tissue of the non-squamous NSCLC having 3+ membrane staining or membrane + cytoplasmic staining when evaluated by IHC, (b) when the tumor tissue exhibits c-Met moderate expression, administering to a subject having the non-squamous NSCLC tumor a pharmaceutical composition comprising Teliso-V, an anti-c-Met antibody-drug conjugate ("ADC"), wherein the drug of the conjugate is monomethyl auristatin E ("MMAE"), and the ADC has the following structure:

[0183] [Chemical Formula] wherein Ab is an IgG antibody composed of a heavy chain each composed of the amino acid sequence of SEQ ID NO: 5 and a light chain each composed of the amino acid sequence of SEQ ID NO: 10, n is a numerical value of 2 or 4, and the binding to Ab is effected via a thioether bond formed with the sulfhydryl group of a cysteine residue, A method comprising. 44. The method according to embodiment 43, wherein the non-squamous NSCLC tumor does not carry a mutant EGFR gene. 45. The method according to Embodiment 43, wherein the non-squamous NSCLC tumor possesses a mutated EGFR gene. 46. ​​The method according to any one of Embodiments 43 to 45, wherein administration of Teliso-V achieves an objective response rate (ORR) of more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, or more than 55% in the subjects. 47. The method according to Embodiment 46, wherein the ORR has a posterior probability of at least 70%. 48. The method according to any one of embodiments 43 to 47, wherein administration of Teliso-V achieves a median duration of response (DoR) of at least 6 months, at least 8 months, or at least 10 months in the subjects. 49. The method according to any one of Embodiments 43 to 48, wherein administration of Teliso-V achieves a progression-free survival (PFS) of at least 5 months, or at least 5.5 months, in the subjects. 50. The method according to any one of embodiments 43 to 48, wherein administration of Teliso-V achieves an overall survival (OS) of at least 13 months or at least 14 months in the subject. 51. The method according to any one of Embodiments 43 to 48, wherein administration of Teliso-V achieves a partial response (PR) in the subject. 52. The method according to any one of Embodiments 43 to 48, wherein administration of Teliso-V achieves a complete response (CR) in the subject. 53. The method according to Embodiment 43, wherein the non-squamous NSCLC tumor does not possess a mutated EGFR gene, and administration of Teliso-V achieves an objective response rate (ORR) of more than 25% in the subjects. 54. The method according to any one of Embodiments 43 to 53, wherein the pharmaceutical composition comprising Teliso-V has an E2 to E4 ratio of about 1:1. 55. The method according to any one of Embodiments 43 to 54, wherein the pharmaceutical composition comprising Teliso-V has a drug-antibody ratio ("DAR") of about 2.4 to about 3.6, or about 2.9 to about 3.1. The method according to any one of embodiments 43 to 55, wherein 56.1.9 mg / kg of Teliso-V is administered intravenously once every two weeks. 57. The method according to any one of Embodiments 43 to 56, wherein 1.9 mg / kg of Teliso-V is administered intravenously once every two weeks to subjects weighing 100 kg or less, and 190 mg is administered intravenously to subjects weighing more than 100 kg. 58. The method according to any one of embodiments 43 to 57, wherein the tumor tissue is collected from the subject before the administration of the first dose of Teliso-V. 59. The method according to any one of Embodiments 43 to 58, wherein the subject has a history of prior treatment with systemic therapy for locally advanced or metastatic disease. 60. The method according to any one of Embodiments 43 to 58, wherein the subject has no prior history of systemic therapy for locally advanced or metastatic disease. 61. The method according to any one of embodiments 43 to 60, wherein the c-Met IHC is performed according to a c-Met Teliso-V staining protocol. 62. A method for treating non-squamous non-small cell lung cancer ("NSCLC") tumors that express c-Met in human subjects, (a) A step of determining whether the tumor exhibits i) c-Met negative expression, ii) c-Met positive expression, iii) moderate c-Met expression, or iv) high c-Met expression, and here i) c-Met negative expression is defined as <25% of neoplastic cells from the tumor tissue of the non-squamous NSCLC having 3+ membrane staining or membrane+ cytoplasmic staining, as assessed by IHC; ii) c-Met positive expression is defined as ≥25% of neoplastic cells from the tumor tissue of the non-squamous NSCLC having 3+ membrane staining or membrane + cytoplasmic staining, as assessed by IHC; iii) Moderate c-Met expression is defined as having 25% to less than 50% of neoplastic cells from the tumor tissue of the non-squamous NSCLC having 3+ membrane staining or membrane + cytoplasmic staining, as assessed by IHC. iv) High c-Met expression is defined as having ≥50% of neoplastic cells from the tumor tissue of non-squamous NSCLC having 3+ membrane staining or membrane + cytoplasmic staining, as assessed by IHC. (b) If the tumor tissue shows high c-Met expression, administer to the subject having the non-squamous NSCLC tumor a pharmaceutical composition containing Teliso-V, which is an anti-c-Met antibody drug conjugate ("ADC"), wherein the drug of the conjugate is monomethyl auristatin E ("MMAE"), and the ADC has the following structure:

