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Introduction <p><i>KRAS-</i>mutant NSCLC resistance to MEK inhibitors (MEKi) is related to compensatory upregulation of fibroblast growth factor receptor (FGFR) signaling. Futibatinib is a potent, covalent FGFR1–4 inhibitor approved for locally advanced/metastatic cholangiocarcinoma with <i>FGFR2</i> fusions. We conducted a bench-to-bedside study evaluating futibatinib plus the MEKi binimetinib preclinically, followed by a Phase Ib trial of patients with advanced cancer.</p> Methods <p>The effect of futibatinib ± MEKi on cell signaling and proliferation of <i>KRAS</i>mt NSCLC lines (A549, LU99) were assessed in vitro. In a Phase Ib study, patients with advanced cancer who had exhausted standard therapies received futibatinib QD plus binimetinib BID orally following a “3 + 3” dose-escalation design. Primary objective was to establish the recommended Phase 2 dose (RP2D) based on safety. Secondary endpoints included pharmacokinetics and anti-tumor activity.</p> Results <p>In vitro, MEKi with futibatinib resulted in additive or synergistic anti-tumor activity in <i>KRAS</i>mt NSCLC lines. Twenty-three patients received futibatinib with binimetinib at 4 dose levels. The most prevalent adverse events were reversible retinopathies in 20 patients, including 2 DLTs and limiting dose escalation beyond futibatinib 16&#xa0;mg QD plus binimetinib 15&#xa0;mg BID (MTD). There were no relevant drug-drug interactions between binimetinib and futibatinib. One patient harboring an <i>FGFR2</i> fusion had a partial response. No RP2D could be defined as the MTD was below active dose levels of binimetinib.</p> Conclusion <p>Despite additive anti-tumor activity for FGFR and MEK inhibition in KRASmt NSCLC lines, the trial was stopped after dose escalation, as no RP2D was identified for futibatinib/binimetinib due to reversible retinopathies.</p> <p>Trial register number.</p> <p>NCT04965818.</p> <p>Trial registration date.</p> <p>20-September-2021.</p>

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Preclinical and clinical evaluation of futibatinib in combination with binimetinib in patients with advanced cancer

  • 期刊论文

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  • 发表日期：

    2026年5月18日

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  • Jordi Rodon,
  • Bert O’Neil,
  • Christopher Lim,
  • Natraj R. Ammakkanavar,
  • Carlos Torrado,
  • Kazuaki Matsuoka,
  • Hiroshi Hirai,
  • Akihiro Miura,
  • Bailey Anderson,
  • Leah Jin,
  • Nanae Hangai,
  • Amanda Long,
  • Volker Wacheck,
  • Lee Rosen

摘要

Introduction

KRAS-mutant NSCLC resistance to MEK inhibitors (MEKi) is related to compensatory upregulation of fibroblast growth factor receptor (FGFR) signaling. Futibatinib is a potent, covalent FGFR1–4 inhibitor approved for locally advanced/metastatic cholangiocarcinoma with FGFR2 fusions. We conducted a bench-to-bedside study evaluating futibatinib plus the MEKi binimetinib preclinically, followed by a Phase Ib trial of patients with advanced cancer.

Methods

The effect of futibatinib ± MEKi on cell signaling and proliferation of KRASmt NSCLC lines (A549, LU99) were assessed in vitro. In a Phase Ib study, patients with advanced cancer who had exhausted standard therapies received futibatinib QD plus binimetinib BID orally following a “3 + 3” dose-escalation design. Primary objective was to establish the recommended Phase 2 dose (RP2D) based on safety. Secondary endpoints included pharmacokinetics and anti-tumor activity.

Results

In vitro, MEKi with futibatinib resulted in additive or synergistic anti-tumor activity in KRASmt NSCLC lines. Twenty-three patients received futibatinib with binimetinib at 4 dose levels. The most prevalent adverse events were reversible retinopathies in 20 patients, including 2 DLTs and limiting dose escalation beyond futibatinib 16 mg QD plus binimetinib 15 mg BID (MTD). There were no relevant drug-drug interactions between binimetinib and futibatinib. One patient harboring an FGFR2 fusion had a partial response. No RP2D could be defined as the MTD was below active dose levels of binimetinib.

Conclusion

Despite additive anti-tumor activity for FGFR and MEK inhibition in KRASmt NSCLC lines, the trial was stopped after dose escalation, as no RP2D was identified for futibatinib/binimetinib due to reversible retinopathies.

Trial register number.

NCT04965818.

Trial registration date.

20-September-2021.