Phase Ib of repotrectinib plus osimertinib in patients with EGFR-mutated advanced non-small cell lung cancer.

BACKGROUND

Overcoming resistance to osimertinib in EGFR-mutated non-small cell lung cancer (NSCLC) is a clinically unmet need. Osimertinib plus repotrectinib inhibited Src and FAK phosphorylation and the downstream activation of STAT3, paxillin, and YAP1 in preclinical models, enhancing osimertinib efficacy.

PATIENTS AND

METHODS

TOTEM (NCT04772235) was a phase Ib study assessing the safety, tolerability, pharmacokinetics, and antitumour activity of repotrectinib plus osimertinib in patients with EGFR-mutated NSCLC resistant to previous treatments. Dose-escalation followed 3 + 3 model with osimertinib 80 mg QD plus repotrectinib at three doses: 80 mg QD, 160 mg QD, and 160 mg BID. Dose-expansion evaluated efficacy in two cohorts after progression to osimertinib or after progression to osimertinib and chemotherapy.

RESULTS

Thirty-one patients were enrolled between February 2022 and January 2025. Seventeen patients had two or more prior lines of therapy. The recommended phase 2 dose was 80 mg QD osimertinib plus 160 mg BID repotrectinib. Grade 3-4 treatment-related adverse events occurred in 14 patients (45.2%), mainly dizziness (16.1%) and anaemia (12.9%). The ORR was 22.2% (95% CI: 8.6-42.3), with six patients achieving confirmed PR lasting 6.9 months (95% CI: 2.7-13.1). Median PFS was 4.0 months (95% CI: 2.8-9.7). In patients with intracranial disease, icORR was 33.3% (7.5-70.1) and median icPFS was 4.4 months (95% CI: 2.7-NR).

CONCLUSION

Osimertinib plus repotrectinib showed safety and promising icORR. Results were comparable to new combinations, considering heavily pretreated patients. Efficacy in biomarker-selected NSCLC patients requires further investigation.