[0184] [ka] The formula contains an IgG antibody in which Ab is composed of a heavy chain consisting of the amino acid sequence of SEQ ID NO: 5 and a light chain consisting of the amino acid sequence of SEQ ID NO: 10, n is a numerical value of 2 or 4, and binding to Ab occurs via a thioether bond formed with the sulfhydryl group of a cysteine ​​residue. Methods that include... 63. The method according to Embodiment 62, wherein the non-squamous NSCLC tumor does not possess a mutated EGFR gene. 64. The method according to Embodiment 62, wherein the non-squamous NSCLC tumor possesses a mutated EGFR gene. 65. The method according to any one of Embodiments 62 to 64, wherein administration of Teliso-V achieves an objective response rate (ORR) of more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, or more than 55% in the subjects. 66. The method according to embodiment 65, wherein the ORR has a posterior probability of at least 70%. 67. The method according to any one of embodiments 62 to 66, wherein administration of Teliso-V achieves a median duration of response (DoR) of at least 6 months, at least 8 months, or at least 10 months in the subjects. 68. The method according to any one of embodiments 62 to 67, wherein administration of Teliso-V achieves a progression-free survival (PFS) of at least 5 months, or at least 5.5 months, in the subjects. 69. The method according to any one of embodiments 62 to 68, wherein administration of Teliso-V achieves an overall survival (OS) of at least 13 months or at least 14 months in the subject. 70. The method according to any one of embodiments 62 to 69, wherein administration of Teliso-V achieves a partial response (PR) in the subject. 71. The method according to any one of Embodiments 62 to 70, wherein administration of Teliso-V achieves a complete response (CR) in the subject. 72. The method according to Embodiment 62, wherein the NSCLC tumors do not possess a mutated EGFR gene, administration of Teliso-V achieves an objective response rate (ORR) of more than 25%, preferably more than 50%, in the subjects, the ORR has a posterior probability of at least 70%, preferably at least 95%, and optionally, administration of Teliso-V achieves a median duration of response (DoR) of at least 6 months in the subjects. 73. The method according to any one of Embodiments 62 to 72, wherein the pharmaceutical composition comprising Teliso-V has an E2 to E4 ratio of about 1:1. 74. The method according to any one of Embodiments 62 to 73, wherein the pharmaceutical composition comprising Teliso-V has a drug-antibody ratio ("DAR") of about 2.4 to about 3.6. The method according to any one of embodiments 62 to 74, wherein 75.1.9 mg / kg of Teliso-V is administered intravenously once every two weeks. 76. The method according to any one of Embodiments 62 to 75, wherein 1.9 mg / kg of Teliso-V is administered intravenously once every two weeks to subjects weighing 100 kg or less, and 190 mg is administered intravenously to subjects weighing more than 100 kg. 77. The method according to any one of embodiments 62 to 76, wherein the tumor tissue is collected from the subject before the administration of the first dose of Teliso-V. 78. The method according to any one of embodiments 62 to 77, wherein the subject has a prior treatment history with systemic therapy in a locally advanced or metastatic setting. 79. The method according to any one of embodiments 62 to 78, wherein the subject has no prior treatment history with systemic therapy in a locally advanced or metastatic setting. 80. The method according to any one of embodiments 62 to 79, wherein the c-Met IHC is performed according to the c-Met Teliso-V staining protocol. 81. A method of treating non-squamous non-small cell lung cancer ("NSCLC") tumors expressing c-Met in a plurality of human subjects, comprising: (a) determining whether the tumor exhibits any of i) c-Met negative expression, ii) c-Met positive expression, iii) c-Met intermediate expression, or iv) c-Met high expression, where i) c-Met negative expression is defined as < 25% of the neoplastic cells from the tumor tissue of the non-squamous NSCLC having 3+ membrane staining or membrane + cytoplasmic staining when evaluated by IHC; ii) c-Met positive expression is defined as ≧ 25% of the neoplastic cells from the tumor tissue of the non-squamous NSCLC having 3+ membrane staining or membrane + cytoplasmic staining when evaluated by IHC; iii) c-Met intermediate expression is defined as 25% or more and less than 50% of the neoplastic cells from the tumor tissue of the non-squamous NSCLC having 3+ membrane staining or membrane + cytoplasmic staining when evaluated by IHC, iv) c-Met high expression is defined as ≧ 50% of the neoplastic cells from the tumor tissue of the non-squamous NSCLC having 3+ membrane staining or membrane + cytoplasmic staining when evaluated by IHC; (b) excluding from treatment subjects having the non-squamous NSCLC tumor exhibiting c-Met negative expression when the tumor tissue exhibits c-Met negative expression; (c) If the tumor tissue shows high c-Met expression, the subject is selected for treatment, and the selected subject is administered a pharmaceutical composition containing Teliso-V, which is an anti-c-Met antibody drug conjugate ("ADC"), wherein the drug of the conjugate is monomethyl auristatin E ("MMAE"), and the ADC has the following structure:

