Treatment of non-small cell lung cancer with 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 April 6, 2021, and U.S. Provisional Application No. 63 / 171,571, filed April 6, 2021, each of which is incorporated by reference in its entirety.

[0002] 1. Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format, the entire contents of which are incorporated herein by reference. The ASCII copy was created on April 5, 2022, has the file name 381493_190077_SL.txt, and is 13,581 bytes in size.

[0003] 2.Technical Field The present application relates, inter alia, to improved methods for the treatment of non-small cell lung cancer using telisotuzumab vedotin (Teliso-V; ABBV-399) and methods for selecting specific patient populations for treatment. [Background technology]

[0004] 3.Background technology c-Met is a signaling tyrosine kinase receptor expressed on the surface of epithelial and endothelial cells. Activation of c-Met by its only known ligand, hepatocyte growth factor (HGF), 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 by receptor upregulation has been implicated in 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 recognized in NSCLC and are thought to arise through multiple mechanisms. Dysregulation of c-Met signaling has been 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] A first-in-class ADC, telisotuzumab vedotin (Teliso-V), was developed by linking the anti-c-Met humanized monoclonal antibody ABT-700 with monomethyl auristatin E (MMAE) via a valine-citrulline linker (ABT-700-vcMMAE). ABT-700 has been shown to specifically deliver Teliso-V with high affinity to target 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 been demonstrated to show promising antitumor activity independent of MET amplification status in preclinical studies in cells overexpressing c-Met, potentially expanding the target population of this agent to patients with tumors expressing c-Met (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 who were not initially preselected by c-Met protein expression (NCT02099058). Using preliminary data from this study, we designed a phase 2 multicenter nonrandomized single-arm two-stage adaptive enrichment study in patients with c-Met+ locally advanced or metastatic NSCLC (NCT03539536). The first phase (i.e., Stage 1) of the study was designed to evaluate the efficacy of Teliso-V monotherapy (1.9 mg / kg every 2 weeks) in three c-Met+ NSCLC cohorts (based on histopathology and EGFR mutation status) and five groups (by further evaluating the non-squamous cohort based on whether they have moderate or high c-Met expression levels) to identify the population most likely to benefit from Teliso-V treatment. The second phase (Stage 2) of the study is designed to further evaluate the efficacy of Teliso-V in a given group if the objective response rate (ORR) in that group is greater than 25%. [Prior art documents] [Non-patent literature]

[0007]

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[0008] 4. Overview The present application provides a method for treating a subject with NSCLC with known EGFR status, where the NSCLC has positive, moderate, or high c-Met expression levels as determined by immunohistochemistry (IHC), comprising administering to the subject a therapeutically effective amount of Teliso-V, the therapeutically effective amount being sufficient to induce stable disease, a partial response, or a confirmed response in the subject according to RECIST version 1.1, and / or to prolong the time to progression.

[0009] Further provided herein is a method of treating NSCLC in a subject, comprising determining that an NSCLC sample from the subject contains a positive, intermediate or high c-Met expression level as determined by IHC, and administering to the subject an effective amount of Teliso-V, thereby treating the NSCLC. In certain embodiments, the subject is excluded from treatment if the subject's NSCLC sample contains a negative c-Met expression level as determined by IHC.

[0010] The present application provides a method for treating NSCLC comprising administering an effective amount of Teliso-V, the treatment being based on c-Met overexpression in an NSCLC sample, and resulting in an objective response rate of greater than 25%.

[0011] The present application provides a diagnostic method for determining c-Met expression in NSCLC, where positive, moderate, or high c-Met expression as determined by IHC is assumed to be associated with high efficacy of administering Teliso-V to a subject with NSCLC, and negative c-Met expression as determined by IHC is detected, excluding the patient from administration of Teliso-V.

[0012] 5. Brief description of the drawings The patent or application contains at least one drawing of color. Copies of this patent or patent application publication containing color drawing(s) will be provided by the Office upon request and payment of the necessary fee. [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) are shown for IHC scores of 0 (Figure 1A), 1+ (Figure 1B), 2+ (Figure 1C), and 3+ (Figure 1D). [Figure 1B] Figures 1A-1D show representative cytoplasmic staining intensities of c-Met on non-squamous NSCLC. SP44 OptiView IHC cytoplasmic staining intensities (20x) are shown for IHC scores of 0 (Figure 1A), 1+ (Figure 1B), 2+ (Figure 1C), and 3+ (Figure 1D). [Figure 1C] Figures 1A-1D show representative cytoplasmic staining intensities of c-Met on non-squamous NSCLC. SP44 OptiView IHC cytoplasmic staining intensities (20x) are shown for IHC scores of 0 (Figure 1A), 1+ (Figure 1B), 2+ (Figure 1C), and 3+ (Figure 1D). [Figure 1D] Figures 1A-1D show representative cytoplasmic staining intensities of c-Met on non-squamous NSCLC. SP44 OptiView IHC cytoplasmic staining intensities (20x) are shown for IHC scores of 0 (Figure 1A), 1+ (Figure 1B), 2+ (Figure 1C), and 3+ (Figure 1D). [Figure 2A]Figures 2A-2D show representative membrane staining intensities of c-Met on non-squamous NSCLC. SP44 OptiView IHC membrane staining intensities (20x) are shown for IHC scores of 0 (Figure 2A), 1+ (Figure 2B), 2+ (Figure 2C), and 3+ (Figure 2D). [Figure 2B] Figures 2A-2D show representative membrane staining intensities of c-Met on non-squamous NSCLC. SP44 OptiView IHC membrane staining intensities (20x) are shown for IHC scores of 0 (Figure 2A), 1+ (Figure 2B), 2+ (Figure 2C), and 3+ (Figure 2D). [Figure 2C] Figures 2A-2D show representative membrane staining intensities of c-Met on non-squamous NSCLC. SP44 OptiView IHC membrane staining intensities (20x) are shown for IHC scores of 0 (Figure 2A), 1+ (Figure 2B), 2+ (Figure 2C), and 3+ (Figure 2D). [Figure 2D] Figures 2A-2D show representative membrane staining intensities of c-Met on non-squamous NSCLC. SP44 OptiView IHC membrane staining intensities (20x) are shown for IHC scores of 0 (Figure 2A), 1+ (Figure 2B), 2+ (Figure 2C), and 3+ (Figure 2D). [Figure 3A-1] Figures 3A1-3C3, 3B1-3B3, and 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, 3B1-3B3, and 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 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 3B-1] Figures 3A1-3C3, 3B1-3B3, and 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 3B-2] Figures 3A1-3C3, 3B1-3B3, and 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 3B-3] Figures 3A1-3C3, 3B1-3B3, and 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 3C-1] Figures 3A1-3C3, 3B1-3B3, and 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 3C-2]Figures 3A1-3C3, 3B1-3B3, and 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 3C-3] Figures 3A1-3C3, 3B1-3B3, and 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 4] 1 shows the distribution of SP44 UltraView and OptiView IHC in 3+ intense staining on a commercial NSCLC cohort. [Diagram 5] The 3+ cutoff value of ≥25% for SP44 OptiView indicates a similar patient population selection as 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) = oV positive uV positives / total uV positives; NPA (negative agreement rate) = oV negative uV negatives / total uV negatives; OPA (overall agreement rate) = oV positive uV positives + oV negative uV negatives / total number of samples tested; PPV (positive predictive value) = oV positive uV positives / total oV positives; NPV (negative predictive value) = oV negative uV negatives / total oV negatives. %BOR stands for best overall response rate. [Figure 6] The 3+ cutoff value of ≥50% for SP44 OptiView indicates a similar patient population selection as 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) = oV positive uV positives / total uV positives; NPA (negative agreement rate) = oV negative uV negatives / total uV negatives; OPA (overall agreement rate) = oV positive uV positives + oV negative uV negatives / total number of samples tested; PPV (positive predictive value) = oV positive uV positives / total oV positives; NPV (negative predictive value) = oV negative uV negatives / total oV negatives. %BOR stands for best overall response rate. [Figure 7]The design of a Phase 2, multicenter, non-randomized, single-arm, two-stage, adaptive enrichment trial (NCT03539536) in patients with c-Met+ locally advanced or metastatic NSCLC is shown. [Figure 8A] Figures 8A-8B summarize the overall response rate (ORR) in patients from a phase 2 multicenter nonrandomized single-arm two-stage adaptive enrichment trial (NCT03539536) in patients with c-Met+ locally advanced or metastatic NSCLC, as well as the probability of achieving an ORR of 25%. Figure 8A shows the results grouped according to tumor histology, c-Met expression levels, and EGFR status (WT = wild type, MU = mutated). Figure 8B shows the results grouped according to tumor histology and EGFR status. [Figure 8B] Figures 8A-8B summarize the overall response rate (ORR) in patients from a phase 2 multicenter nonrandomized single-arm two-stage adaptive enrichment trial (NCT03539536) in patients with c-Met+ locally advanced or metastatic NSCLC, as well as the probability of achieving an ORR of 25%. Figure 8A shows the results grouped according to tumor histology, c-Met expression levels, and EGFR status (WT = wild type, MU = mutated). Figure 8B shows the results grouped according to tumor histology and EGFR status. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] 6. Detailed Description 6.1. Anti-c-Met ADC: terisotuzumab vedotin As described elsewhere herein, telisotuzumab vedotin (Teliso-V) is an ADC in which ABT-700 (PR-1266688, h224G11), an antibody targeting c-Met, is conjugated to monomethyl auristatin E (MMAE), a potent cytotoxin, via a valine-citrulline (vc) linker. Conjugation to ABT-700 is via a thioether bond formed with the sulfhydryl group of a cysteine ​​residue of ABT-700. The production and bioactivity of ABT-700 is described in U.S. Pat. No. 8,741,290. The production and bioactivity of telisotuzumab vedotin is described in U.S. Pat. No. 10,603,389.

[0015] As used herein, terisotuzumab vedotin has the following structural formula:

[0016] [ka] where n is 2 or 4, Ab is ABT-700, and conjugation of the drug to the antibody is via a bond formed with the sulfhydryl group of a cysteine ​​residue of ABT-700. In a preferred embodiment, n is the value of 2. In a preferred embodiment, n is the value of 4. The purification and characterization of terisotuzumab vedotin, where n is 2 or 4, is described in U.S. Pat. No. 10,603,389.

