Multicenter phase 1b trial of repotrectinib plus osimertinib for EGFR-mutated advanced non-small cell lung cancer

Overcoming resistance to osimertinib in EGFR-mutated non-small cell lung cancer (NSCLC) is an unmet need. In preclinical models, the combination of osimertinib and repotrectinib inhibited Src and FAK phosphorylation and the downstream activation of STAT3, paxillin, and YAP1. The multicenter phase 1b TOTEM trial in Spain evaluated the combination of repotrectinib and osimertinib in patients with EGFR-mutated advanced NSCLC resistant to previous treatments. Thirty-one patients were enrolled, of whom 17 had two or more prior lines of therapy. After the dose-escalation part, 80 mg osimertinib QD plus 160 mg repotrectinib BID was selected as the recommended phase 2 dose. Grade 3-4 treatment-related adverse events occurred in 14 patients (45.2%), mainly dizziness and anemia. The objective response rate was 22.2% (95% CI 8.6-42.3), with six patients achieving confirmed partial response lasting a median of 6.9 months. Median progression-free survival was 4.0 months (95% CI 2.8-9.7). In patients with intracranial disease, icORR was 33% (95% CI 7.5-70.1) and median icPFS was 4.4 months (2.7-NR). The authors conclude that the combination of osimertinib plus repotrectinib showed safety and promising activity in patients with advanced EGFR-mutated NSCLC, including patients with intracranial disease.