The Efficacy and Safety of Treating Acquired MET Resistance Through Combinations of Parent and MET Tyrosine Kinase Inhibitors in Patients With Metastatic Oncogene-Driven NSCLC

Tejas Patil; Alyse Staley; Yunan Nie; Mandy Sakamoto; Margaret Stalker; James M Jurica; Kenna Koehler; Amanda Cass; Halle Kuykendall; Emily Schmitt; Emma Filar; Evelina Reventaite; Kurt D Davies; Hala Nijmeh; Mary Haag; Benjamin A Yoder; Paul A Bunn; Erin L Schenk; Dara L Aisner; Wade T Iams; Melina E Marmarelis; D Ross Camidge

doi:10.1016/j.jtocrr.2024.100637

The Efficacy and Safety of Treating Acquired MET Resistance Through Combinations of Parent and MET Tyrosine Kinase Inhibitors in Patients With Metastatic Oncogene-Driven NSCLC

JTO Clin Res Rep. 2024 Jan 18;5(2):100637. doi: 10.1016/j.jtocrr.2024.100637. eCollection 2024 Feb.

Authors

Tejas Patil¹, Alyse Staley², Yunan Nie³, Mandy Sakamoto¹, Margaret Stalker⁴, James M Jurica¹, Kenna Koehler⁵, Amanda Cass⁵, Halle Kuykendall¹, Emily Schmitt¹, Emma Filar¹, Evelina Reventaite¹, Kurt D Davies⁶, Hala Nijmeh⁶, Mary Haag⁶, Benjamin A Yoder¹, Paul A Bunn¹, Erin L Schenk¹, Dara L Aisner⁶, Wade T Iams⁵, Melina E Marmarelis⁴, D Ross Camidge¹

Affiliations

¹ Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado.
² University of Colorado Cancer Center Biostatistics Core, University of Colorado School of Medicine, Aurora, Colorado.
³ Department of Medical Oncology, Yale School of Medicine, Yale University, New Haven, Connecticut.
⁴ Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
⁵ Division of Medical Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.
⁶ Department of Pathology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado.

Abstract

Introduction: Acquired MET gene amplification, MET exon 14 skip mutations, or MET fusions can emerge as resistance mechanisms to tyrosine kinase inhibitors (TKIs) in patients with lung cancer. The efficacy and safety of combining MET TKIs (such as crizotinib, capmatinib, or tepotinib) with parent TKIs to target acquired MET resistance are not well characterized.

Methods: Multi-institutional retrospective chart review identified 83 patients with metastatic oncogene-driven NSCLC that were separated into the following two pairwise matched cohorts: (1) MET cohort (n = 41)-patients with acquired MET resistance continuing their parent TKI with a MET TKI added or (2) Chemotherapy cohort (n = 42)-patients without any actionable resistance continuing their parent TKI with a platinum-pemetrexed added. Clinicopathologic features, radiographic response (by means of Response Evaluation Criteria in Solid Tumors version 1.1), survival outcomes, adverse events (AEs) (by means of Common Terminology Criteria for Adverse Events version 5.0), and genomic data were collected. Survival outcomes were assessed using Kaplan-Meier methods. Multivariate modeling adjusted for lines of therapy, brain metastases, TP53 mutations, and oligometastatic disease.

Results: Within the MET cohort, median age was 56 years (range: 36-83 y). Most patients were never smokers (28 of 41, 68.3%). Baseline brain metastases were common (21 of 41, 51%). The most common oncogenes in the MET cohort were EGFR (30 of 41, 73.2%), ALK (seven of 41, 17.1%), and ROS1 (two of 41, 4.9%). Co-occurring TP53 mutations (32 of 41, 78%) were frequent. Acquired MET alterations included MET gene amplification (37 of 41, 90%), MET exon 14 mutations (two of 41, 5%), and MET gene fusions (two of 41, 5%). After multivariate adjustment, the objective response rate (ORR) was higher in the MET cohort versus the chemotherapy cohort (ORR: 69.2% versus 20%, p < 0.001). Within the MET cohort, MET gene copy number (≥10 versus 6-10) did not affect radiographic response (54.5% versus 68.4%, p = 0.698). There was no difference in ORR on the basis of MET TKI used (F [2, 36] = 0.021, p = 0.978). There was no difference in progression-free survival (5 versus 6 mo; hazard ratio = 0.64; 95% confidence interval: 0.34-1.23, p = 0.18) or overall survival (13 versus 11 mo; hazard ratio = 0.75; 95% confidence interval: 0.42-1.35, p = 0.34) between the MET and chemotherapy cohorts. In the MET cohort, dose reductions for MET TKI-related toxicities were common (17 of 41, 41.4%) but less frequent for parent TKIs (two of 41, 5%). Grade 3 AEs were not significant between crizotinib, capmatinib, and tepotinib (p = 0.3). The discontinuation rate of MET TKIs was 17% with no significant differences between MET TKIs (p = 0.315). Among pre- and post-treatment biopsies (n = 17) in the MET cohort, the most common next-generation sequencing findings were loss of MET gene amplification (15 of 17, 88.2%), MET on-target mutations (seven of 17, 41.2%), new Ras-Raf-MAPK alterations (three of 17, 17.6%), and EGFR gene amplification (two of 17, 11.7%).

Conclusions: The efficacy and safety of combining MET TKIs (crizotinib, capmatinib, or tepotinib) with parent TKIs for acquired MET resistance are efficacious. Radiographic response and AEs did not differ significantly on the basis of the underlying MET TKI used. Loss of MET gene amplification, development of MET on-target mutations, Ras-Raf-MAPK alterations, and EGFR gene amplification were molecular patterns found on progression with dual parent and MET TKI combinations.

Keywords: Acquired resistance; MET amplification; MET exon 14 skipping; NSCLC; Tyrosine kinase inhibitor.