Safety and efficacy of lapatinib, binimetinib, and vinorelbine for RAS mutant metastatic colorectal cancer: results of the RASTRIC Phase I/II trial

Background: Treatment options for RAS-mutant metastatic colorectal cancer (mCRC) remain limited. Based on preclinical work with patient-derived organoids, we investigated a triple therapy of binimetinib, lapatinib, and vinorelbine in a Phase I/II trial. Methods: Forty patients with RAS-mutant mCRC received escalating doses of binimetinib and lapatinib with vinorelbine 17.5 mg/m² in three-weekly schedules. Phase I aimed to determine the Recommended Phase II Regimen (RP2R), while Phase II evaluated Overall Response Rate using Simon’s two-stage design. Pharmacokinetic analyses were performed on cycle 1 day 3. Results: The Maximum Tolerated Dose was established at lapatinib 750 mg QD and binimetinib 30 mg BID (both 5 days on/2 days off), with vinorelbine 17.5 mg/m² on days 3 and 10 every 21 days. Toxicities included diarrhoea (75%), rash (65%), and increased CPK (57%). Among 33 evaluable patients, no objective responses occurred, with 9 (27%) achieving stable disease, lasting beyond 3 months (maximum: 297 days) in three patients. Pharmacokinetics showed dose-proportional exposure for binimetinib but not lapatinib. Binimetinib absorption may be affected by colostomy and loperamide-induced constipation. Conclusions: The triple combination showed moderate tolerability and termination occurred after the first stage of Phase II due to insufficient efficacy. Our findings highlight challenges in translating organoid-derived drug combinations to clinical practice. Clinical Trial Registration: EudraCT: 2019-004987-23.