Tepotinib in patients with advanced non-small cell lung cancer (NSCLC) harboring MET exon 14-skipping mutations: Phase II trial.

9016 Background: MET mutations causing exon 14 skipping (METΔex14) produce c-Met receptors lacking a negative regulatory site, with the result that METΔex14 mutations are oncogenic drivers. 3-4% of NSCLCs harbor METΔex14 mutations; these tumors appear to be sensitive to c-Met inhibition. Selective c-Met inhibitors have the potential to be effective and well tolerated in patients (pts) with NSCLC. This single-arm phase II trial (NCT02864992) is investigating the efficacy and safety of the potent, selective c-Met inhibitor tepotinib in pts with METΔex14+ NSCLC. Methods: Adults with stage IIIB/IV METΔex14+ NSCLC without EGFR-activating mutations or ALK rearrangements who have received 0–2 lines of prior therapy are eligible. METΔex14 mutations are identified in tumor and/or circulating tumor DNA (ctDNA) in plasma by a central laboratory. Pts receive tepotinib 500 mg QD until disease progression, intolerable toxicity, or withdrawal for other reasons. Primary endpoint: objective response. Secondary endpoints include safety. Recruitment of approx. 90 pts (60 tumor + 60 ctDNA METΔex14+, overlap anticipated) in Europe, USA, and Japan is planned. Results: 34 pts have been treated to date; data are available for 22 (male, n=16; Caucasian/Asian, n=17/5; median age 73.5 years; prior lines of therapy: 0, n=8, 1, n=8; 2, n=5; 3, n=1; METΔex14+ tumor and ctDNA, n=11, METΔex14+ tumor only, n=10, METΔex14+ ctDNA only, n=1); 19 remain on treatment. Based on investigator assessment, 9/15 (60.0%) evaluable pts had a confirmed PR and 3 (20.0%) had SD. All responders remain in response. 13 pts were evaluable for response by independent review: confirmed PR, n=6 (46.2%); SD, n=1 (7.7%). 13/22 pts with data available had tepotinib-related treatment-emergent adverse events (TRTEAEs; G1/2 peripheral edema = 9, G1/2 diarrhea = 7), with 3 having G3 TRTEAEs (asymptomatic amylase increase = 2; GGT increase = 1) and one a serious TRTEAE (interstitial pneumonia). 2 deaths not related to therapy have occurred (disease progression and bronchopulmonary hemorrhage). Conclusions: Tepotinib 500 mg QD has promising activity in METΔex14+ NSCLC. Its safety profile is as expected based on prior studies. Recruitment is ongoing. Clinical trial information: NCT02864992.