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

[0018] Terisotuzumab vedotin can be used at an E2 / E4 ratio of 1:1, which corresponds to an average DAR of 3.0 or about 3.0. In other words, terisotuzumab vedotin is used in a composition comprising an E2 purified fraction and an E4 purified fraction of an antibody drug conjugate at a ratio of 1:1. In another alternative embodiment, terisotuzumab vedotin can be used at a DAR of 2.9.

[0019] As used herein, ABT-700 refers to an optional antibody having the following heavy and light chain sequences. The heavy chain of ABT-700 has the following sequence:

[0020] [ka] (The constant regions are shown in bold and the CDRs are underlined (numbering is according to Kabat, the CDR sequences are disclosed as SEQ ID NOs: 1 to 3, respectively, in order of appearance). (The variable region is disclosed as SEQ ID NO:4) (The full length sequence is disclosed as SEQ ID NO:5) and the light chain of ABT-700 comprises the following sequence:

[0021] [ka] (The CDR sequences are disclosed in order of appearance as SEQ ID NOs: 6 to 8, respectively.) (The variable region is disclosed as SEQ ID NO: 9) (The full length sequence is disclosed as SEQ ID NO: 10) Includes.

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

[0023] [ka] In the above sequence, the secretory signal peptide shown in bold capital letters includes the final stop codon (TGA), the constant region is shown in bold, and the CDRs are underlined (CDR sequences are disclosed as SEQ ID NOs: 12 to 14, respectively, in order of appearance).

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

[0025] [ka] In the above sequence, the secretory signal peptide shown in bold capital letters includes the final stop codon (tga), the constant region is shown in bold, and the CDRs are underlined (CDR sequences are disclosed as SEQ ID NOs: 16 to 18, respectively, in order of appearance).

[0026] 6.2. Composition Teliso-V is provided as an aqueous composition suitable for administration by intravenous infusion. In certain embodiments, the aqueous composition contains 20 mg / mL 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, which upon reconstitution with 5.2 mL of sterile water or other solution suitable for injection or infusion (e.g., 0.9% saline, Ringer's solution, lactated Ringer's solution, etc.) provides the aqueous composition.

[0027] 6.3.How to use The methods described herein include administering Teliso-V to patients with non-squamous NSCLC with c-Met overexpression and known EGFR status. NSCLC cancer can be recurrent, refractory, or recurrent-refractory, or metastatic or metastatic forms of tumors overexpressing c-Met. Teliso-V is typically administered at a dose of 1.9 mg / kg once every 2 weeks (14 days). In one embodiment, Teliso-V is administered at a dose of 1.6 mg / kg once every 2 weeks (14 days). To demonstrate efficacy, subjects administered Teliso-V should have an objective response rate (ORR) of 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] Results from stage 1 interim analysis 3 of an ongoing Phase 2 study (NCT03539536) in c-Met positive advanced NSCLC subjects previously treated with platinum-based chemotherapy and immune checkpoint inhibitors (or standard TKI prior therapy, second / third line) demonstrated clinical proof of concept for Teliso-V in non-squamous NSCLC EGFR wild-type subjects (see Figures 8A and 8B). In EGFR wild-type subjects with c-Met positive NSCLC, the 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% vs. 25% in the c-Met intermediate EGFR WT cohort (Figure 8A). According to the results of stage 1 interim analysis 3, it is recommended to start a stage 2 trial in subjects 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 continue until the number of subjects evaluable for efficacy is reached. According to the results of interim analysis 3, the use of Teliso-V to treat subjects with squamous NSCLC is not recommended (Figures 8A and 8B).

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

[0030] Administration of Teliso-V to non-squamous NSCLC subjects with EGFR wild-type status will result in a favorable safety profile with adverse events (i.e., peripheral neuropathy, neutropenia, pneumonitis, and ocular toxicity) occurring in less than 20%, optionally less than 15% or less than 10%, leading to discontinuation of Teliso-V administration. Less than 20%, optionally less than 15% or less than 10% of subjects will experience adverse events of 3+ or greater.

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

[0032] Administration of Teliso-V to non-squamous NSCLC subjects with EGFR mutant status will result in a favorable safety profile with less than 20%, optionally less than 15% or less than 10% of adverse events (i.e., peripheral neuropathy, neutropenia, pneumonitis, and ocular toxicity) leading to discontinuation of Teliso-V administration. Less than 20%, optionally less than 15% or less than 10% of subjects will experience 3+ or higher adverse events.

[0033] IHC assays for assessing expression levels of target proteins are known to those of 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 the present disclosure assesses the overexpression level of c-Met in tumor tissue from a subject with non-squamous NSCLC. One preferred example of a method for determining the c-Met overexpression level is the c-Met IHC assay detailed in Example 1, referred to herein as the "c-Met Teliso-V staining protocol."

[0034] In one embodiment, the method of treatment comprises determining the level of c-Met overexpression in a non-squamous NSCLC tumor by performing c-Met immunohistochemistry (IHC) on tumor tissue from the subject (i.e., tumor tissue obtained from a biopsy, resection specimen, or cytology sample, which can be archival tumor tissue or fresh tumor tissue), and further comprising determining whether the tumor tissue exhibits a) negative c-Met expression, b) positive c-Met expression, c) intermediate c-Met expression, and / or d) high c-Met expression. c-Met negative expression is defined as <25% of neoplastic cells from tumor tissue have 3+ membranous or membrane + cytoplasmic staining as assessed by c-Met IHC, c-Met positive expression is defined as ≧25% of neoplastic cells from tumor tissue have 3+ membranous or membrane + cytoplasmic staining as assessed by c-Met IHC, c-Met moderate expression is defined as ≧25% but <50% of neoplastic cells from tumor tissue have 3+ membranous or membrane + cytoplasmic staining as assessed by c-Met IHC, and c-Met high expression is defined as ≧50% of neoplastic cells from tumor tissue have 3+ membranous or membrane + cytoplasmic staining as assessed by c-Met IHC. The c-Met overexpression level of a NSCLC tumor is taken as the overexpression level of that sample tissue as determined by c-Met IHC. In some embodiments, the c-Met IHC is performed according to a c-Met Teliso-V staining protocol.

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

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

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

[0038] Subjects receiving Teliso-V should achieve one or more of the following clinical endpoints: overall response rate (ORR) greater than 25%, median duration of response (DoR) of at least 6 months, progression-free survival (PFS) of at least 5 months, or overall survival (OS) of at least 13 months, and should demonstrate stable disease (SD), partial response (PR), or confirmed response (CR) according to RECIST 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 a dose 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 appreciated by those skilled in the art, the recommended dose of Teliso-V may need to be adjusted to optimize patient response and maximize therapeutic benefit. For example, to manage peripheral neuropathy, the dose of Teliso-V may be reduced to 1.6 mg / kg. In one embodiment, the dose for subjects weighing more than 100 kg is calculated as if the subject 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 are selected for treatment with Teliso-V based on their known EGFR status, prior treatment status, and c-Met overexpression levels as determined by immunohistochemical staining (c-Met IHC).

[0041] In one embodiment, the inclusion 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 tumour type Patients selected for treatment are those with non-squamous NSCLC that overexpress c-Met. Patients are selected for treatment based on their known EGFR status, pretreatment status, and c-Met expression levels as determined by immunohistochemical staining (IHC).

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

[0046] In certain embodiments, patients excluded from administration of Teliso-V have squamous NSCLC.

[0047] The decision to select a particular patient for treatment with Teliso-V requires a determination of whether the patient's NSCLC harbors cells that have a mutation in the epidermal growth factor receptor gene (EGFR).

[0048] In certain embodiments, patients selected for treatment have NSCLC that overexpresses c-Met without a mutation in the EGFR gene, e.g., EGFR wild-type (WT) NSCLC. In certain embodiments, patients excluded from treatment have NSCLC that overexpresses c-Met with a mutation in the EGFR gene. Kinase domain mutations in EGFR lead to ligand-independent activation of TK activity and are referred to as "activating mutations." In some tumors, partially activated mutant EGFR can be rendered completely ligand-independent and thus constitutively active by a second mutation (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 administration of Teliso-V. In one embodiment, subjects with actionable mutations in genes other than EGFR are eligible for administration of Teliso-V.

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

[0050] One example of such a test 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 test has been clinically validated in multiple clinical trials as a companion diagnostic (CDx) for first- 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 c-Met expression levels (i.e., negative, positive, moderate, and high c-Met expression) and EGRF status (wild type or mutated) as determined by IHC, and treatment decisions are made for each of the resulting groups.

[0052] 6.4.2. Selection criteria: prior treatment In certain embodiments, subjects selected for treatment have been pretreated with no more than two lines of systemic therapy (including no more than one line of systemic cytotoxic chemotherapy) in the locally advanced or metastatic setting.

[0053] In other embodiments, subjects selected for treatment are undergoing systemic cytotoxic chemotherapy (or are ineligible for systemic cytotoxic chemotherapy), are undergoing immune checkpoint inhibitor therapy as monotherapy or in combination with systemic cytotoxic chemotherapy, or are ineligible for immune checkpoint inhibitor therapy and, where applicable, are undergoing prior tyrosine kinase inhibitor (TKI) targeted anti-cancer therapy.

[0054] In other embodiments, the patient selected for treatment has been previously treated 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 the subject has not been previously treated 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 certain embodiments, the cytotoxic chemotherapeutic agent is a platinum-based chemotherapeutic agent, such as cisplatin, oxaliplatin, and carboplatin, or a platinum-based two-drug combination, such as cisplatin / pemetrexed, carboplatin / pemetrexed, or carboplatin / paclitaxel.

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

[0057] In some embodiments, 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, vatalanib, or radotinib.

[0058] In certain embodiments, subjects selected for treatment have not been previously treated with systemic therapy in the locally advanced or metastatic setting.

[0059] 6.4.3. Selection criteria: c-Met expression by IHC IHC is used to assess candidate patients for selection for administration of Teliso-V based on c-Met overexpression levels observed in non-squamous NSCLC tumor tissue. In some embodiments, c-Met IHC is performed on at least one non-squamous NSCLC tumor tissue from the subject, and the at least one tumor tissue is selected from archival tumor tissue and / or fresh tumor tissue.

[0060] In one embodiment, the level of c-Met overexpression in non-squamous NSCLC tumors is determined by performing c-Met immunohistochemistry staining (c-Met IHC) on neoplastic cells from tumor tissue from the subject and determining whether the neoplastic cells exhibit i) negative c-Met expression, ii) positive c-Met 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] Negative c-Met expression is defined as <25% of neoplastic cells from tumor tissue having 3+ membranous staining or membrane + cytoplasmic staining as assessed by c-Met IHC.

