A randomized phase II study of capmatinib plus osimertinib with or without ramucirumab in patients with <i>EGFR</i> -mutant, <i>MET</i> -amplified stage IV or recurrent no–small cell lung cancer (Lung-MAP Sub-Study S1900G).

Abstract

TPS8677 Background: Patients (pts) with advanced EGFR -mutant non-small cell lung cancer (NSCLC) typically respond well to first-line tyrosine kinase inhibitor (TKI) therapy, however disease progression is inevitable. A common mechanism of resistance to third-generation EGFR TKIs is MET amplification in up to 15% of patients. Prior trials have demonstrated efficacy of combined EGFR and MET TKI for patients with acquired MET amplification, however treatment can be limited by toxicity due to peripheral edema. Preclinical evidence demonstrates the benefit of VEGF inhibition combined with an EGFR TKI and MET TKI, both in efficacy and reduced edema. Lung MAP S1900G is a randomized phase II trial of osimertinib and capmatinib plus or minus the VEGFR2 inhibitor ramucirumab in patients with EGFR -mutant NSCLC and MET amplification after progression on osimertinib. Methods: Pts have stage IV or recurrent NSCLC with a sensitizing EGFR mutation and have disease progression on osimertinib alone or in combination with other agents. Documentation of MET amplification must be determined by tissue- or blood-based assay; testing for MET amplification can be done locally or centrally through the LUNGMAP screening process and any level of amplification is allowed. Measurable disease is not required. Patients with asymptomatic treated or untreated brain metastases are eligible. Prior VEGF inhibitor or MET antibody (such as amivantamab) are allowed. Pts are randomly assigned to receive osimertinib 80mg by mouth daily, capmatinib 400mg by mouth twice daily, and ramucirumab 10m/kg intravenously on days 1 and 15 of a 28 day cycle, or osimertinib plus capmatinib alone. Treatment continues until disease progression, symptomatic deterioration, unacceptable toxicity or treatment delay greater than 28 days. Disease assessment per RECIST 1.1 is performed every 8 weeks for the first year and every 12 weeks thereafter. The primary endpoint is investigator-assessed progression-free survival (PFS) and secondary endpoints include toxicity, ORR, duration of response, overall survival, rates of edema, and change in weight. A safety run-in of the first 10 pts in each arm evaluable for dose-limiting toxicity is included due to limited safety data on both the doublet and triplet combinations. The target sample size is 40 eligible pts (20 per arm) which will provide 85% power to rule out no difference at a 1-sided 15% level if the true hazard ratio is 0.5. A hazard ratio of 0.71 or less, equivalent to a 2.4 month difference in median PFS, will be consistent with rejecting the null hypothesis. Accrual is ongoing, with 24 of 40 patients enrolled. S1900G is the first Lung-MAP sub-study that focuses on EGFR -mutant lung cancer, representing a new era for this platform trial. Clinical trial information: NCT05642572 .