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

Area of Science:

• Oncology
• Pharmacology
• Clinical Trials

Background:

• Resistance to osimertinib is a significant challenge in EGFR-mutated non-small cell lung cancer (NSCLC).
• Preclinical studies indicated that combining osimertinib with repotrectinib can overcome resistance by inhibiting key signaling pathways like Src, FAK, STAT3, paxillin, and YAP1.

Purpose of the Study:

• To assess the safety, tolerability, pharmacokinetics, and antitumour activity of repotrectinib plus osimertinib in patients with EGFR-mutated NSCLC who developed resistance to prior treatments.
• To determine the recommended phase 2 dose (RP2D) for the combination therapy.

Main Methods:

• The TOTEM study (NCT04772235) was a Phase Ib trial involving dose-escalation (3+3 design) and dose-expansion cohorts.
• Osimertinib (80 mg QD) was combined with repotrectinib at escalating doses (80 mg QD, 160 mg QD, 160 mg BID).
• Patients had EGFR-mutated NSCLC with progression after osimertinib or osimertinib and chemotherapy.

Main Results:

• The recommended phase 2 dose was determined to be osimertinib 80 mg QD plus repotrectinib 160 mg BID.
• The overall response rate (ORR) was 22.2%, with a median progression-free survival (PFS) of 4.0 months.
• For patients with intracranial disease, the intracranial ORR (icORR) was 33.3% and median intracranial PFS (icPFS) was 4.4 months.

Conclusions:

• The combination of osimertinib and repotrectinib demonstrated acceptable safety and promising efficacy, particularly in patients with intracranial disease.
• The observed results are comparable to other novel combinations in heavily pretreated NSCLC populations.
• Further investigation is warranted to explore the efficacy of this combination in biomarker-selected NSCLC patients.