Safety and Activity of Fibroblast Growth Factor Receptor Inhibitors in Advanced Malignancies: A Pooled Analysis of Early-Phase Clinical Trials

PURPOSE Aberrant signaling through the fibroblast growth factor receptor ( FGFR ) due to activating somatic alterations has been associated with multiple malignancies. FGFR inhibitors (FGFRi) with distinct profiles recently entered standard of care. This work summarizes the experience of a dedicated clinical trial unit with FGFRi developed in the last decade within the context of clinical trials. METHODS Demographic and clinical data were collected for patients enrolled in FGFR-targeting phase I to II trials conducted at Sarah Cannon Research Institute, United Kingdom between January 2012 and August 2023. RESULTS Fifty-four patients across seven trials were identified: 50% male; median age 55 years. An FGFR alteration was present in 81% of cases; rearrangements, amplifications, and mutations were present in 59%, 43%, and 9.1% of the cases, respectively, with coexisting alterations in 27%. The most frequent primary tumors were cholangiocarcinomas (31%), urothelial (15%), and colorectal (15%); 85% of the patients were FGFRi-naïve. The most common adverse events (AEs) were hyperphosphatemia (42%), dry mouth (35%), fatigue (24%), mucositis (24%), nail changes (22%), and palmar-plantar erythrodysesthesia (20%), with significant differences between pan-FGFRi and FGFR-2i. The rate of G3 AEs was 22%; no G4-5 events were observed. The median time on treatment was 3.5 months (0.2-72.8). Higher disease control rate was observed in the presence of any FGFR alteration, compared with all-comers (odds ratio [OR], 7; P = .0226). The objective response rate was 38%, 25%, and 25% in patients with gene rearrangements, amplification, and mutations, respectively. The median duration of response was 2.3 months (1.6-7.7). After a median follow-up time of 20 months (95% CI, 12.9 to 71.8), median progression-free survival (mPFS) was 3.2 months (95% CI, 1.9 to 4.6) and median overall survival was 13 months (95% CI, 6.4 to 19.6). PFS was significantly different by response, FGFR status, and tumor type. Patients who experienced a G2-3 AE were more likely to achieve a response (OR, 5.24; P = .0256). CONCLUSION FGFRi are effective treatment strategies for patients with advanced solid tumors harboring FGFR alterations, with manageable toxicities in most patients.