[0185] [ka] The formula contains an IgG antibody in which Ab is composed of a heavy chain consisting of the amino acid sequence of SEQ ID NO: 5 and a light chain consisting of the amino acid sequence of SEQ ID NO: 10, n is a numerical value of 2 or 4, and binding to Ab occurs via a thioether bond formed with the sulfhydryl group of a cysteine ​​residue. Methods that include... 82. The method according to Embodiment 81, wherein step b) further includes the step of excluding subjects having the non-squamous NSCLC tumor exhibiting c-Met-positive expression from treatment if the tumor tissue exhibits c-Met-positive expression. 83. The method according to Embodiment 81 or 82, wherein step b) further includes the step of excluding subjects having the non-squamous NSCLC tumor exhibiting moderate c-Met expression from treatment if the tumor tissue exhibits moderate c-Met expression. 84. The method according to any one of embodiments 81 to 83, wherein the non-squamous NSCLC tumor does not possess a mutated EGFR gene. 85. The method according to any one of embodiments 81 to 83, wherein the NSCLC tumor possesses a mutated EGFR gene. 86. The method according to any one of Embodiments 81 to 85, wherein administration of Teliso-V achieves an objective response rate (ORR) of more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, or more than 55% in the subjects. 87. The method according to embodiment 86, wherein the ORR has a posterior probability of at least 70%. 88. The method according to any one of embodiments 81 to 87, wherein administration of Teliso-V achieves a median duration of response (DoR) of at least 6 months, at least 8 months, or at least 10 months in the selected subjects. 89. The method according to any one of Embodiments 81 to 88, wherein administration of Teliso-V achieves a progression-free survival (PFS) of at least 5 months, or at least 5.5 months, in the subjects. 90. The method according to any one of embodiments 81 to 88, wherein administration of Teliso-V achieves an overall survival (OS) of at least 13 months or at least 14 months in the subject. 91. The method according to any one of Embodiments 81 to 88, wherein administration of Teliso-V achieves a partial response (PR) in the subject. 92. The method according to any one of Embodiments 81 to 88, wherein administration of Teliso-V achieves a complete response (CR) in the subject. 93. The method according to any one of embodiments 81 to 83, wherein the NSCLC tumor does not possess a mutated EGFR gene, administration of Teliso-V achieves an objective response rate (ORR) of more than 25%, preferably more than 50%, in the selected subjects, the ORR has a posterior probability of at least 70%, preferably at least 95%, and optionally, administration of Teliso-V achieves a median duration of response (DoR) of at least 6 months in the subjects. 94. The method according to any one of Embodiments 81 to 93, wherein the pharmaceutical composition comprising Teliso-V has an E2 to E4 ratio of about 1:1. 95. The method according to any one of Embodiments 81 to 94, wherein the pharmaceutical composition comprising Teliso-V has a drug-antibody ratio ("DAR") of about 2.6 to about 3.4, or about 2.9 to about 3.1. The method according to any one of embodiments 81 to 95, wherein 96.1.9 mg / kg of Teliso-V is administered intravenously once every two weeks. 97. The method according to any one of Embodiments 81 to 96, wherein 1.9 mg / kg of Teliso-V is administered intravenously once every two weeks to subjects weighing 100 kg or less, and 190 mg is administered intravenously to subjects weighing more than 100 kg. 98. The method according to any one of embodiments 81 to 97, wherein the tumor tissue is collected from the subject before the administration of the first dose of Teliso-V. 99. The method according to any one of Embodiments 81 to 98, wherein the subject has a history of prior treatment with systemic therapy for locally advanced or metastatic disease. 100. The method according to any one of Embodiments 81 to 98, wherein the subject has no prior history of systemic therapy for locally advanced or metastatic disease. 101. The method according to any one of embodiments 81 to 100, wherein the c-Met IHC is performed according to a c-Met Teliso-V staining protocol. The method according to any one of Embodiments 1-17, 20-36, 39-55, 58-74, 77-95, or 98-101, wherein 102.1.6 mg / kg of Teliso-V is administered intravenously once every two weeks. 103. The method according to Embodiment 102, wherein the subject achieves a partial response or a complete response. 104. The method according to any one of Embodiments 18, 19, 37, 38, 56, 57, 75, 76, 96, or 97, wherein the subject achieves a partial response or a complete response. The method according to any one of Embodiments 1 to 104, wherein Teliso-V at a dose of 105.1.2 to 2.4 mg / kg is administered intravenously once every two weeks, and the subject achieves a partial response or a complete response.