[0062] Positive c-Met expression is defined as ≧25% of neoplastic cells from tumor tissue having 3+ membranous staining or membrane + cytoplasmic staining as assessed by c-Met IHC.

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

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

[0066] In certain embodiments, patients selected for administration of Teliso-V have non-squamous NSCLC that exhibits positive c-Met expression.

[0067] In certain embodiments, patients selected for administration of Teliso-V have non-squamous NSCLC that exhibits intermediate c-Met expression.

[0068] In certain embodiments, patients selected for administration of Teliso-V have non-squamous NSCLC that exhibits high c-Met expression.

[0069] 6.4.3.1.IHC determination of c-Met expression c-Met specific immunohistochemical staining (c-Met IHC) is envisioned as a means to determine c-Met overexpression in NSCLC in patients who are candidates for Teliso-V treatment. To this end, IHC scores of 0, 1+, 2+, and 3+ are used to define: 0 = no staining 1+ = Weak staining 2+ = moderate staining 3+ = Strong staining The visual c-Met staining intensity of individual neoplastic cells from tumor tissue is represented according to the chart.

[0070] Typically, there are about 100 human NSCLC cells in a 20x fixed field. As used herein, IHC scoring refers to the intensity of membrane c-Met staining or the intensity of membrane + cytoplasmic c-Met staining.

[0071] In some embodiments, patients with NSCLC selected for administration of Teliso-V exhibit c-Met overexpression as determined by IHC, said IHC comprising: 1) staining the membrane or the membrane and cytoplasm of neoplastic cells of NSCLC with a diagnostic reagent specific for c-Met; 2) 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+ to score the intensity of membranous staining or membranous plus cytoplasmic staining; The score 0 corresponds to a minimum visual membrane staining or membrane + cytoplasmic staining intensity at or near the intensity of the negative control, the score 3+ corresponds to a maximum visual membrane staining or membrane + cytoplasmic staining intensity at or near the intensity of the positive control, and the scores 1+ and 2+ correspond to visual membrane staining or membrane + cytoplasmic staining intensities at or near about 1 / 3 and about 2 / 3, respectively, of the maximum visual membrane staining or membrane + cytoplasmic staining intensity of the positive control.

[0072] Further details regarding the method for visualizing and determining c-Met overexpression levels are provided below and in Example 1. For purposes 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, a c-Met IHC staining assay for c-Met overexpression was developed using the Ventana c-Met CONFIRM (SP44) kit (catalog number 790-4430) for use in selecting patients for Teliso-V administration. The assay involves staining tissue samples with Ventana anti-c-Met antibody and then scoring by determining the percentage of neoplastic cells in the tumor tissue that stain at a predefined intensity level from weak / low to strong / high (i.e., 0, 1+, 2+, 3+). The assay results in staining of c-Met protein in both the cytoplasm and cell membrane, with membrane staining or membrane + cytoplasmic staining being used in the IHC scoring.

[0073] In cases where different IHC methods produce 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 embodiments. For example, the "c-Met Teliso-V staining protocol" is used to assess c-Met protein expression. If the reagents used in this protocol are no longer available, other FDA-approved protocols for assessing c-Met expression levels by IHC can 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 some embodiments, the primary anti-c-Met antibody is selected from mouse IgG, mouse IgM, or rabbit antibody. In some embodiments, the IHC detection comprises direct visualization of the primary anti-cMet antibody. In some embodiments, the IHC detection comprises indirect visualization of the primary anti-cMet antibody. In some embodiments, the indirect visualization comprises a secondary antibody specific for the primary anti-cMet antibody species. In some embodiments, the indirect visualization further comprises a tertiary antibody that binds to the secondary antibody, the tertiary antibody being conjugated to at least one enzyme. In some embodiments, the indirect visualization further comprises a chromogen having a substrate specific for the at least one enzyme of the tertiary antibody. In some embodiments, the chromogen produces a detectable precipitate, the precipitate being preferably detectable by a visual and / or colorimetric change. In certain embodiments, the substrate is hydrogen peroxide. In certain embodiments, the chromogen is 3,3'-diaminobenzidine tetrahydrochloride (DAB).

[0075] In certain embodiments, expression of c-Met is determined using the OptiView DAB IHC Detection Kit (Ventana Catalog No. 760-700). The Optiview kit uses an indirect method to visualize specific mouse and rabbit primary antibodies bound to antigens by depositing a brown precipitate.

[0076] Preparation of tissue for IHC detection In some embodiments, IHC detection of c-Met expression involves staining frozen, formalin-fixed, and / or paraffin-embedded tumor tissue. In some embodiments, tumor tissue membrane staining is performed by a slide stainer. As envisioned, such a slide stainer automates the slide staining process (e.g., washing the slide to remove unbound material after an antibody incubation step and / or applying a coverslip to the slide). In some embodiments, the slide stainer is a VENTANA® slide stainer. In some embodiments, the slide stainer is a VENTANA® Benchmark series instrument (i.e., Benchmark ULTRA IHC / ISH System).

[0077] For use with the OptiView DAB IHC Detection Kit and the VENTANA® Benchmark Series Instrument, formalin-fixed paraffin-embedded tissue is suitable. In some embodiments, preparing tumor tissue for IHC detection includes contacting the tumor tissue with a fixative. In some embodiments, a formalin-based fixative (e.g., 10% neutral buffered formalin (NBF)) is used.

[0078] Tumor tissue section thickness, fixation type and time can be optimized to minimize variability in visualization results. In certain embodiments, the tumor tissue section is about 2 μm to about 6 μm thick. In certain embodiments, the tumor tissue section is about 2 μm, about 3 μm, about 4 μm, about 5 μm, or about 6 μm thick. Slide heating is contemplated to dry the tumor tissue section after slide mounting or to enhance tissue adhesion to the microscope glass slide. In certain embodiments, the slide with the mounted tumor tissue section is preferably heated and baked. In certain embodiments, the slide is heated at 60° C.±5° C. for 2 to 24 hours. Overheating the tumor tissue is avoided as overheating may reduce antigen availability. In certain embodiments, the slide is contacted with cold acetone (i.e., 4 to 8° C.) for 10 minutes. In certain embodiments, the slide is air-dried for at least 30 minutes, preferably overnight, after contacting with cold acetone.

[0079] Control In the c-Met IHC staining method, it is contemplated that a positive tissue control is tested. The positive tissue control can be, for example, tumor tissue or non-neoplastic gallbladder tissue. Some or all of the positive tissue controls will show strong staining. The positive tissue control may include both positive and negative staining and may serve as both positive and negative control tissues. Unstained cellular components would demonstrate the absence of specific staining and provide an indication of background staining. In certain embodiments, the same tissue used for the positive tissue control is used as the negative tissue control. In certain embodiments, the positive or negative control tissues are prepared similarly to the test tissue.

[0080] Negative controls aid in the interpretation of c-Met IHC scores. In certain embodiments, a negative reagent control is used in place of the primary anti-c-Met antibody to assess non-specific staining. In certain embodiments, the negative control reagent is diluent alone. In preferred embodiments, the incubation time of the negative reagent control is equal to the incubation time of the primary antibody.

[0081] Prior to initial use of a primary anti-cMet antibody in the therapeutic methods described herein, the specificity of the antibody should be verified by testing its performance in a panel of tissues with known immunohistochemical staining performance characteristics for c-Met expression versus positive and negative tissues.

[0082] Interpretation of results The OptiView DAB IHC Detection Kit (Ventana Catalog No. 760-700) contemplated by the present invention precipitates a brown reaction product at or near the c-Met antigenic site localized by the primary anti-c-Met antibody.

[0083] In certain embodiments, detection of c-Met expression by IHC is performed by a board-certified pathologist skilled in immunohistochemical staining. In certain embodiments, detection of c-Met expression is performed after the steps of evaluating positive and negative controls. The staining of the negative reagent control is recorded and these results are compared to the stained material to verify that the visualization observed is not due to non-specific interactions. The positive tissue control is tested to verify that the reagent is functioning properly. 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 methods disclosed herein. To verify specific labeling of the target antigen by the primary antibody, a negative tissue control should be tested after the positive tissue control. If specific staining does not occur in the negative tissue control, this confirms the absence of anti-c-Met primary antibody binding. 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 methods disclosed herein. Non-specific staining may have a diffuse appearance. Sparse, light staining may also indicate excessive formalin fixation of the cells. Necrotic or degenerative cells may stain non-specifically.

[0084] In certain embodiments of the Teliso-V treatment method, intact cells of NSCLC tissue are assayed for c-Met expression by IHC. Following controls, patient tissue sample biopsies, resection specimens or cytology samples are tested as described herein, with staining intensity assessed within the context of optional non-specific background staining of the controls (i.e., negative tissue controls and negative reagent controls). Cell morphology of the NSCLC tissue sample should also be examined by a board-certified pathologist skilled in immunohistochemical staining. In certain embodiments, the NSCLC tissue sample is contacted with hematoxylin or eosin dye.

[0085] Automated Slide Staining In some embodiments, patients with NSCLC selected for administration of Teliso-V exhibit c-Met overexpression as determined on tumor tissue by a c-Met IHC assay, the c-Met IHC assay being a c-Met Teliso-V staining protocol. In some embodiments, the c-Met IHC assay is performed on an automated slide stainer. In some embodiments, the c-Met IHC assay includes the steps of: 1) preparing a barcode label having a printed barcode corresponding to one or more automated IHC protocols to be performed by an automated slide stainer, and attaching the barcode label to a slide containing tumor tissue; 2) loading a primary anti-c-Met antibody, at least one negative control, and / or one or more detection reagents into the automated slide stainer; 3) loading at least one slide containing tumor tissue into the automated slide stainer; 4) running the automated slide stainer according to the one or more automated IHC protocols to stain the c-Met tumor tissue on the slide; and 5) detecting and scoring the c-Met IHC staining of the slide. In some embodiments, the automated slide stainer is a Ventana Benchmark series instrument, optionally a Ventana Benchmark Ultra automated stainer. In some embodiments, the barcode corresponds to a SP44 IHC protocol. In some embodiments, 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., for SP44, Ventana catalog number 790-4430, or for rabbit monoclonal negative control Ig, Ventana catalog number 790-4795), a detection protocol (i.e., for OptiView DAB IHC detection kit, Ventana catalog number 760-700), or a counterstaining protocol (i.e., for Hematoxylin II, Ventana catalog number 790-2208, or for bluing agent, catalog number 760-2037). In some embodiments, the primary anti-cMet antibody is an SP44 antibody.In some embodiments, the one or more negative reagent controls are negative control immunoglobulins. In some embodiments, the one or more detection reagents are components of an OptiView detection kit, 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. Working Example The following examples highlight certain features and characteristics of representative embodiments of the antibodies and binding fragments described herein and are provided for illustrative purposes.

