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 () 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 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 alteration, compared with all-comers (odds ratio [OR], 7; .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, status, and tumor type. Patients who experienced a G2-3 AE were more likely to achieve a response (OR, 5.24; = .0256).

CONCLUSION

FGFRi are effective treatment strategies for patients with advanced solid tumors harboring alterations, with manageable toxicities in most patients.