A Phase II Study of Telisotuzumab Vedotin in Patients With c-MET-positive Stage IV or Recurrent Squamous Cell Lung Cancer (LUNG-MAP Sub-study S1400K, NCT03574753)

Abstract

Introduction: Lung-MAP S1400K was designed to evaluate the response to telisotuzumab vedotin, an antibody-drug conjugate targeting c-MET, in patients with c-MET-positive squamous cell carcinoma (SCC).

Patients and methods: Patients with previously treated SCC with c-MET-positive tumors (H score ≥ 150, Ventana SP44 assay) were enrolled into 2 cohorts: Cohort 1 (immune checkpoint inhibitor-naive) and Cohort 2 (immune checkpoint inhibitor refractory). Telisotuzumab vedotin 2.7 mg/kg was administered intravenously every 3 weeks until disease progression or unacceptable toxicity. Response assessments were performed every 6 weeks. The primary endpoint was response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints included progression-free survival, overall survival, response within cohort, duration of response, and toxicities. Interim analysis was planned after 20 evaluable patients, with ≥ 3 responses needed to continue enrollment.

Results: Forty-nine patients (14% of screened patients) were assigned to S1400K, 28 patients enrolled (15 in Cohort 1 and 13 in Cohort 2), and 23 were eligible. S1400K closed on December 21, 2018 owing to lack of efficacy. Two responses (response rate of 9%; 95% confidence interval, 0%-20%) were reported in cohort 1 (1 complete and 1 unconfirmed partial response), whereas 10 patients had stable disease, with a disease control rate of 52%. The median overall and progression-free survival was 5.6 and 2.4 months, respectively. There were 3 grade 5 events (2 pneumonitis, in Cohort 2, and 1 bronchopulmonary hemorrhage, in Cohort 1).

Conclusion: Telisotuzumab vedotin failed to meet the pre-specified response needed to justify continuing enrollment to S1400K. Pneumonitis was an unanticipated toxicity observed in patients with SCC.

Trial registration: ClinicalTrials.gov NCT03574753.

Keywords: Antibody-drug conjugate; Lung-MAP; Squamous cell carcinoma; Telisotuzumab vedotin; c-MET.

Conflict of interest statement

Conflicts of Interest

Dr. Waqar reports grants from 1 UM1 CA186704–01 outside of this submitted work, and research support to Washington University School of Medicine from AbbVie outside of this submitted work. Dr. Arnold reports grants from AbbVie for other clinical trials, outside the submitted work. Dr. Hirsch has received research grants from AbbVie for laboratory studies at University of Colorado (through University of Colorado), laboratory support (through University of Colorado) from Merck, Biodesix, Amgen, Rain Therapeutics and Mersana and has also participated in scientific advisory boards for AbbVie, BMS, Merck, Genentech, Lilly, Novartis, AstraZeneca. Dr. Mack reports personal fees from AstraZeneca and Amgen outside the submitted work. Dr. Schwartz has served as a DSMB member for independent review of response assessment imaging studies blinded to treatment and outcomes for Merck, Boehringer Ingelheim, Hoffman La Roche and Novartis outside this submitted work. Dr. Gandara has served on the advisory board for AbbVie, outside of this submitted work. Dr. Ramalingam reports personal fees for Advisory board from AbbVie, Amgen, BMS, Genentech, Lilly, Takeda and Loxo and grants from AstraZeneca, Merck, and Tesaro outside the submitted work. Dr. Kelly reports research grants and personal fees for Advisory Board from AbbVie outside this submitted work, personal fees from AstraZeneca for participation in Advisory Board and DMC meeting, research grant (drug only) and personal fees for Advisory Board from Bristol Meyers Squibb, research funding (drug only) and personal fees for DMC meeting from Genentech, personal fees for Advisory Board from Pfizer outside the submitted work. Dr. Herbst reports personal fees from Abbvie Pharmaceuticals, ARMO Biosciences, Biodesix, Bristol-Myers Squibb, EMD Serrano, Genmab, Halozyme, Heat Biologics, Loxo Oncology, Nektar, Novartis, Pfizer, Sanofi, Seattle Genetics, Shire PLC, Spectrum Pharmaceuticals, Symphogen, Tocagen, Tesaro, IMAB Biopharma, Immunocore, Midas Health Analytics, Mirati Tnerapeutics, and Takeda; and grants and personal fees from AstraZeneca, Merck and Company, Eli Lilly and Company, Genentech/Roche; personal fees for Scientific Advisory Board from Infinity Pharmaceuticals, , Neon Therapeutics, and NextCure; and personal fees for Board Membership (non-executive/ independent) from Junshi Pharmaceuticals outside the submitted work. Dr Papadimitrakopoulou is currently an employee of Pfizer, Inc. and has received personal fees for Advisory Board from Abbvie, and personal fees from Eli Lilly, Novartis, Merck, Nektar Therapeutics, Janssen, Araxes, Arrys Therapeutics, Clovis Oncology, Exelixis, Gritstone, Ideaya, Leeds Biolabs, Loxo Oncology, Takeda, Tesaro, TRM Oncology outside this submitted work, and grants from Eli Lilly, Novartis, Merck, Nektar Therapeutics, Janssen Checkmate and Incyte outside the submitted work.

No Conflicts of Interest

Dr. Redman, Dr. Stinchcombe, Dr. Leighl, Dr. Tanna, Dr. Raddin, Dr. Minichiello, and Dr. Bradley report no relevant conflicts of interest.

Copyright © 2020 Elsevier Inc. All rights reserved.

Figures

Figure 1:

Flow diagram showing patients screened and enrolled to S1400K

Figure 2.

Waterfall Plot with Annotations for Individual Alterations All patients who received at least one dose of telisotuzumab vedotin are represented in this plot. From left to right, best change in tumor measurements included in the plot are displayed as:

1. IA: Measurements for patients who did not have any follow-up tumor disease assessments are are labeled with “IA” and displayed as a 20% increase, the threshold for progressive disease.

2. SD: Measurements for patients who had symptomatic deterioration at first disease assessment are labeled as “SD” and displayed as a 20% increase, the threshold for progressive disease.

3. NL: Measurements for patients who had progressive disease at their first assessment based on new lesions are labeled by “NL”. Their best percent decrease in tumor burden is displayed.

4. UP: Measurements for patients who had unequivocal progression in non-target lesions at their first follow-up assessment are labeled as “UP”. Their best percent decrease in tumor burden is displayed.

5. Unlabeled bars: To the right of the labeled bars are bars representing the change in measurements for patients not coded as SD, NL, or UP with at least one follow-up disease assessment.

Bars extending above the dashed line at +20% or labeled as IA, SD, NL, or UP are coded as progressive disease. Unlabeled bars between the dashed lines (+20% to −30%) are coded as best response of stable disease and unlabeled bars extending below the −30% line are coded as best response of partial or complete response.

Figure 3.

PFS and OS for Eligible Patients