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

  • Br J Cancer. 2026 Jun;134(12):1744-1753. doi: 10.1038/s41416-026-03398-x.
Maarten A Huismans  1  2  3 ,  Eelke H Gort  1 ,  Lisa T van der Heijden  4 ,  Sermin M Guven Mese  1 ,  Helena M Klein Wolterink  1 ,  Manon N G J A Braat  5 ,  Sjoerd G Elias  6 ,  Filip Y F L de Vos  1 ,  Lot A Devriese  1 ,  Henk M W Verheul  7 ,  Frans L Opdam  8 ,  Miriam Koopman  1 ,  Hilde H Nienhuis  1 ,  Heleen A Crommelin  9 ,  Hugo J G Snippert  2  3 ,  Alwin D R Huitema  4 ,  Jeanine M L Roodhart  10
Affiliations
  • 1. Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
  • 2. Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
  • 3. Oncode Institute, Utrecht, the Netherlands.
  • 4. Department of Pharmacy and Pharmacology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • 5. Department of Radiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
  • 6. Department of Epidemiology, Julius Center for Health Sciences and Primary Care, Utrecht University, Utrecht, the Netherlands.
  • 7. Department of Medical Oncology, Erasmus Medical Center, Erasmus University Rotterdam, Rotterdam, the Netherlands.
  • 8. Early Drug Development Center, Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • 9. Department of Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
  • 10. Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. [email protected].
PMID: 41946829 DOI: 10.1038/s41416-026-03398-x
Abstract

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.

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