Barcelona, Spain (UroToday.com) Erdafitinib is a pan-FGFR inhibitor which recently garnered accelerated US FDA approval for patients with locally advanced or metastatic platinum-refractory urothelial cancer harboring fusions in FGFR2 or FGFR3 or activating mutations in FGFR3. This approval was based upon the results of BLC2001, a single-arm phase II study of 99 patients in which erdafitinib achieved an impressive 40% confirmed objective response rate in this clinical setting.1 Given the absence of prospective randomized data on erdafitinib monotherapy, investigators conducted a retrospective matching adjusted indirect comparison of erdafitinib versus anti-PD-1 and anti-PD-L1 checkpoint blockade immunotherapy as well as second-line non-platinum chemotherapy in platinum-refractory disease.
On the basis of a systematic review of available literature from the year 1990 and on, investigators identified 9 applicable randomized clinical trials of a total of 6 types of systemic therapy: the PD-L1 antibody atezolizumab, the PD-1 antibody pembrolizumab, and various cytotoxic chemotherapies including docetaxel, vinflunine, mixed chemotherapy, and paclitaxel. While the numbers of patients derived from some trials are small, there appear to be no gross differences between the erdafitinib patients and those patients treated with immunotherapy or chemotherapy.
With respect to the overall response rate, erdafitinib was associated with a statistically significantly higher odds ratio of response after matching adjusted indirect comparisons across virtually every comparison – both immunotherapy and cytotoxic chemotherapy. In terms of survival, erdafitinib was also associated with a lower hazard ratio for overall survival across almost every comparison. However, the comparator data are largely derived from a period prior the widespread use of immune checkpoint blockade in advanced urothelial cancer and is known that many of the BLC2001 patients went on to receive immunotherapy in later lines of therapy. Nevertheless, progression-free survival hazard ratios also appear promising across all comparators, though do not rise to statistical significance.
Perhaps most relevant to the current treatment paradigm in metastatic urothelial cancer is the comparison with second-line checkpoint blockade immunotherapy. Within the limitations of this retrospective analysis, patients who received erdafitinib exhibit excellent overall survival relative to the observed survival with anti-PD-1 or anti-PD-L1 checkpoint blockade. Still, it must be emphasized that the erdafitinib patients were selected for tumors harboring genomic alterations in FGFR2 and FGFR3 and may, therefore, represent a distinct phenotype relative to the patient patients enrolled in the other studies. More information regarding subsequent lines of therapy would be very helpful in placing these data in context.
In the absence of direct comparisons, the investigators have performed a matching adjusted indirect comparison of erdafitinib versus checkpoint blockade immunotherapy and chemotherapy for the treatment of metastatic urothelial carcinoma in the second-line platinum-refractory setting. While these data appear very promising, longer-term follow up from BLC2001 is eagerly awaited. Future trials may investigate the optimal sequencing and combinations of erdafitinib with chemotherapy and immunotherapy for the treatment of FGFR-altered metastatic urothelial cancer.
Presented by: Yohann Loriot, MD, PhD, Medical Oncologist, Gustave Roussy Institute, Villejuif, France
Written by: Michael Lattanzi, MD, Medical Oncology Fellow, Memorial Sloan Kettering Cancer Center, Twitter: @MikeLattanzi at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct 2019 in Barcelona, Spain
1. Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, Fleming M, Rezazadeh A, Mellado B, Varlamov S, Joshi M. Erdafitinib in locally advanced or metastatic urothelial carcinoma. New England Journal of Medicine. 2019 Jul 25;381(4):338-48.