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Phase 1 dose escalation study of FGFR4 inhibitor in combination with pembrolizumab in advanced solid tumors patients
Jianming Xu1, Jiuwei Cui2, Haiping Jiang3
1Oncology Department, Chinese PLA General Hospital, Beijing, China.
Objective:
Inhibition of fibroblast growth factor (FGF) 19-FGF Receptor 4 (FGFR4) signaling demonstrates potent anticancer activity. EVER4010001 is a highly selective FGFR4 inhibitor and pembrolizumab is approved for the treatment of several solid tumors. This study determined the maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), pharmacokinetics, safety, and preliminary efficacy of EVER4010001 plus pembrolizumab in patients with advanced solid tumors.
Methods:
This Phase 1, multicenter, open-label study enrolled 19 Asian-Chinese patients (57.9% male: median age 58 years) with advanced solid tumors. For "3+3" dose escalation, 3-6 patients received treatment at each dose level (EVER4010001 40, 60, 80, or 100 mg twice daily [BID] plus pembrolizumab 200 mg every 3 weeks).
Results:
At the data cutoff (August 12, 2021), no dose-limiting toxicities (DLTs) were reported at 40 mg-80 mg. At 100 mg, 2 (40.0%) patients had 3 DLTs within the 28-day DLT observation period after first administration. Median time to peak EVER4010001 concentration (Tmax ) was 0.55-1.03 hours. Mean terminal EVER4010001 half-life (T1/2 ) was 4.00-4.92 hours. The area under the concentration-time curve (AUC0-t ) and maximum observed concentration (Cmax ) ranged from 2370.87-5475.77 hour*ng/ml and 606.07-1348.86 ng/ml, respectively. The most common EVER4010001-related treatment-emergent adverse events were diarrhea (94.7%), increased aspartate aminotransferase (57.9%), and increased alanine aminotransferase (47.4%).
Conclusion:
Eighty milligrams BID was the MTD and RP2D for EVER4010001 plus pembrolizumab. Efficacy results were promising, and no new safety risks were reported, justifying the Phase 2 portion of this study.
Insights
The recommended Phase 2 dose for EVER4010001 plus pembrolizumab in advanced solid tumors is 80 mg twice daily. This combination showed promising efficacy and a manageable safety profile, supporting further clinical investigation.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Fibroblast growth factor (FGF) 19-FGF Receptor 4 (FGFR4) signaling is a target for anticancer therapies.
- EVER4010001 is a selective FGFR4 inhibitor, and pembrolizumab is an established immunotherapy for various solid tumors.
Purpose of the Study:
- To determine the maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), pharmacokinetics, safety, and preliminary efficacy of EVER4010001 combined with pembrolizumab.
- To evaluate this combination in patients with advanced solid tumors.
Main Methods:
- A Phase 1, multicenter, open-label study involving 19 Asian-Chinese patients with advanced solid tumors.
- Dose escalation using a "3+3" design with EVER4010001 (40, 60, 80, or 100 mg twice daily) and pembrolizumab (200 mg every 3 weeks).
Main Results:
- The MTD and RP2D were established at 80 mg twice daily for EVER4010001.
- No dose-limiting toxicities (DLTs) occurred at doses up to 80 mg.
- Common adverse events included diarrhea, increased aspartate aminotransferase, and increased alanine aminotransferase.
Conclusions:
- Eighty milligrams twice daily of EVER4010001 in combination with pembrolizumab is the recommended dose for Phase 2 studies.
- The combination demonstrated promising preliminary efficacy and no new safety concerns, warranting further investigation.
