Article Impact Level: HIGH Data Quality: STRONG Summary of JAMA Oncology. https://doi.org/10.1001/jamaoncol.2024.3900 Dr. Randy F. Sweis et al.
Points
- This phase 1b nonrandomized trial evaluated the safety and efficacy of combining rogaratinib, a pan-FGFR inhibitor, with atezolizumab, a PD-L1 inhibitor, in patients with FGFR mRNA-positive urothelial carcinoma (UC).
- Rogaratinib 600 mg twice daily with atezolizumab 1200 mg every 21 days was determined to be tolerable and set as the recommended phase 2 dose (RP2D). The most common treatment-emergent adverse events (TEAEs) were diarrhea, hyperphosphatemia, and fatigue.
- The overall response rate at the RP2D was 53.8%, with 15% of patients achieving a complete response and 73% experiencing grade 3 or higher TEAEs.
- Notably, 86% of responders did not have FGFR3 gene alterations, and 79% had low PD-L1 expression, suggesting efficacy beyond traditional biomarkers.
- The study concluded that FGFR mRNA overexpression could broaden the therapeutic application of FGFR inhibitors in advanced UC, warranting further research on this combination therapy.
Summary
This phase 1b nonrandomized clinical trial aimed to evaluate the safety and preliminary efficacy of combining rogaratinib, an oral pan-fibroblast growth factor receptor (FGFR) inhibitor, with atezolizumab, a programmed cell death ligand 1 (PD-L1) inhibitor, in patients with locally advanced or metastatic urothelial carcinoma (UC) who had FGFR1/3 messenger RNA (mRNA) overexpression. The study was conducted in 30 centers across Asia, Europe, and North America between May 2018 and July 2021. Eligible patients were ineligible for cisplatin-based chemotherapy. A total of 153 patients were screened, and 37 were enrolled and treated, with a median age of 75. The primary objectives included determining the drug combination’s safety, tolerability and recommended phase 2 dose (RP2D).
The results demonstrated that rogaratinib 600 mg twice daily, combined with atezolizumab 1200 mg every 21 days, was tolerable and identified as RP2D. The most common treatment-emergent adverse events (TEAEs) included diarrhea (62%), hyperphosphatemia (51%), and fatigue (41%), with 73% of patients experiencing grade 3 or higher TEAEs. Four grade 5 adverse events were reported but were deemed unrelated to the treatment. The overall response rate at the RP2D was 53.8%, including 15% of patients achieving a complete response. Notably, 86% of responders did not have FGFR3 gene alterations, and 79% had low PD-L1 expression, suggesting a broader potential for efficacy beyond traditional biomarkers.
In conclusion, the combination of rogaratinib and atezolizumab showed a manageable safety profile with promising efficacy in patients with FGFR mRNA-positive UC, particularly those with low PD-L1 expression. The findings indicate that FGFR mRNA overexpression, rather than FGFR3 gene alterations alone, could expand the therapeutic benefit of FGFR inhibitors in advanced UC, supporting further investigation into this combination for broader patient populations.
Link to the article: https://jamanetwork.com/journals/jamaoncology/fullarticle/2823971
References Sweis, R. F., Gajate, P., Morales-Barrera, R., Lee, J.-L., Necchi, A., de Braud, F., Penel, N., Grünwald, V., Maruzzo, M., Meran, J., Ishida, T. C., Bao, W., Zhou, Y., Ellinghaus, P., & Rosenberg, J. E. (2024). Rogaratinib plus atezolizumab in cisplatin-ineligible patients with fgfr rna-overexpressing urothelial cancer: The fort-2 phase 1b nonrandomized clinical trial. JAMA Oncology. https://doi.org/10.1001/jamaoncol.2024.3900