[0087] 7.1. Example 1: c-Met Teliso-V Staining Protocol The following assays were developed to determine the suitability of candidate patients with NSCLC for selection for treatment with Teliso V. 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 assay and its protocol aspects are suitable for prescreening of patients with NSCLC for treatment with telisotuzumab vedotin or for treatment with a biological product that is biosimilar to telisotuzumab vedotin.

[0089] 7.1.1. Materials and Methods Specimen preparation Routinely processed, formalin-fixed, paraffin-embedded tumor tissues were sectioned at approximately 4 microns and floated onto positively charged glass slides. Tissues were fixed using 10% neutral buffered formalin. Slides were stained immediately after sectioning to avoid time-dependent loss of antigenicity.

[0090] Immunohistochemical staining procedure Immunohistochemistry (IHC) for c-Met was performed on a 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 for the Ventana benchmark instrument is as follows: 1) affixing a barcode label to a slide that corresponds to the SP44 IHC protocol to be performed (Table 3); 2) placing the SP44 antibody, rabbit monoclonal negative control Ig, and OptiView detection kit dispensers in the reagent tray, and optionally checking that the auxiliary solutions (Table 4) are ready and that the waste tank is empty; 3) placing the slide to be tested into an automated slide stainer; 4) Included the step of initiating a staining run on the Ventana instrument.

[0092] Once the Ventana instrument run was completed, slides were removed and immersed in mild detergent to remove the oil coverslip. Slides were rinsed thoroughly in distilled water and then dehydrated through a graded alcohol series. Slides were cleared in xylene and coverslipped 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 assessed based on the intensity of the diaminobenzidine (DAB) signal. The IHC signal may be uniformly distributed throughout the neoplasm or may be heterogeneously distributed with few positively staining cells.

[0096] c-MET (SP44) IHC staining in NSCLC showed that membranous staining was often accompanied by cytoplasmic staining (i.e., showed both cytoplasmic and membranous staining). The membranous staining pattern could be circumferential (widespread appearance) or partial (i.e., basal-lateral staining in adenocarcinoma). Both membranous and cytoplasmic staining showed intensity ranging from absent (IHC score 0) to strong (IHC score 3+). Cytoplasmic staining was generally less intense than membranous staining. In some situations, cytoplasmic staining showed an intensity comparable to that of the membranous staining (i.e., especially when it was moderate or high intensity), so careful distinction of membranous from cytoplasmic staining was required.

[0097] Normal lung, bronchial epithelial cells, pneumocytes, and alveolar macrophages generally did not show strong levels of c-Met overexpression. However, bronchial epithelial cells and pneumocytes stained in a basolateral-lateral pattern with IHC scores of 2+ to 3+. Staining of normal cellular components appears to be adequate for the internal control of the method. Representative staining intensity guidelines for cytoplasmic and membranous 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 membranous staining on neoplastic cells. Non-squamous NSCLC samples with 3+ membranous staining <25% were considered c-Met negative. Non-squamous NSCLC samples with ≥25% but <50% of viable tumor cells showing 3+ membranous staining were considered c-Met positive. Non-squamous NSCLC samples with ≥25% but <50% of viable tumor cells showing 3+ membranous staining were considered c-Met intermediate. Non-squamous NSCLC samples with ≥50% of viable tumor cells showing 3+ membranous staining were considered c-Met high. Table 7 shows the various membranous staining intensities and positive / negative status according to the scoring algorithm.

[0101] [Table 7]

[0102] 7.1.3. Validation of IHC Platform Comparison of c-Met IHC assays SP44 "Ultraview" and SP44 "Optiview" A comparison of the SP44 Ultraview and SP44 OptiView analytical methods in a large cohort of commercially available NSCLC tissues was performed (Figure 4). According to these results, the SP44 OptiView IHC assay selected a similar patient population as the SP44 Ultraview with a cutoff of ≥25% 3+ membrane staining. The overall concordance at this cutoff between the two assays was 93%. In a human phase I clinical trial, patients with an H-score of 150 were first enrolled using the SP44 UltraView assay. When slides were rescored, the optimal cutoff was ≥25% 3+, with a best overall response rate of 56% using the SP44 Ultraview IHC assay. 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 demonstrated 99% overall concordance with the SP44 Ultraview IHC assay at a cutoff of ≥50% 3+ membrane staining (Figure 6). A human Phase I clinical trial first enrolled patients with an H-score of 150 using the SP44 UltraView assay. When slides were rescored, the SP44 Ultraview IHC assay demonstrated a best overall response rate of 67% at a cutoff of ≥50% 3+ membrane staining. Statistical modeling demonstrated a best overall response rate of 63% for the OptiView IHC assay utilizing Phase I data (Figure 6).

[0104] 7.2. Example 2: A Phase 2, Open-Label Safety and Efficacy Study of Telisotuzumab Vedotin (ABBV-399) in Subjects with Previously Treated c-Met+ Non-Small Cell Lung Cancer Overview An ongoing Phase 2, open-label study (clinicaltrials.gov Identifier NCT03539536, incorporated herein by reference) is evaluating the safety and efficacy of telisotuzumab vedotin in subjects with previously treated c-Met+ non-small cell lung cancer. This is a Phase 2, multicenter, non-randomized, single-arm, adaptive study evaluating the efficacy, safety, pharmacokinetic, and pharmacodynamic properties of telisotuzumab vedotin in subjects with c-Met+ locally advanced or metastatic NSCLC that demonstrates c-Met overexpression according to specified IHC laboratory assay specifications using a pre-defined c-Met positivity cutoff value. The study consists of two stages, designed to identify a target NSCLC population overexpressing c-Met optimal for telisotuzumab vedotin treatment in the second- or third-line setting (Stage 1), followed by group expansion and further efficacy evaluation in selected populations (Stage 2). The study design is shown in Figure 7. The data presented in this application correspond to stage 1 interim analysis 3 and demonstrate favorable results for telisotuzumab vedotin in a validated clinical setting in a selected cohort of patients.

[0105] Subjects were required to have c-Met+ NSCLC with known EGFR status as assessed by a designated IHC laboratory. Subjects were required to submit archival or fresh tumor material for assessment of c-Met overexpression during the prescreening period.

[0106] Approximately 150 efficacy-evaluable c-Met+ NSCLC subjects will be randomized to receive telisotuzumab vedotin monotherapy in Stage 1. The primary efficacy analysis will include the subset of subjects with measurable disease by independent central review (ICR). Non-squamous EGFR wild-type NSCLC (up to N=60) Non-squamous EGFR mutant NSCLC (up to N=60) Squamous NSCLC (up to N=30).

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

[0108] To evaluate efficacy in stage 1 of the study, NSCLC patients will be divided into five groups in the non-squamous and squamous cohorts, with a maximum of 30 patients in each group, and treated with telisotuzumab 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 EGFR mutant NSCLC c-Met high (N=~30) Non-squamous EGFR mutant NSCLC c-Met intermediate (up to N=30) Squamous NSCLC c-Met+ (N=~30).

[0109] Stage 2 will further evaluate the efficacy of telisotuzumab vedotin as monotherapy in select groups showing promising results during Stage 1, and further in a single-arm expansion cohort.

[0110] All subjects will receive telisotuzumab vedotin monotherapy until disease progression or meeting study discontinuation criteria.

[0111] Stage 1 will enroll approximately 30 additional c-Met+ efficacy-evaluable subjects with measurable disease by ICR each, and will perform an interim analysis to formally assess efficacy after at least 12 weeks of follow-up in the cohorts / groups recruited to the enrollment. The number of subjects entering the interim analysis may be adjusted as needed based on whether a cohort / group progresses to or is completed in Stage 2, or reaches the group enrollment limit.

[0112] The ORR of each group is further assessed using a hierarchical Bayesian model that allows for information borrowing between groups, with the degree of borrowing depending on the similarity of efficacy observed between groups. The model considers the influence of disease histology and c-Met expression levels. The decision to stop enrolling a group in stage 1 due to futility or to move the group to an expansion cohort in stage 2 is made by comparing the estimated posterior probability of success with upper and lower decision thresholds. 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 analyses are also performed at the cohort level.

[0113] At 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 mutant). When the posterior probability of success of more than 25% in a particular group is less than 0.10, it is considered futility. On the other hand, if the same posterior probability estimate is high (greater than 0.70), the group can be expanded, i.e., "progressed" to stage 2 expansion. Even if the posterior probability of success of this group is intermediate, this group can also be expanded if the posterior probability of success of the cohort to which it belongs meets the expansion criteria. In all other scenarios, the group continues to be enrolled unless the upper sample size limit, which is about 30, is reached. Thus, multiple groups can be "progressed" from stage 1 at various intermediate time points and moved to a single stage 2 expansion to confirm efficacy. One possible case for a group in stage 1 is when the evidence is indeterminate for futility or expansion when enrollment has reached the upper limit (indeterminate and upper limit). A fourth possibility is that the enrollment cap was not reached after a reasonable time (i.e., a reasonable number of interim assessments) and some groups were indeterminate relative to others.

[0114] Stage 2 will further evaluate the efficacy of telisotuzumab vedotin as monotherapy in select groups showing promising results during Stage 1, and will be further evaluated in a single-arm expansion cohort to enroll a total of approximately 160 subjects.

[0115] 7.2.2. Purpose The objective of this study was to evaluate the safety and efficacy of telisotuzumab vedotin in a cohort (based on histopathology 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 telisotuzumab vedotin in subjects with c-Met+ NSCLC with ≥12 weeks of follow-up by independent central review (ICR).

[0117] Secondary objectives include: Duration of response (DoR) Disease control rate (DCR) Progression-free survival (PFS) ·Overall survival (OS) Safety and tolerability The purpose was to seek...