Claims

1. A pharmaceutical composition comprising terisotuzumab vedotin for use in a method for treating non-squamous non-small cell lung cancer ("NSCLC") tumors expressing c-Met in multiple human subjects, wherein the method is: (a) A step of determining or having determined in advance whether the tumor exhibits high c-Met expression, wherein high c-Met expression is defined as having ≥50% of neoplastic cells from non-squamous NSCLC tumor tissue having 3+ membrane staining or membrane+ cytoplasmic staining when assessed by the c-Met Teliso-V staining protocol. (b) If the tumor tissue does not show high c-Met expression, the step of excluding subjects with tumors that do not show high c-Met expression from treatment, (c) If the tumor tissue shows high c-Met expression, a subject is selected for treatment, and 1.6 mg / kg or 1.9 mg / kg of terisotuzumab vedotin is administered intravenously to the selected subject once every two weeks (Q2W). Includes, The aforementioned non-squamous NSCLC tumors do not possess the mutated EGFR gene. Pharmaceutical composition.

2. A pharmaceutical composition comprising terisotuzumab vedotin for use in a method for treating non-squamous non-small cell lung cancer ("NSCLC") tumors in multiple human subjects having non-small cell lung cancer that do not possess a mutated EGFR gene and express c-Met, wherein the method is applied to each of the multiple human subjects having NSCLC, (a) Selecting subjects for treatment who have tumors that are i) non-squamous, ii) do not possess a mutated EGFR gene, and iii) show c-Met positive expression, and excluding patients from treatment if a subject has a tumor that meets any of the following criteria: i) squamous, ii) possess a mutated EGFR gene, and iii) do not show c-Met positive expression, (b) If a subject is selected for treatment, the selected subject is treated by intravenously administering 1.6 mg / kg or 1.9 mg / kg of terisotuzumab vedotin to the selected subject once every two weeks (Q2W), A pharmaceutical composition comprising, wherein c-Met positive expression is defined as ≥25% of neoplastic cells from non-squamous NSCLC tumor tissue having 3+ membrane staining or membrane+ cytoplasmic staining, as assessed by the c-Met Teliso-V staining protocol.

