In the phase 2 GEOMETRY mono-1 study, capmatinib has demonstrated clinically meaningful efficacy and a manageable safety profile in patients with advanced NSCLC harboring MET exon 14 skipping (METΔex14) mutations. Here, we report the biomarker analysis for the predefined METΔex14 pretreated cohort 4 (C4) and treatment naïve cohort 5b (C5b) patients of this study. Baseline tissue biopsy samples were tested for METΔex14 by qualitative RT-PCR and MET gene copy number (GCN) by Vysis MET CDx FISH assay for patient selection. Subsequently, these METΔex14 positive tissue biopsy samples were retrospectively tested using the FoundationOne hybrid capture based next-generation sequencing (NGS) assay. From 97 enrolled patients (C4, n=69; C5b, n=28), 73 had baseline tumor biopsy samples (C4, n=53; C5b, n=20) that met the requirements for the FoundationOne NGS assay. SNVs or indels leading to METΔex14 were identified in 72 of 73 samples sequenced and ~20% of patients in both cohorts had co-occurring MET amplification (≥6 GCN) detected by the FoundationOne NGS assay (C4, 23% [n=12]; C5b, 20% [n=4]). Anti-tumor activity and duration of response (DOR) in both cohorts were independent of the type of MET genomic alteration that results in METΔex14 or the co-occurrence of MET amplification. TP53 mutations and MDM2 amplification were nearly mutually exclusive and were detected in 77% (n=40) of C4 (TP53, 45%; MDM2, 36%) and 75% (n=15) of C5b (TP53, 40%; MDM2, 40%) patients. In both cohorts, co-occurring CDKN2A, CDKN2B, and MTAP deletions occurred in 20−25% of patients while KRAS alterations were detected in 5−8% of patients. EGFR amplification occurred in 11% (n=6) of pretreated patients and none of the treatment-naïve patients. Previously described mechanisms of resistance to MET tyrosine kinase inhibitors involving genes such as EGFR, NF1, CDK4, KRAS, NRAF, BRAF were detected in ~30% of the baseline tissue biopsies. There was no statistically significant difference in tumor mutational burden or genomic landscape as per ethnicity or smoking history in both cohorts. FoundationOne NGS assay identified METΔex14 in 72 of 73 positive patients, previously tested by qualitative RT-PCR. The genomic landscape of pretreated and treatment-naïve METΔex14 patients in this study was similar and consistent with previous reports. In this study, anti-tumor activity and DOR were independent of the type of alteration leading to METΔex14 or baseline alterations in other genes previously described as potential bypass mechanisms to MET inhibitors. Larger datasets are required for validating and extending these observations.

Citation Format: Rebecca S. Heist, Edward B. Garon, Daniel S.W. Tan, Harry J.M. Groen, Takashi Seto, Egbert F. Smit, Lauren Fairchild, Alejandro Balbin, Ming Yan, Monica Giovannini, Mikhail Akimov, Banu Sankaran, Ngozi Nwana, Juergen Wolf. Biomarker analysis of patients with METΔex14 mutated non-small-cell lung cancer (NSCLC) treated with capmatinib in the GEOMETRY mono-1 study [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A029. doi:10.1158/1535-7163.TARG-19-A029