[0118] 7.2.3. Patient Selection: Key Inclusion / Exclusion Criteria Some key eligibility criteria for the phase 2, non-randomized, single-arm, adaptive trial of telisotuzumab vedotin include: · Subjects must be 18 years of age or older. Subjects must have locally advanced or metastatic NSCLC and subjects have measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. Subjects must have c-Met+ NSCLC as assessed by a designated IHC laboratory. Subjects with non-squamous NSCLC of known EGFR status (wild-type or mutant) with documented histology or squamous NSCLC with documented histology. Have been previously treated with ≤2 lines of systemic therapy in the locally advanced or metastatic setting, including cytotoxic chemotherapy (1 line), immunotherapy, and (if eligible) driver mutation-targeted therapy. -Subjects will have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0119] Some key exclusion criteria are listed below. Subjects should not have had prior treatment with a c-Met targeted antibody therapy or a history of a major immune response to an IgG-containing agent. Subjects must not have adenosquamous carcinoma by histology. Subjects must not have a history of interstitial lung disease or pneumonitis requiring systemic steroid treatment. Uncontrolled central nervous system metastases, unless patients have received curative therapy, are asymptomatic, and have withdrawn systemic corticosteroids and anticonvulsants for at least 2 weeks before the first dose of terisotuzumab vedotin. Subjects must not have undergone major surgery within 21 days prior to their first dose of ABBV-399. Subjects must not have had any unresolved clinically significant adverse events of grade 2 or higher attributable to prior anticancer therapy other than alopecia or anemia. Subjects should not have evidence of pulmonary fibrosis or pneumonitis, or a history of interstitial lung disease requiring systemic steroid treatment within 3 months of the planned first dose of telisotuzumab vedotin. Subjects must not have received a live vaccine within 30 days of the first dose of the study drug. Subjects undergoing ongoing systemic cytotoxic therapy (or who are ineligible for systemic cytotoxic chemotherapy), ongoing immune checkpoint inhibitor therapy (either as monotherapy or in combination with systemic cytotoxic chemotherapy) (or who are ineligible for immune checkpoint inhibitor therapy), and (where applicable) previously treated with anti-cancer therapy targeting a driver gene mutation. Subjects must not have received pulmonary radiation therapy <6 months prior to the first dose of telisotuzumab vedotin. Subjects must have been previously treated with ≤2 lines of systemic therapy (including ≤1 line of systemic cytotoxic chemotherapy) in the locally advanced or metastatic setting. Multiple lines of TKI targeting the same TK count as the 1st line of therapy for the purposes of this eligibility criterion. - Exclude any of the following therapies within the specified time period prior to the first dose of telisotuzumab vedotin: Within 4 weeks (28 days): systemic cytotoxic chemotherapy; small molecule targeted drugs with half-lives of 7 days or more; monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or T-cell or other cellular therapies. ··For less than 1 week (7 days): Herbal remedies or strong cytochrome P450 3A4 (CYP3A4) inhibitors. Within 2 weeks (14 days): Small molecule targeted agents with half-lives less than 7 days; radiation therapy that does not affect the thoracic cavity. None of the following therapies require a drug holiday: Palliative radiation therapy in 10 fractions or less for bone, cutaneous, or subcutaneous metastases; for CNS metastases, see below. Patients currently receiving EGFR TKI therapy. Subjects with central nervous system (CNS) metastases who have undergone definitive treatment (e.g., surgery or radiation therapy) are eligible only if they meet the following criteria: ···No evidence of progression of CNS metastases at least 4 weeks after curative therapy. ...are asymptomatic and have discontinued systemic corticosteroids and anticonvulsants for at least 2 weeks prior to the first dose of terisotuzumab vedotin. Subjects must have no history of other malignancies except for the following: Malignant tumors that have been treated with curative intent, have been free of known active disease for at least 2 years prior to the first dose of the investigational drug, and are felt by the investigator to be at low risk of recurrence. Non-melanoma skin cancer or lentigo maligna that has been adequately treated and has no evidence of disease. ··Adequately treated carcinoma in situ with no evidence of current disease. Subjects should not have any clinically significant medical conditions, including but not limited to: Grade ≥ 2 edema or lymphedema. Grade ≥2 ascites or pleural effusion. ··Grade ≥2 neuropathy or history of Grade ≥3 neuropathy. ··Uncontrolled active bacterial or viral infection. New York Heart Association Class ≥III congestive heart failure. ··Unstable angina or cardiac arrhythmia.

[0120] Dosing regimen Terisotuzumab vedotin was administered by intravenous (IV) infusion at a dose of 1.9 mg / kg over 30 ± 10 minutes every 14 days (once per cycle) until the subject experienced disease progression or met study discontinuation criteria.

[0121] 7.2.5.Grading Prescreening for c-Met involved reviewing eligibility criteria, medical history, and cancer history. c-Met overexpression was determined by a central c-Met IHC assay (Ventana; Tucson, AZ) and tumor tissue was considered non-squamous if >25% of neoplastic cells from the tumor tissue showed 3+ intensity c-Met staining, c-Met intermediate if >25% but <50% showed 3+ intensity staining, c-Met high if >50% showed 3+ intensity staining, and squamous if >75% of neoplastic cells from the tumor tissue showed 1+ intensity c-Met staining (i.e., c-Met Teliso-V staining protocol as described in Example 1).

[0122] Study visits and evaluations occurred at prescreening, screening, days 1 and 8 of cycle 1, and day 1 of each subsequent cycle. Assessments included limited physical examination, hematology, urinalysis, and chemistry tests before any study drug administration and at the final visit. ECGs and ECOG performance status were obtained at screening, day 1 of cycle 1, day 1 of cycle 2, and the final visit. Adverse events, laboratory values, and vital signs were assessed throughout the entire study period.

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

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

[0125] [Table 8]

[0126] Effectiveness All efficacy analyses were exploratory in nature. Exploratory efficacy endpoints included objective response rate (ORR) using RECIST version 1.1, duration of overall response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

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

[0128] An interim analysis was performed using a hierarchical Bayesian model to assess the ORR in each group, with a posterior probability of at least 70% of a true ORR >25% set as the threshold for progression to stage 2. Patients who experienced clinical progression or death before their first post-baseline tumor assessment were considered non-responders.

[0129] Duration of overall response DoR was defined as the time from the subject's initial response (CR or PR) to first confirmed radiographic progression by independent central review or death from any cause for confirmed responders. DoR time for responders without progression or death was censored at the time of last tumor assessment.

[0130] Disease control rate DCR was defined as the percentage of subjects experiencing a best overall response of confirmed CR, confirmed PR, or stable disease (SD) for at least 12 weeks (two planned tumor assessments) after the first dose of telisotuzumab vedotin according to RECIST version 1.1.

[0131] Progression-free survival PFS was defined as the time from a subject's first dose of study drug to first confirmed radiographic progression by independent central review or death from any cause. PFS for subjects without progression or death was censored at the time of last tumor assessment.

[0132] overall survival OS was defined as the time from a subject's first dose of study drug to death from any cause. Subjects who did not die were censored at the last date the subject was known to be alive.

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

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

[0135] Safety analyses included all patients who received at least one dose of telisotuzumab vedotin. Efficacy analyses included patients who were enrolled ≥12 weeks prior to the data cut-off date, received at least one dose of telisotuzumab vedotin, and had at least one post-baseline tumor assessment (or had clinical evidence of progression or died prior to a post-baseline assessment).

[0136] Pharmacokinetic and Pharmacodynamic Properties Pharmacokinetic samples were collected at visits and evaluations. Serum samples were collected at designated time points for assay of terisotuzumab vedotin conjugate and total ABT-700, and plasma samples were collected for free MMAE concentrations. Serum samples were collected at designated time points for assay of anti-drug antibodies (ADA) and neutralizing anti-drug antibodies (nAb). When data were warranted, noncompartmental methods were used to determine PK parameters for terisotuzumab vedotin conjugate, total ABT-700, and MMAE, including maximum observed plasma concentration (Cmax), time to Cmax (peak time, Tmax), and area under the concentration-time curve (AUC).

[0137] A nonlinear mixed-effects modeling approach was used to estimate population PK parameters of the telisotuzumab vedotin conjugate and MMAE, including clearance (CL) and volume (V).

[0138] c-Met biomarker Subjects were prospectively screened for c-Met protein overexpression in their archival or fresh tumor tissue using a c-Met IHC assay to determine eligibility (Example 1 provides an IHC assay suitable for pre-screening of patients).

[0139] Biological samples (plasma, tumor material, whole blood) were collected at designated time points throughout the study period to evaluate known and / or novel disease-related or telisotuzumab vedotin-related biomarkers in the circulation or tumor tissue.

[0140] RECIST (version 1.1) criteria for tumor response Response criteria were assessed using RECIST (version 1.1). The following criteria were used to evaluate changes in measurable lesions during the course of treatment:

[0141] Eligibility Subjects with measurable disease at baseline may have an objective tumor response as assessed by RECIST criteria. Measurable disease is defined by the presence of at least one measurable lesion. If measurable disease is limited to a solitary lesion, the neoplastic nature should be confirmed by cytology / histology, if possible.

[0142] b.Measurability

[0143] [Table 9]

[0144] All measurements should be taken and recorded in metric units and calipers used when making clinical assessments. All baseline evaluations should be performed as close as possible to the start of treatment but no more than 4 weeks prior.

[0145] The same scoring methods and identical techniques should be used to characterize each lesion identified and reported at baseline and during follow-up.

[0146] Clinical lesions are considered measurable only if they are superficial (e.g., skin nodules and palpable lymph nodes) and have a diameter ≥ 10 mm as assessed using a caliper. In the case of skin lesions, color photographic documentation showing a ruler to estimate the size of the lesion is recommended.

[0147] c.Measurement method Conventional CT should be performed with slice thicknesses of 5 mm or less in succession. This is applicable for tumors of the chest and abdomen. All radiographic measurements should include a scale bar.

[0148] In rare instances, when indicated, cytology and histology can be used to distinguish partial response (PR) from complete response (CR).

[0149] d. Baseline documentation of "target" and "non-target" lesions All measurable lesions, up to two per organ representing all affected organs and a total of five lesions, were identified as target lesions and recorded and measured at baseline. Tumor lesions located in previously irradiated areas or areas receiving other locoregional treatments were not routinely considered measurable unless disease progression had been documented.