3. A pharmaceutical composition comprising terisotuzumab vedotin for use in a method for treating non-squamous non-small cell lung cancer ("NSCLC") tumors in multiple human subjects having non-small cell lung cancer that do not possess a mutated EGFR gene and express c-Met, wherein the method is applied to each of the multiple human subjects having NSCLC, (a) A step in selecting subjects for treatment who have tumors that are i) non-squamous, ii) do not possess a mutated EGFR gene, and iii) show high c-Met expression, and excluding subjects from treatment if they have tumors that satisfy any of the following conditions: i) squamous, ii) possess a mutated EGFR gene, and iii) do not show positive c-Met expression, (b) If a subject is selected for treatment, the selected subject is treated by intravenously administering 1.6 mg / kg or 1.9 mg / kg of terisotuzumab vedotin to the selected subject once every two weeks (Q2W), This includes, where c-Met high expression is defined as ≥50% of neoplastic cells from non-squamous NSCLC tumor tissue having 3+ membrane staining or membrane+ cytoplasmic staining, as assessed by the c-Met Teliso-V staining protocol. Pharmaceutical composition.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the overall response rate in the target of treatment is at least 35% by the method described above.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the overall response rate in the target of treatment is at least 25% by the method described above.

6. The pharmaceutical composition according to any one of claims 1 to 3, wherein the overall response rate in the target of treatment is at least 20% by the method described above.

7. A pharmaceutical composition comprising terisotuzumab vedotin for the treatment of c-Met-expressing non-squamous non-small cell lung cancer ("NSCLC") in human subjects, The pharmaceutical composition is administered intravenously to the subject once every two weeks (Q2W) at a dose of 1.6 mg / kg or 1.9 mg / kg of terisotuzumab vedotin. The subjects were selected for having tumors exhibiting high c-Met expression, where high c-Met expression is defined as ≥50% of neoplastic cells from non-squamous NSCLC tumor tissue having 3+ membrane staining or membrane+ cytoplasmic staining, as assessed by the c-Met Teliso-V staining protocol. The aforementioned non-squamous NSCLC tumors do not possess the mutated EGFR gene. Pharmaceutical composition.

8. A pharmaceutical composition comprising terisotuzumab vedotin for treating non-squamous non-small cell lung cancer ("NSLC") tumors in human subjects having non-squamous non-small cell lung cancer ("NSLC") that do not possess a mutated EGFR gene and express c-Met, The pharmaceutical composition is administered intravenously to the subject once every two weeks (Q2W) at a dose of 1.6 mg / kg or 1.9 mg / kg of terisotuzumab vedotin. The subjects selected for treatment are those who have tumors that are i) non-squamous, ii) do not possess the mutated EGFR gene, and iii) show c-Met positive expression. The aforementioned c-Met-positive expression is defined as the presence of ≥25% of neoplastic cells from non-squamous NSCLC tumor tissue having 3+ membrane staining or membrane+ cytoplasmic staining, as assessed by the c-Met Telitho-V staining protocol. Pharmaceutical composition.

9. A pharmaceutical composition comprising terisotuzumab vedotin for treating non-squamous non-small cell lung cancer ("NSLC") tumors in human subjects having non-squamous non-small cell lung cancer ("NSLC") that do not possess a mutated EGFR gene and express c-Met, The pharmaceutical composition is administered intravenously to the subject once every two weeks (Q2W) at a dose of 1.6 mg / kg or 1.9 mg / kg of terisotuzumab vedotin. The subjects selected for treatment are those who have tumors that are i) non-squamous, ii) do not possess the mutated EGFR gene, and iii) exhibit high c-Met expression. The aforementioned c-Met high expression is defined as the presence of ≥50% of neoplastic cells from non-squamous NSCLC tumor tissue having 3+ membrane staining or membrane+ cytoplasmic staining, as assessed by the c-Met Telitho-V staining protocol. Pharmaceutical composition.

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