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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p> Clinical Trial Registration: EudraCT <p>2019-004987-23</p>

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

  • 期刊论文

  • 发表日期：

    2026年4月7日

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  • Maarten A. Huismans,
  • Eelke H. Gort,
  • Lisa T. van der Heijden,
  • Sermin M. Guven Mese,
  • Helena M. Klein Wolterink,
  • Manon N. G. J. A. Braat,
  • Sjoerd G. Elias,
  • Filip Y. F. L. de Vos,
  • Lot A. Devriese,
  • Henk M. W. Verheul,
  • Frans L. Opdam,
  • Miriam Koopman,
  • Hilde H. Nienhuis,
  • Heleen A. Crommelin,
  • Hugo J. G. Snippert,
  • Alwin D. R. Huitema,
  • Jeanine M. L. Roodhart

摘要

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