[0150] Lymph nodes deserve special mention because they are normal anatomical structures that can be seen by imaging studies even when not affected by tumor. To be defined as measurable, pathological lymph nodes that can be identified as target lesions must meet the criteria of a short axis ≥ 15 mm by CT scan. Only the short axis of these lymph nodes will be added to 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 in the plane in which the image is acquired (in CT scans, 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 x 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 (those with a short axis ≥ 10 mm but < 15 mm) should be considered non-target lesions. Lymph nodes with a short axis <10 mm are considered nonpathological and should not be recorded or followed.

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

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

[0153] e. Evaluation of target lesions Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) must have reduced in size to <10 mm in their short axis.

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

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

[0156] Stable disease (SD): Compared to the smallest sum diameter since the start of treatment (since baseline), there is neither a sufficient decrease to consider PR nor a sufficient increase to consider PD.

[0157] Target Lesion Assessment: Lymph nodes identified as target lesions should always have an actual short axis recorded measurement (measured in the same anatomical plane as the baseline study) even if they regress to less than 10 mm during the study. That is, since a normal lymph node is defined as having a short axis <10 mm, the "sum diameter" of the lesion does not have to be zero when the lymph node is included as a target lesion, even if it meets the complete response criteria. For PR, SD, and PD, the actual short axis measurement of the lymph node will be included in the sum diameter of the target lesion.

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

[0159] f. Evaluation of non-target lesions Complete response (CR): Disappearance 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 tumor marker levels above normal limits.

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

[0162] In this setting, to reach "definite progression" based on non-target disease, there must be substantial overall progression in the non-target disease such that the total tumor burden has increased sufficiently to merit treatment interruption even if there is SD or PR in the target disease. A modest "increase" in size of one or more non-target lesions is usually not sufficient to qualify as definite progression status. Thus, it would be extremely rare to designate overall progression based solely on changes in non-target disease when the target disease is SD or PR.

[0163] Note: If a subject discontinues treatment due to symptomatic deterioration, every effort should be made to document objective progress following cessation of treatment.

[0164] New lesions The appearance of new malignant lesions signifies disease progression. There are no specific criteria for the identification of new radiographic lesions, but the finding of a new lesion should be unequivocal, i.e., not attributable to differences in scanning technique, timing of scan, phase of contrast administration, changes in imaging modality, or findings that are thought to represent something other than a tumor (e.g., a "new" bone lesion may simply be a healed or recurrent pre-existing lesion). Lesions identified during follow-up studies in anatomical locations not scanned at baseline would be considered new lesions and judged as disease progression. An example of this would be a subject with visceral disease at baseline who is ordered to undergo brain CT or MRI during the study and is found to have metastases. Even if the subject did not undergo brain imaging at baseline, brain metastases in the subject would be considered evidence of disease progression.

[0165] If the new lesion is equivocal (i.e., too small to measure), treatment and follow-up evaluation should continue to determine whether it is truly new disease. If repeat scans confirm the presence of new lesions, progression should be declared as of the date of the initial scan.

[0166] 7.2.7.Results As of December 2020, 841 patients had been screened with evaluable c-Met IHC data (Table 10). c-Met+ rates were generally lower in EGFR WT (25%) than EGFR MU (37%) in the non-squamous cohort. In the squamous cohort, 39% of patients had c-Met+ tumors. Figures 8A-8B summarize the observed overall response rates (ORR). Figure 8A shows the results grouped according to both c-Met expression levels and EGFR status (WT = wild type, MU = mutated), while Figure 8B shows the results grouped by EGFR status alone.

[0167] [Table 10]

[0168] One hundred and thirteen patients with c-Met+ NSCLC were enrolled in stage 1, with 90 who met efficacy-evaluable criteria followed up for ≥12 weeks (Table 11). c-Met expression based on H-score was generally lower in the squamous cohort compared to the non-squamous cohort. In the non-squamous 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 mutated EGFR.

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

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

[0171] [Table 11] TIFF2024514506000018.tif71161

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

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

[0174] [Table 12]

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

[0176] safety In total, 96% of patients experienced treatment-emergent adverse events (TEAEs) as assessed by the investigator, and 72% experienced TEAEs related to Teliso-V. TEAEs (all grades) occurring in ≥10% of total patients are summarized in Table 13. 50 patients (44%) experienced grade ≥3 TEAEs. The most frequent was malignant neoplasm progression, occurring in 6% of patients. The most common serious TEAEs were pneumonia (n=6,5%), malignant neoplasm progression (n=4,4%), and pneumonitis (n=4,4%). Three patients died as a result of TEAEs considered by the investigator to be possibly related to teliso-V (sudden death, dyspnea, pneumonitis, n=1 each).

[0177] [Table 13] TIFF2024514506000021.tif49161

[0178] 7.3. Discussion Teliso-V at a dose of 1.9 mg / kg administered every 2 weeks demonstrated encouraging ORR and an acceptable safety profile in the non-squamous EGFR WT NSCLC cohort. Based on prespecified criteria, this cohort was expanded and progressed to stage 2 enrollment. ORR was highest in the c-Met high group, but was also clinically meaningful in the c-Met intermediate group.

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

[0180] 8. Exemplary Embodiments Various specific embodiments have been described above, some of which are exemplified below, but it should be understood that various modifications can be made without departing from the spirit and scope of the present invention. 1. A method of treating a non-squamous non-small cell lung cancer ("NSCLC") tumor expressing c-Met, comprising administering to a human subject having said NSCLC tumor a pharmaceutical composition comprising an anti-c-Met antibody drug conjugate ("ADC"), Teliso-V, wherein the drug of said conjugate is monomethyl auristatin E ("MMAE") and said ADC has the following structure:

[0181] [ka] wherein Ab is an IgG antibody composed of heavy chains each having the amino acid sequence of SEQ ID NO:5 and light chains each having the amino acid sequence of SEQ ID NO:10, n is a number of 2 or 4, and the bond with Ab is made via a thioether bond formed with the sulfhydryl group of a cysteine ​​residue; A method, wherein >25% of neoplastic cells from c-Met-expressing non-squamous NSCLC tumor tissue from said subject have 3+ membranous staining or membrane + cytoplasmic staining as assessed by c-Met immunohistochemical staining (IHC). 2. The method of embodiment 1, wherein said non-squamous NSCLC tumor does not harbor a mutated EGFR gene. 3. The method of embodiment 1, wherein the non-squamous NSCLC tumor harbors a mutated EGFR gene. 4. The method of any one of embodiments 1-3, wherein greater than or equal to 25% but less than 50% of neoplastic cells from c-Met-expressing non-squamous NSCLC tumor tissue derived from said subject have 3+ membranous staining or membrane + cytoplasmic staining as assessed by c-Met IHC. 5. The method of any one of embodiments 1-3, wherein >50% of neoplastic cells from c-Met-expressing non-squamous NSCLC tumor tissue from said subject have 3+ membranous staining or membrane + cytoplasmic staining as assessed by c-Met IHC. 6. The method of any one of embodiments 1-5, wherein administration of Teliso-V achieves an objective response rate (ORR) of greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, or greater than 55% in said subject. 7. The method of embodiment 6, wherein said ORR has a posterior probability of at least 70%. 8. The method of 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 said subject. 9. The method of 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 said subject. 10. The method of any one of embodiments 1 to 8, wherein administration of Teliso-V achieves an overall survival (OS) of at least 13 months, or an OS of at least 14 months in the subject. 11. The method of any one of embodiments 1 to 8, wherein administration of Teliso-V achieves a partial response (PR) in the subject. 12. The method of any one of embodiments 1 to 8, wherein administration of Teliso-V achieves a complete response (CR) in the subject. 13. The method of embodiment 1, wherein said non-squamous NSCLC tumor does not harbor a mutated EGFR gene, and wherein administration of Teliso-V achieves an objective response rate (ORR) of greater than 25%, preferably greater than 30%, preferably greater than 35%, preferably greater than 40% in said subject, said ORR having a posterior probability of at least 70%, and optionally, 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 said subject. 14. The method of embodiment 4, wherein the non-squamous NSCLC tumor does not harbor a mutated EGFR gene and administration of Teliso-V achieves an objective response rate (ORR) of greater than 25% in the subject. 15. The method of embodiment 5, wherein said non-squamous NSCLC tumor does not harbor a mutated EGFR gene, and wherein administration of Teliso-V achieves an objective response rate (ORR) of greater than 25%, preferably greater than 50%, in said subject, said ORR having a posterior probability of at least 70%, preferably at least 95%, and optionally, wherein administration of Teliso-V achieves a median duration of response (DoR) of at least 6 months in said subject. 16. The method according to any one of the preceding embodiments, wherein the pharmaceutical composition comprising Teliso-V has a ratio of E2 to E4 of about 1:1. 17. The method of any one of embodiments 1 to 16, wherein the pharmaceutical composition comprising Teliso-V has a drug-to-antibody ratio ("DAR") of about 2.6 to about 3.4, or about 2.9 to about 3.1. 18. The method of any one of embodiments 1-17, wherein 1.9 mg / kg of Teliso-V is administered intravenously once every two weeks. 19. The method according to any one of the preceding embodiments, 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 of any one of embodiments 1 to 19, wherein the tumor tissue is obtained from the subject prior to administration of the first dose of Teliso-V. 21. The method of any one of embodiments 1-20, wherein the subject has been previously treated with systemic therapy in the locally advanced or metastatic setting. 22. The method of any one of embodiments 1-20, wherein the subject has not been previously treated with systemic therapy in the locally advanced or metastatic setting. 23. The method of any one of embodiments 1 to 22, wherein said c-Met IHC is performed according to a c-Met Teliso-V staining protocol. 24. A method for treating a c-Met-expressing non-squamous non-small cell lung cancer ("NSCLC") tumor in a human subject, comprising: (a) determining whether the tumor exhibits i) negative c-Met expression, ii) positive c-Met expression, iii) intermediate c-Met expression, or iv) high c-Met expression; i) c-Met negative expression is defined as <25% of neoplastic cells from said non-squamous NSCLC tumor tissue having 3+ membranous staining or membrane + cytoplasmic staining as assessed by IHC; ii) c-Met positive expression is defined as ≧25% of neoplastic cells from said non-squamous NSCLC tumor tissue having 3+ membranous staining or membrane + cytoplasmic staining as assessed by IHC; iii) moderate c-Met expression is defined as 25% to less than 50% of neoplastic cells from the non-squamous NSCLC tumor tissue having 3+ membranous staining or membrane + cytoplasmic staining as assessed by IHC; iv) high c-Met expression is defined as ≧50% of neoplastic cells from the non-squamous NSCLC tumor tissue having 3+ membranous staining or membrane+cytoplasmic staining as assessed by IHC; (b) administering to the subject having a non-squamous NSCLC tumor a pharmaceutical composition comprising an anti-c-Met antibody drug conjugate ("ADC"), Teliso-V, if the tumor tissue exhibits positive c-Met expression, wherein the drug of the conjugate is monomethylauristatin E ("MMAE") and the ADC has the following structure:

