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Background <p>Targeting <i>RAS</i> mutant (MT) colorectal cancer (CRC) remains a difficult challenge, mainly due to the pervasiveness of RAS/MEK-mediated feedback loops. Preclinical studies identified MET/STAT3 as an important mediator of resistance to KRAS-MEK1/2 blockade in <i>RAS</i>MT CRC. This dose escalation/expansion study assessed safety and initial efficacy of the MEK1/2 inhibitor binimetinib with MET inhibitor crizotinib in <i>RAS</i>MT advanced CRC patients.</p> Methods <p>In the dose escalation phase, patients with advanced solid tumours received binimetinib with crizotinib, using a rolling- 6 design to determine the maximum tolerable dose (MTD) and safety/tolerability. A subsequent dose expansion in <i>RAS</i>MT CRC patients assessed treatment response. Blood samples for pharmacokinetics, MET biomarker and ctDNA analyses, and skin/tumour biopsies for pharmacodynamics, c-MET immunohistochemistry (IHC), <i>MET </i>in situ hybridisation (ISH) and <i>MET</i> DNA-ISH analyses were collected.</p> Results <p>Twenty patients were recruited in 3 cohorts in the dose escalation. The MTD was binimetinib 30 mg B.D, days 1–21 every 28 days, with crizotinib 250 mg O.D continuously. Dose-limiting toxicities included grade ≥ 3 transaminitis, creatinine phosphokinase increases and fatigue. Thirty-six <i>RAS</i>MT metastatic CRC patients were enrolled in the dose expansion. Pharmacokinetic and pharmacodynamic parameters showed evidence of target engagement.</p> <p>Across the entire study, the most frequent treatment-related adverse events (TR-AE) were rash (80.4%), fatigue (53.4%) and diarrhoea (51.8%) with grade ≥ 3 TR-AE occurring in 44.6%. Best clinical response within the <i>RAS</i>MT CRC cohort was stable disease in seven patients (24%). Tumour MET super-expression (IHC H-score &gt; 180 and <i>MET</i> ISH + 3) was observed in 7 patients (24.1%), with <i>MET</i>-amplification only present in 1 of these patients. This patient discontinued treatment early during cycle 1 due to toxicity. Patients with high baseline&#xa0;<i>RAS</i>MT allele frequency had a significant shorter median overall survival compared with that seen for patients with low baseline&#xa0;<i>KRAS</i>MT allele frequency.</p> Conclusions <p>Combination binimetinib/crizotinib showed a poor tolerability with no objective responses observed in <i>RAS</i>MT advanced CRC patients.</p> <p>EudraCT-Number: 2014–000463 - 40 (20/06/2014: A Sequential Phase I study of MEK1/2 inhibitors PD- 0325901 or Binimetinib combined with cMET inhibitor Crizotinib in RAS Mutant and RAS Wild Type with aberrant c-MET).</p>

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A Phase Ia/b study of MEK1/2 inhibitor binimetinib with MET inhibitor crizotinib in patients with RAS mutant advanced colorectal cancer (MErCuRIC)

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  • 发表日期：

    2025年4月10日

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  • Francesca Aroldi,
  • Elena Elez,
  • Thierry André,
  • Geraldine Perkins,
  • Hans Prenen,
  • Vlad Popovici,
  • Peter Gallagher,
  • Jennifer Houlden,
  • Linda Collins,
  • Corran Roberts,
  • Christian Rolfo,
  • Federica Di Nicolantonio,
  • Margaret Grayson,
  • Ruth Boyd,
  • Karolien Bettens,
  • Jurgen Delfavero,
  • Victoria Coyle,
  • Mark Lawler,
  • Hajrah Khawaja,
  • Pierre Laurent-Puig,
  • Manuel Salto-Tellez,
  • Tim S. Maughan,
  • Josep Tabernero,
  • Richard Adams,
  • Robert Jones,
  • Bryan T. Hennessy,
  • Alberto Bardelli,
  • Marc Peeters,
  • Mark R. Middleton,
  • Richard H. Wilson,
  • Sandra Van Schaeybroeck

摘要

Background

Targeting RAS mutant (MT) colorectal cancer (CRC) remains a difficult challenge, mainly due to the pervasiveness of RAS/MEK-mediated feedback loops. Preclinical studies identified MET/STAT3 as an important mediator of resistance to KRAS-MEK1/2 blockade in RASMT CRC. This dose escalation/expansion study assessed safety and initial efficacy of the MEK1/2 inhibitor binimetinib with MET inhibitor crizotinib in RASMT advanced CRC patients.

Methods

In the dose escalation phase, patients with advanced solid tumours received binimetinib with crizotinib, using a rolling- 6 design to determine the maximum tolerable dose (MTD) and safety/tolerability. A subsequent dose expansion in RASMT CRC patients assessed treatment response. Blood samples for pharmacokinetics, MET biomarker and ctDNA analyses, and skin/tumour biopsies for pharmacodynamics, c-MET immunohistochemistry (IHC), MET in situ hybridisation (ISH) and MET DNA-ISH analyses were collected.

Results

Twenty patients were recruited in 3 cohorts in the dose escalation. The MTD was binimetinib 30 mg B.D, days 1–21 every 28 days, with crizotinib 250 mg O.D continuously. Dose-limiting toxicities included grade ≥ 3 transaminitis, creatinine phosphokinase increases and fatigue. Thirty-six RASMT metastatic CRC patients were enrolled in the dose expansion. Pharmacokinetic and pharmacodynamic parameters showed evidence of target engagement.

Across the entire study, the most frequent treatment-related adverse events (TR-AE) were rash (80.4%), fatigue (53.4%) and diarrhoea (51.8%) with grade ≥ 3 TR-AE occurring in 44.6%. Best clinical response within the RASMT CRC cohort was stable disease in seven patients (24%). Tumour MET super-expression (IHC H-score > 180 and MET ISH + 3) was observed in 7 patients (24.1%), with MET-amplification only present in 1 of these patients. This patient discontinued treatment early during cycle 1 due to toxicity. Patients with high baseline RASMT allele frequency had a significant shorter median overall survival compared with that seen for patients with low baseline KRASMT allele frequency.

Conclusions

Combination binimetinib/crizotinib showed a poor tolerability with no objective responses observed in RASMT advanced CRC patients.

EudraCT-Number: 2014–000463 - 40 (20/06/2014: A Sequential Phase I study of MEK1/2 inhibitors PD- 0325901 or Binimetinib combined with cMET inhibitor Crizotinib in RAS Mutant and RAS Wild Type with aberrant c-MET).