Retrospective exposure-response analysis data support 20 mg once daily as the starting dose for futibatinib, whereas exposure-safety analysis for futibatinib demonstrated a significant relationship between hyperphosphatemia and futibatinib exposure.
Results of a retrospective integrated exposure-response analysis of futibatinib safety and efficacy were reported at the 2021 European Society for Medical Oncology Annual Congress.
In this retrospective study, exposure-safety analysis included patients with advanced solid tumors receiving futibatinib once daily (4-24 mg) or 3 times weekly (8-200 mg) in a global phase 1/2 study (ClinicalTrials.gov Identifier: NCT02052778) or a Japanese phase 1 study (JapicCTI-142552) and for whom individual-predicted exposure metrics were generated with a nonlinear mixed-effects population pharmacokinetic model. The efficacy exposure-response analysis included patients with intrahepatic cholangiocarcinoma (CCA) enrolled in the phase 2 study who were treated with futibatinib 20 mg once daily. Exposure-response relationships between efficacy end points (including objective response rate [ORR] and duration of response) or safety end points (including adverse events of special interest) and population pharmacokinetic model-based estimated exposure metrics were determined. The data cutoff date was October 1, 2020.
At data cutoff, a total of 318 patients were included in the exposure-safety analysis. The median participant age was 59 years, 40% had CCA, 42% harbored FGFR fusions, and 46% had other FGFR alterations. Exposure-safety analyses showed a significant relationship between hyperphosphatemia and futibatinib exposure. Among patients who received once-daily dosing (n = 247), a significant correlation with grade ≥3 hyperphosphatemia was observed, with model predictions indicating a steep increase of grade ≥3 hyperphosphatemia at the 24-mg once-daily dose. In multivariate analyses, higher baseline serum phosphate was an independent predictor of hyperphosphatemia, and an increase from baseline correlated with futibatinib exposure. Nail toxicities (once-daily dose only) and retinal toxicities (3-times-weekly dose only) also showed statistically significant exposure-response relationships. Baseline body weight, age, and race had no influence on exposure-safety relationships.
A total of 98 patients were included in the exposure-efficacy analysis. The median participant age was 58 years, and all patients had CCA with FGFR fusions. There were no statistically significant relationships between futibatinib exposure and any efficacy parameter, although a trend toward higher ORR was observed with increasing steady-state futibatinib trough concentrations. The model-predicted ORR was 52% in patients at the highest exposure quartile.
Although the results of the exposure-response analysis support the use of 20 mg once daily as the starting dose for futibatinib, the exposure-safety analysis with futibatinib once-daily dosing demonstrated a significant relationship between hyperphosphatemia and futibatinib exposure.
Source: Hollebecque A, Bridgewater JA, Meric-Bernstam F, et al. Assessment of futibatinib exposure–response (E–R) relationships in patients with advanced solid tumors, including cholangiocarcinoma (CCA). Ann Oncol. 2021;32(suppl_5):S378-S379.
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