[0182] [ka] wherein Ab is an IgG antibody composed of heavy chains each having the amino acid sequence of SEQ ID NO:5 and light chains each having the amino acid sequence of SEQ ID NO:10, n is a number of 2 or 4, and the bond with Ab is made via a thioether bond formed with the sulfhydryl group of a cysteine ​​residue. A method comprising: 25. The method of embodiment 24, wherein the non-squamous NSCLC tumor does not harbor a mutated EGFR gene. 26. The method of embodiment 25, wherein the non-squamous NSCLC tumor harbors a mutated EGFR gene. 27. The method of any one of embodiments 24-26, wherein administration of Teliso-V achieves an objective response rate (ORR) of greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, or greater than 55% in said subject. 28. The method of embodiment 27, wherein the ORR has a posterior probability of at least 70%. 29. The method of 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 said subject. 30. The method of 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 said subject. 31. The method of any one of embodiments 24 to 29, wherein administration of Teliso-V achieves an overall survival (OS) of at least 13 months, or an OS of at least 14 months in the subject. 32. The method of any one of embodiments 24 to 29, wherein administration of Teliso-V achieves a partial response (PR) in the subject. 33. The method of any one of embodiments 24 to 29, wherein administration of Teliso-V achieves a complete response (CR) in the subject. 34. The method of embodiment 24, wherein the non-squamous NSCLC tumor does not harbor a mutated EGFR gene, and administration of Teliso-V achieves an objective response rate (ORR) of greater than 25%, preferably greater than 35%, in the subject, said ORR having 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 of 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 of any one of embodiments 24-36, wherein 1.9 mg / kg of Teliso-V is administered intravenously once every two weeks. 38. The method according to any one of embodiments 24-37, wherein subjects weighing 100 kg or less receive 1.9 mg / kg of Teliso-V intravenously once every two weeks, and subjects weighing more than 100 kg receive 190 mg intravenously. 39. The method according to any one of embodiments 24 to 38, wherein the tumor tissue is taken from the subject prior to administration of the first dose of Teliso-V. 40. The method of any one of embodiments 24-39, wherein the subject has been previously treated with systemic therapy in the locally advanced or metastatic setting. 41. The method of any one of embodiments 24-39, wherein the subject has not been previously treated with systemic therapy in the locally advanced or metastatic setting. 42. The method according to any one of embodiments 24 to 41, wherein said c-Met IHC is performed according to a c-Met Teliso-V staining protocol. 43. A method for treating a c-Met-expressing non-squamous non-small cell lung cancer ("NSCLC") tumor in a human subject, comprising: (a) determining whether the tumor exhibits i) negative c-Met expression, ii) positive c-Met expression, iii) intermediate c-Met expression, or iv) high c-Met expression; i) c-Met negative expression is defined as <25% of neoplastic cells from said non-squamous NSCLC tumor tissue having 3+ membranous staining or membrane + cytoplasmic staining as assessed by IHC; ii) c-Met positive expression is defined as ≧25% of neoplastic cells from said non-squamous NSCLC tumor tissue having 3+ membranous staining or membrane + cytoplasmic staining as assessed by IHC; iii) moderate c-Met expression is defined as 25% to less than 50% of neoplastic cells from the non-squamous NSCLC tumor tissue having 3+ membranous staining or membrane + cytoplasmic staining as assessed by IHC; iv) high c-Met expression is defined as ≧50% of neoplastic cells from the non-squamous NSCLC tumor tissue having 3+ membranous staining or membrane+cytoplasmic staining as assessed by IHC; (b) administering to the subject having a non-squamous NSCLC tumor a pharmaceutical composition comprising an anti-c-Met antibody drug conjugate ("ADC"), Teliso-V, if the tumor tissue exhibits moderate c-Met expression, wherein the drug of the conjugate is monomethylauristatin E ("MMAE") and the ADC has the following structure:

[0183] [ka] wherein Ab is an IgG antibody composed of heavy chains each having the amino acid sequence of SEQ ID NO:5 and light chains each having the amino acid sequence of SEQ ID NO:10, n is a number of 2 or 4, and the bond with Ab is made via a thioether bond formed with the sulfhydryl group of a cysteine ​​residue. A method comprising: 44. The method of embodiment 43, wherein the non-squamous NSCLC tumor does not harbor a mutated EGFR gene. 45. The method of embodiment 43, wherein the non-squamous NSCLC tumor harbors a mutated EGFR gene. 46. ​​The method of any one of embodiments 43-45, wherein administration of Teliso-V achieves an objective response rate (ORR) of greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, or greater than 55% in said subject. 47. The method of embodiment 46, wherein the ORR has a posterior probability of at least 70%. 48. The method of any one of embodiments 43-47, 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 said subject. 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 said subject. 50. The method of any one of embodiments 43-48, wherein administration of Teliso-V achieves an overall survival (OS) of at least 13 months, or an OS of at least 14 months in the subject. 51. The method of any one of embodiments 43 to 48, wherein administration of Teliso-V achieves a partial response (PR) in the subject. 52. The method of any one of embodiments 43 to 48, wherein administration of Teliso-V achieves a complete response (CR) in the subject. 53. The method of embodiment 43, wherein the non-squamous NSCLC tumor does not harbor a mutated EGFR gene and administration of Teliso-V achieves an objective response rate (ORR) of greater than 25% in the subject. 54. The method according to any one of embodiments 43 to 53, wherein the pharmaceutical composition comprising Teliso-V has a ratio of E2 to E4 of about 1:1. 55. The method of any one of embodiments 43 to 54, 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. 56. The method of any one of embodiments 43-55, wherein 1.9 mg / kg of Teliso-V is administered intravenously once every two weeks. 57. The method according to any one of embodiments 43-56, 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 taken from the subject prior to administration of the first dose of Teliso-V. 59. The method of any one of embodiments 43-58, wherein the subject has been previously treated with systemic therapy in the locally advanced or metastatic setting. 60. The method of any one of embodiments 43-58, wherein the subject has not been previously treated with systemic therapy in the locally advanced or metastatic setting. 61. The method according to any one of embodiments 43 to 60, wherein said c-Met IHC is performed according to a c-Met Teliso-V staining protocol. 62. A method for treating a c-Met-expressing non-squamous non-small cell lung cancer ("NSCLC") tumor in a human subject, comprising: (a) determining whether the tumor exhibits i) negative c-Met expression, ii) positive c-Met expression, iii) intermediate c-Met expression, or iv) high c-Met expression; i) c-Met negative expression is defined as <25% of neoplastic cells from said non-squamous NSCLC tumor tissue having 3+ membranous staining or membrane + cytoplasmic staining as assessed by IHC; ii) c-Met positive expression is defined as ≧25% of neoplastic cells from said non-squamous NSCLC tumor tissue having 3+ membranous staining or membrane + cytoplasmic staining as assessed by IHC; iii) moderate c-Met expression is defined as 25% to less than 50% of neoplastic cells from the non-squamous NSCLC tumor tissue having 3+ membranous staining or membrane + cytoplasmic staining as assessed by IHC; iv) high c-Met expression is defined as ≧50% of neoplastic cells from the non-squamous NSCLC tumor tissue having 3+ membranous staining or membrane+cytoplasmic staining as assessed by IHC; (b) administering to the subject having a non-squamous NSCLC tumor a pharmaceutical composition comprising an anti-c-Met antibody drug conjugate ("ADC"), Teliso-V, if the tumor tissue exhibits high c-Met expression, wherein the drug of the conjugate is monomethylauristatin E ("MMAE") and the ADC has the following structure:

[0184] [ka] wherein Ab is an IgG antibody composed of heavy chains each having the amino acid sequence of SEQ ID NO:5 and light chains each having the amino acid sequence of SEQ ID NO:10, n is a number of 2 or 4, and the bond with Ab is made via a thioether bond formed with the sulfhydryl group of a cysteine ​​residue. A method comprising: 63. The method of embodiment 62, wherein the non-squamous NSCLC tumor does not harbor a mutated EGFR gene. 64. The method of embodiment 62, wherein the non-squamous NSCLC tumor harbors a mutated EGFR gene. 65. The method of any one of embodiments 62-64, wherein administration of Teliso-V achieves an objective response rate (ORR) of greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, or greater than 55% in said subject. 66. The method of embodiment 65, wherein the ORR has a posterior probability of at least 70%. 67. The method of any one of embodiments 62-66, 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 said subject. 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 said subject. 69. The method of any one of embodiments 62-68, wherein administration of Teliso-V achieves an overall survival (OS) of at least 13 months, or an OS of at least 14 months in said subject. 70. The method of any one of embodiments 62-69, wherein administration of Teliso-V achieves a partial response (PR) in the subject. 71. The method of any one of embodiments 62 to 70, wherein administration of Teliso-V achieves a complete response (CR) in the subject. 72. The method of embodiment 62, wherein the NSCLC tumor does not harbor a mutated EGFR gene, and wherein administration of Teliso-V achieves an objective response rate (ORR) of greater than 25%, preferably greater than 50%, in the subject, said ORR having a posterior probability of at least 70%, preferably at least 95%, and optionally, wherein administration of Teliso-V achieves a median duration of response (DoR) of at least 6 months in the subject. 73. The method according to any one of embodiments 62-72, wherein the pharmaceutical composition comprising Teliso-V has a ratio of E2 to E4 of about 1:1. 74. The method of any one of embodiments 62-73, wherein the pharmaceutical composition comprising Teliso-V has a drug-to-antibody ratio ("DAR") of about 2.4 to about 3.6. 75. The method of any one of embodiments 62-74, wherein 1.9 mg / kg of Teliso-V is administered intravenously once every two weeks. 76. The method according to any one of embodiments 62-75, 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 of any one of embodiments 62 to 76, wherein the tumor tissue is obtained from the subject prior to administration of the first dose of Teliso-V. 78. The method of any one of embodiments 62-77, wherein the subject has been previously treated with systemic therapy in the locally advanced or metastatic setting. 79. The method of any one of embodiments 62-78, wherein the subject has not been previously treated with systemic therapy in the locally advanced or metastatic setting. 80. The method of any one of embodiments 62-79, wherein said c-Met IHC is performed according to a c-Met Teliso-V staining protocol. 81. A method of treating c-Met-expressing non-squamous non-small cell lung cancer ("NSCLC") tumors in a plurality of human subjects, comprising: (a) determining whether the tumor exhibits i) negative c-Met expression, ii) positive c-Met expression, iii) intermediate c-Met expression, or iv) high c-Met expression; i) c-Met negative expression is defined as <25% of neoplastic cells from said non-squamous NSCLC tumor tissue having 3+ membranous staining or membrane + cytoplasmic staining as assessed by IHC; ii) c-Met positive expression is defined as ≧25% of neoplastic cells from said non-squamous NSCLC tumor tissue having 3+ membranous staining or membrane + cytoplasmic staining as assessed by IHC; iii) moderate c-Met expression is defined as 25% to less than 50% of neoplastic cells from the non-squamous NSCLC tumor tissue having 3+ membranous staining or membrane + cytoplasmic staining as assessed by IHC; iv) high c-Met expression is defined as ≧50% of neoplastic cells from the non-squamous NSCLC tumor tissue having 3+ membranous staining or membrane+cytoplasmic staining as assessed by IHC; (b) excluding from treatment the subject having the non-squamous NSCLC tumor that exhibits negative c-Met expression if the tumor tissue exhibits negative c-Met expression; (c) if the tumor tissue exhibits high c-Met expression, selecting the subject for treatment and administering to the selected subject a pharmaceutical composition comprising an anti-c-Met antibody drug conjugate ("ADC"), Teliso-V, wherein the drug of the conjugate is monomethylauristatin E ("MMAE") and the ADC has the following structure:

