Fibroblast growth factor receptors (FGFRs) are crucial in regulating cell processes, and their alterations drive oncogenesis across various tumor types. FGFR alterations, including fusions, rearrangements, and mutations, are found in up to 7% of cancers. Selective FGFR inhibitors have gained regulatory approval for specific cancer types like urothelial cancer, cholangiocarcinoma, and myeloid/lymphoid neoplasms. However, evidence suggests other FGFR alterations and tumor types might respond to FGFR inhibition. Early-phase studies, including the FIGHT-101 trial of pemigatinib, showed sensitivity to FGFR inhibition in diverse histologies. The FIGHT-207 basket study aimed to evaluate pemigatinib in patients with previously treated solid tumors, exploring the sensitivity of various FGFR alterations, the impact of co-alterations on response, and resistance mechanisms. This tumor-agnostic approach addressed crucial questions regarding the clinical utility of FGFR inhibition beyond established indications. The study leveraged preclinical and phase 1 data to investigate the therapeutic importance of FGFR alterations in multiple tumor types and to analyze biological correlates of resistance using tissue and ctDNA samples.

The literature extensively documents the role of FGFR alterations in cancer development. Babina & Turner (2017) reviewed advances and challenges in targeting FGFR signaling, highlighting its importance as a therapeutic target. Studies such as Murugesan et al. (2022) and Helsten et al. (2016) have characterized the pan-tumor landscape of FGFR genomic alterations, showing their prevalence across various cancer types. Xie et al. (2020) further elaborated on FGF/FGFR signaling in health and disease. The approval of FGFR inhibitors like erdafitinib (Janssen Biotech, 2022), pemigatinib (Incyte, 2022), and futibatinib (Taiho Oncology, 2023) for specific cancers demonstrated the clinical relevance of targeting FGFR. However, the spectrum of responsive FGFR alterations and tumor types remained incompletely understood, prompting the need for broader, basket-trial approaches like FIGHT-207 and other similar studies (Pant et al., 2023; Meric-Bernstam et al., 2022; Schram et al., 2021). Preclinical and early clinical data (Liu et al., 2020; Sootome et al., 2020; Karkera et al., 2017; Subbiah et al., 2023; Nogova et al., 2017) supported the exploration of pemigatinib’s efficacy across a wider range of FGFR-altered cancers.

FIGHT-207 was an open-label, single-arm, multicenter phase 2 basket trial enrolling 111 patients with previously treated unresectable or metastatic solid tumors harboring FGFR1-FGFR3 alterations. Patients were stratified into three cohorts based on the type of FGFR alteration: Cohort A (fusions/rearrangements, n=49), Cohort B (activating non-kinase domain SNVs, n=32), and Cohort C (kinase domain mutations/VUS, n=26). All patients received pemigatinib 13.5 mg orally once daily. The primary endpoint was objective response rate (ORR) in cohorts A and B, assessed by an independent review committee (IRC) using RECIST v1.1 or RANO criteria. Secondary endpoints included progression-free survival (PFS), duration of response (DOR), overall survival (OS), and safety. Exploratory endpoints included ORR in cohort C and genomic analysis of baseline and on-treatment samples. The study adhered to ICH GCP, the Declaration of Helsinki, and local regulations. Statistical analyses included the Clopper-Pearson method for ORR, Kaplan-Meier method for PFS, DOR, and OS, and Fisher's exact test and log-rank test for co-alteration analysis. Translational analyses used next-generation sequencing (NGS) of tissue and plasma ctDNA samples to identify markers of response and resistance.

The study demonstrated varying ORRs across the three cohorts: Cohort A (26.5%), Cohort B (9.4%), and Cohort C (3.8%). Objective responses were observed across multiple tumor histologies, including those without approved FGFR inhibitors. Median PFS was 4.5 months (Cohort A) and 3.7 months (Cohort B); median DOR was 7.8 months (Cohort A) and 6.9 months (Cohort B); median OS was 17.5 months (Cohort A) and 11.4 months (Cohort B). The most common adverse events were hyperphosphatemia (84%) and stomatitis (53%). Genomic analysis revealed that TP53 co-mutations were associated with a lack of response, while BAP1 alterations correlated with higher response rates. Acquired resistance mechanisms frequently involved mutations in FGFR gatekeeper and molecular brake residues. Analysis of combined data from FIGHT-207 and previous pemigatinib studies (FIGHT-101, FIGHT-201, FIGHT-202) strengthened the association between BAP1 and TP53 alterations and response to pemigatinib, though limitations in study design were acknowledged.

FIGHT-207 demonstrated pemigatinib's antitumor activity in various cancers beyond those with established FGFR inhibitor indications. The findings confirm the sensitivity of FGFR2 fusions in cholangiocarcinoma and highlight the potential benefit of pemigatinib for specific FGFR2 SNVs. The study provides insights into the response of previously unvalidated FGFR mutations and the role of co-alterations in primary and acquired resistance. The identification of TP53 mutations as a negative prognostic factor and BAP1 mutations as a positive prognostic factor are significant. The study also identified common mechanisms of acquired resistance across multiple histologies, primarily involving gatekeeper and molecular brake mutations in FGFRs. These results are consistent with observations in previous studies on cholangiocarcinoma and urothelial cancer and demonstrate the importance of considering co-alterations in predicting treatment outcomes. The compilation of data across multiple FGFR inhibitor trials expands our understanding of actionable FGFR alterations and offers guidance for future clinical development.

The FIGHT-207 study expanded the understanding of pemigatinib’s clinical activity in FGFR-altered solid tumors, revealing its efficacy across multiple histologies and previously untested FGFR alterations. The study identified new therapeutic opportunities and clarified mechanisms of acquired resistance. Further research is needed to refine patient selection strategies and develop more effective treatment approaches for patients with FGFR-driven cancers.

The basket study design inherent limitations due to tumor heterogeneity, some cohorts were underpowered due to early termination of the study, and the possibility that heavily pretreated patients had more co-alterations impacting response. The study was not designed to determine if identified co-alterations were predictive of response. The interpretation of co-alteration associations should consider the possibility that these might be prognostic rather than predictive.