Effects of genome-wide modifiers of response to next-generation FGFR inhibitors in solid tumors—An Indian multicentric study.

Abstract

e23422 Background: FGFR alterations are established actionable drivers in solid tumors, with particular clinical relevance in hepatobiliary malignancies. The advent of selective and next-generation FGFR inhibitors has expanded therapeutic options; however, durable responses remain inconsistent. Emerging evidence suggests that co-occurring genomic alterations significantly influence sensitivity and resistance to FGFR-directed therapies. We report a large Indian multicentric genomic analysis evaluating FGFR alterations, actionability, and resistance mechanisms with direct relevance to contemporary FGFR inhibitors. Methods: Comprehensive genome-wide next-generation sequencing data from 791 patients with solid tumors across multiple Indian centers were analyzed. Alterations in FGFR1–4 were characterized by type, oncogenicity, and clinical actionability. Known and putative resistance mechanisms—including FGFR gatekeeper mutations and co-alterations in bypass signaling pathways—were systematically evaluated. Results: A total of 848 FGFR alterations were identified in 791 patients. FGFR1 (35.5%), FGFR3 (34.6%), and FGFR2 (23.7%) were most frequently altered. Missense variants predominated (56.5%), followed by amplifications (26.9%), deletions (9.3%), and fusions (2.7%). Only 4.2% of FGFR alterations met Level 1 or 2 evidence for clinical actionability, emphasizing the need for careful variant interpretation when considering FGFR inhibitor therapy. FGFR amplifications are also targetable through panTKI agents which result in variable therapeutic response. Clinically relevant resistance mechanisms were identified in 41.8% of patients. FGFR gatekeeper mutations—including FGFR2 N549K, FGFR3 V555M, and FGFR4 V550M were observed in about 2% cases and may impact sensitivity even to newer-generation FGFR inhibitors. Additionally, frequent co-alterations were detected in key oncogenic pathways, notably PIK3CA (15.5%), KRAS (13.4%), PTEN (6.8%), and NRAS (2.5%), suggesting parallel MAPK and PI3K pathway activation as major contributors to intrinsic or early acquired resistance. Our data indicate that both drug-agnostic (pathway bypass) and drug-specific (FGFR gatekeeper) mechanisms coexist at conspicuous frequencies. Conclusions: In the era of next-generation FGFR inhibitors, FGFR alterations alone are insufficient to guide precision therapy. This Indian multicentric pan cancer real-world dataset demonstrates that a substantial proportion of FGFR-altered tumors harbor concurrent genomic events with potential to attenuate therapeutic benefit. Genome-wide profiling should be considered standard in FGFR-driven solid tumors to refine patient selection, anticipate resistance, and inform rational combination or sequencing strategies in precision oncology practice.