[0185] [ka] wherein Ab is an IgG antibody composed of heavy chains each having the amino acid sequence of SEQ ID NO:5 and light chains each having the amino acid sequence of SEQ ID NO:10, n is a number of 2 or 4, and the bond with Ab is made via a thioether bond formed with the sulfhydryl group of a cysteine ​​residue. A method comprising: 82. The method of embodiment 81, wherein step b) further comprises excluding from treatment subjects having said non-squamous NSCLC tumors that exhibit positive c-Met expression if said tumor tissue exhibits positive c-Met expression. 83. The method of embodiment 81 or 82, wherein step b) further comprises excluding from treatment subjects having said non-squamous NSCLC tumors that exhibit moderate c-Met expression if said tumor tissue exhibits moderate c-Met expression. 84. The method of any one of embodiments 81-83, wherein the non-squamous NSCLC tumor does not harbor a mutated EGFR gene. 85. The method of any one of embodiments 81-83, wherein the NSCLC tumor harbors a mutated EGFR gene. 86. The method of any one of embodiments 81-85, wherein administration of Teliso-V achieves an objective response rate (ORR) of greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, or greater than 55% in said subject. 87. The method of embodiment 86, wherein the ORR has a posterior probability of at least 70%. 88. The method of any one of embodiments 81-87, 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 subject. 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 said subject. 90. The method of any one of embodiments 81-88, wherein administration of Teliso-V achieves an overall survival (OS) of at least 13 months, or an OS of at least 14 months in said subject. 91. The method of any one of embodiments 81-88, wherein administration of Teliso-V achieves a partial response (PR) in the subject. 92. The method of any one of embodiments 81-88, wherein administration of Teliso-V achieves a complete response (CR) in the subject. 93. The method of any one of embodiments 81-83, wherein the NSCLC tumor does not harbor a mutated EGFR gene, and wherein administration of Teliso-V achieves an objective response rate (ORR) of greater than 25%, preferably greater than 50%, in the selected subject, said ORR having 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 subject. 94. The method according to any one of embodiments 81 to 93, wherein the pharmaceutical composition comprising Teliso-V has a ratio of E2 to E4 of about 1:1. 95. The method of any one of embodiments 81 to 94, wherein the pharmaceutical composition comprising Teliso-V has a drug-to-antibody ratio ("DAR") of about 2.6 to about 3.4, or about 2.9 to about 3.1. The method of any one of embodiments 81-95, wherein 1.9 mg / kg of Teliso-V is administered intravenously once every two weeks. 97. The method according to any one of embodiments 81-96, 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 of any one of embodiments 81 to 97, wherein the tumor tissue is obtained from the subject prior to administration of the first dose of Teliso-V. 99. The method of any one of embodiments 81-98, wherein the subject has been previously treated with systemic therapy in the locally advanced or metastatic setting. 100. The method of any one of embodiments 81-98, wherein the subject has not been previously treated with systemic therapy in the locally advanced or metastatic setting. 101. The method according to any one of embodiments 81 to 100, wherein said c-Met IHC is performed according to a c-Met Teliso-V staining protocol. 102. The method of any one of embodiments 1-17, 20-36, 39-55, 58-74, 77-95, 98-101, wherein 1.6 mg / kg of Teliso-V is administered intravenously once every two weeks. 103. The method of embodiment 102, wherein the subject achieves a partial or complete response. 104. The method of any one of embodiments 18, 19, 37, 38, 56, 57, 75, 76, 96, 97, wherein the subject achieves a partial or complete response. 105. The method of any one of embodiments 1-104, wherein 1.2-2.4 mg / kg of Teliso-V is administered intravenously once every two weeks, and the subject achieves a partial or complete response.

Claims

1. A pharmaceutical composition comprising telisotuzumab vedotin for use in a method for treating non-squamous non-small cell lung cancer ("NSCLC") tumors expressing c-Met in a plurality of human subjects, the method comprising: (a) determining or having previously determined whether said tumor exhibits high c-Met expression, wherein 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 c-Met Teliso-V staining protocol; (b) excluding from treatment subjects having tumors that do not exhibit high c-Met expression if the tumor tissue does not exhibit high c-Met expression; (c) if the tumor tissue exhibits high c-Met expression, selecting the subject for treatment and administering 1.6 mg / kg or 1.9 mg / kg of terisotuzumab vedotin intravenously to the selected subject once every two weeks (Q2W); Including, the non-squamous NSCLC tumor does not harbor a mutated EGFR gene; Pharmaceutical compositions.

2. A pharmaceutical composition comprising telisotuzumab vedotin for use in a method for treating non-squamous non-small cell lung cancer ("NSCLC") tumors that do not harbor a mutated EGFR gene and express c-Met in a plurality of human subjects having non-small cell lung cancer, the method comprising: (a) selecting for treatment subjects having tumors that are i) non-squamous, ii) do not harbor a mutant EGFR gene, and iii) exhibit positive c-Met expression, and excluding said patient from treatment if the subject has a tumor that meets any of the following criteria: i) is squamous, ii) harbors a mutant EGFR gene, and iii) does not exhibit positive c-Met expression; (b) if the subject is selected for treatment, treating the selected subject by administering 1.6 mg / kg or 1.9 mg / kg of telisotuzumab vedotin intravenously to the selected subject once every two weeks (Q2W), 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 c-Met Teliso-V staining protocol. Pharmaceutical compositions.

3. A pharmaceutical composition comprising telisotuzumab vedotin for use in a method for treating non-squamous non-small cell lung cancer ("NSCLC") tumors that do not harbor a mutated EGFR gene and express c-Met in a plurality of human subjects having non-small cell lung cancer, the method comprising: (a) selecting for treatment subjects having tumors that are i) non-squamous, ii) do not harbor a mutant EGFR gene, and iii) exhibit positive c-Met expression, and excluding subjects from treatment if they have tumors that are i) squamous, ii) harbor a mutant EGFR gene, and iii) do not exhibit positive c-Met expression; (b) if the subject is selected for treatment, treating the selected subject by administering 1.6 mg / kg or 1.9 mg / kg of telisotuzumab vedotin intravenously to the selected subject once every two weeks (Q2W), wherein c-Met positive 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 c-Met Teliso-V staining protocol. Pharmaceutical compositions.

4. A pharmaceutical composition described in any one of claims 1 to 3, wherein the method results in an overall response rate in treated subjects of at least about 35%.

5. A pharmaceutical composition described in any one of claims 1 to 3, wherein the method results in an overall response rate in treated subjects of at least about 25%.

6. A pharmaceutical composition described in any one of claims 1 to 3, wherein the method results in an overall response rate in treated subjects of at least about 20%.

7. A pharmaceutical composition for treating c-Met-expressing non-squamous non-small cell lung cancer ("NSCLC") in a human subject, comprising telisotuzumab vedotin, the pharmaceutical composition is administered intravenously to a subject once every two weeks (Q2W) at a dose of 1.6 mg / kg or 1.9 mg / kg of terisotuzumab vedotin; The subject is selected as having a tumor that exhibits 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 a c-Met Teliso-V staining protocol; the non-squamous NSCLC tumor does not harbor a mutated EGFR gene; Pharmaceutical compositions.

8. A pharmaceutical composition comprising telisotuzumab vedotin for treating non-squamous non-small cell lung cancer ("NSCLC") tumors that do not harbor a mutated EGFR gene and express c-Met in a human subject with NSCLC, comprising: the pharmaceutical composition is administered intravenously to a subject once every two weeks (Q2W) at a dose of 1.6 mg / kg or 1.9 mg / kg of terisotuzumab vedotin; The subject is selected for treatment to have a tumor that: i) is non-squamous; ii) does not harbor a mutated EGFR gene; and iii) exhibits positive c-Met expression; The 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 c-Met Teliso-V staining protocol. Pharmaceutical compositions.

9. A pharmaceutical composition comprising telisotuzumab vedotin for treating non-squamous non-small cell lung cancer ("NSCLC") tumors that do not harbor a mutated EGFR gene and express c-Met in a human subject with NSCLC, comprising: the pharmaceutical composition is administered intravenously to a subject once every two weeks (Q2W) at a dose of 1.6 mg / kg or 1.9 mg / kg of terisotuzumab vedotin; The subject is selected for treatment to have a tumor that: i) is non-squamous; ii) does not harbor a mutated EGFR gene; and iii) exhibits positive c-Met expression; The c-Met positive 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 c-Met Teliso-V staining protocol. Pharmaceutical compositions.

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