FGFR inhibition more effective in cases of fusion or mutation vs amplification

Retrospective analysis of phase I/II trials targeting solid tumours harbouring FGFR alterations presented at European Society for Medical Oncology Targeted Anticancer Therapies (ESMO TAT) Virtual Congress 2021 suggests that FGFR inhibition is more effective in tumours with FGFR fusions or mutations vs FGFR amplification.

A number of FGFR inhibitors are undergoing early- to late-phase development for a wide range of solid tumours. “To assess which FGFR alterations are associated with greatest clinical efficacy, we retrospectively analyzed data from patients treated with one of four pan-FGFR inhibitors [erdafitinib, infigratinib, futibatinib or pemigatinib] in phase I/II trials at our institution from February 2011 to June 2020. No cross-treatment comparisons were made due to population heterogeneity,” explained Dr Cédric Pobel of the Département d'Innovation Thérapeutique et d'Essais Précoces, Institut Gustave Roussy in Villejuif, France.

In the 92 patients with FGFR alterations included in the analysis, FGFR fusions (n=33) and mutations (n=37) occurred more frequently than FGFR amplification (n=22). Patients with FGFR amplification tended to be younger (median age, 43 years; p=0.02), while patients with FGFR mutations were older (median age, 60.5 years; p=0.03) compared with patients with other FGFR alterations. Most frequent tumour types were urothelial cancer (23.9 percent), cholangiocarcinoma (21.7 percent), breast cancer (20.7 percent) and central nervous system cancer (13 percent). [Ann Oncol 2021;32(Suppl 1):S14-S19]

“Patients with FGFR amplification were more likely to be women [92 percent; p=0.01] and most of the patients with FGFR amplification had breast cancer [68 percent],” reported Pobel. “Patients with FGFR amplification were also significantly more likely to have had >3 prior lines of treatment [77 percent; p=0.05].”

“The tumour type that demonstrated the best response to pan-FGFR inhibitor treatment was cholangiocarcinoma, with the greatest number of patients experiencing a partial response,” noted Pobel. “Patients with urothelial carcinoma also tended to have good responses in general, with the exception of a patient with a FGFR3-BAIAP2L1 fusion and a patient with a FGFR^Y373C mutation.”

“Patients with FGFR amplification were less responsive to treatment with FGFR inhibitors, while patients with FGFR fusions responded to treatment more frequently compared with the other groups [p<0.05 for both comparisons],” noted Pobel. Median progression-free survival (PFS) was 6.2 months in patients with FGFR fusion treated with a pan-FGFR inhibitor, compared with 2.77 months in patients with a FGFR mutation and 2.23 months in patients with FGFR amplification who received pan-FGFR inhibitor treatment.

The unadjusted hazard ratios for PFS were 2.64 (95 percent confidence interval [CI], 1.55 to 4.51; p<0.01) for patients with FGFR amplification vs those with other alterations and 0.61 (95 percent CI, 0.38 to 0.98; p=0.04) for patients with FGFR fusion vs other alterations. “The differences were found to be significant in the analyses adjusted for sex, cancer types, individual FGFR inhibitors, and previous treatment lines,” added Pobel.

The best response in the FGFR amplification, fusion, and mutation cohorts was partial response, which was observed in one (4.5 percent), 13 (39.4 percent), and 10 (27 percent) patients, respectively (p=0.03). In respective cohorts, stable disease was achieved by 14 (63.6 percent), 12 (36.4 percent), and 17 (45.9 percent) patients, whereas seven (31.8 percent), eight (24.2 percent), and 10 (27.0 percent) patients experienced disease progression.