Summary 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 KRAS 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. Results In vitro, MEKi with futibatinib resulted in additive or synergistic anti-tumor activity in KRAS 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 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.
Rodon et al. (Mon,) studied this question.