Neoadjuvant and adjuvant capmatinib in resectable non–small cell lung cancer with MET exon 14 skipping mutation or high MET amplification: GEOMETRY-N trial.

TPS8590 Background: Neoadjuvant therapy is the earliest opportunity to eliminate micrometastatic disease. Emerging data suggest that neoadjuvant therapy in non-small cell lung cancer (NSCLC) can elicit major pathological responses (MPRs) that translate into prolonged survival outcomes, serving as an early surrogate for efficacy. Adjuvant therapy can improve overall and disease-free survival (DFS) in patients with completely resected NSCLC. DFS observed with osimertinib in patients with early-stage EGFR-mutated tumors supports evaluation of other tyrosine kinase inhibitors (TKIs) in the neoadjuvant and adjuvant settings. In early-stage NSCLC, MET exon 14 skipping mutation ( METex14) and de novo MET amplification ( METamp) are estimated to occur in up to 2.8% and 1.7% of patients, respectively. Capmatinib, a selective MET TKI, is FDA approved for patients with metastatic METex14 NSCLC. It was studied in GEOMETRY mono-1 in patients with advanced/metastatic NSCLC with METex14 or METamp. In 2 treatment-naive METex14 cohorts, overall response rate (ORR) was 68% and 66%. In a treatment-naive high-level METamp cohort, ORR was 40%. Capmatinib had a tolerable safety profile; most adverse events were reversible with dose adjustments. Based on the ORRs and safety profile observed in treatment-naive patients with advanced/metastatic MET-dysregulated NSCLC, GEOMETRY-N (NCT04926831), a Phase II, 2-cohort, 2-stage study, is evaluating the efficacy and safety of neoadjuvant and adjuvant capmatinib therapy in improving the MPR rate and outcomes in patients with METex14 or high-level METamp NSCLC. Methods: Adults with resectable, histologically confirmed NSCLC stage IB-IIIA, N2 and select IIIB (T3N2 or T4N2) with either METex14 (cohort A) or high-level METamp (gene copy number ≥10; cohort B) are eligible. METex14 must be determined by a Clinical Laboratory Improvement Amendments (CLIA)-certified lab. METamp must be determined by fluorescence in situ hybridization at a CLIA-certified lab or by FoundationOne CDx next-generation sequencing. Prior systemic anticancer therapy is prohibited. Patients will receive capmatinib 400 mg twice daily for 8 weeks before surgical resection, followed by 3 years of adjuvant capmatinib. In the 2-stage design, stage 1 will enroll 9 patients per cohort, with MPR evaluated in each cohort after 9 patients have completed neoadjuvant therapy; stage 2, enrolling 10 more patients in a cohort, will proceed only if ≥1 of 9 participants has an MPR. About 42 patients will be enrolled, with 19 evaluable patients per cohort. Primary endpoint is MPR rate (local assessment). Secondary endpoints are complete pathological response rate (central and local review), ORR (local assessment), DFS, and safety. Following treatment, there will be a 2-year survival follow-up. Enrollment has started; expected first patient first visit: March 31, 2022. Clinical trial information: NCT04926831.