In a most comprehensive genomic analysis of tissue biopsies and circulating tumour DNA (ctDNA) within the context of an FGFR inhibitor trial, by detailing the detection rates of FGFR1-3 alterations, exploring the molecular underpinnings of treatment responses, and characterising the mechanisms of resistance to futibatinib, findings from the phase I/II FOENIX study offer insights that enhance the understanding of FGFR biology in cholangiocarcinoma and other FGFR-altered tumours.
Furthermore, a multimodal analysis led to a model characterising the biology of acquired resistance, informing the rational design of next generation FGFR inhibitors. Taken together, two manuscripts published by Dr. Lipika Goyal of the Department of Medicine, Division of Oncology, Stanford Cancer Center in Palo Alto, CA, US and colleagues in December 2024 in the Annals of Oncology, add to the growing knowledge of targeting FGFR-altered cancers.
Approximately 7% of cancers harbour FGFR aberrations, underscoring the potential broader application of FGFR inhibitors in oncology. However, heterogeneity in detection, sensitivity, and intrinsic oncogenic potential of different FGFR alterations contributes to uneven utilisation of FGFR targeted agents and leads to variable responses. Moreover, acquired resistance stands as a major barrier to long-term efficacy of FGFR inhibitors.
Distinct binding site and mode of binding render futibatinib less susceptible to many resistance mutations compared with reversible ATP-competitive inhibitors in preclinical studies. In the phase II registrational FOENIX-CCA2 study, futibatinib demonstrated an overall response rate of 42% with a median duration of response of 9.7 months among patients with advanced intrahepatic cholangiocarcinoma harbouring FGFR2 fusions/rearrangements.
Gaining deeper insights into the detection of FGFR alterations through genomic profiling, as well as understanding the mechanisms of primary and secondary resistance to FGFR inhibitors, is crucial for refining the clinical deployment of these targeted agents. In a comprehensive translational analysis conducted as part of the phase I/II FOENIX study, the researchers investigated the molecular underpinnings of response and resistance to futibatinib by analyzing genomic data from tissue biopsies and ctDNA of 226 patients treated with futibatinib across various advanced solid tumours, including cholangiocarcinoma.
Eligible patients included those with ctDNA samples collected per protocol at baseline and/or progression on futibatinib in the phase Ib portion of the study for FGF/FGFR-altered advanced solid tumours or the phase II portion of the study for FGFR2 fusion/rearrangement-positive cholangiocarcinoma. Assessments included analytical concordance between tumour and ctDNA analyses for detection of FGFR alterations, association of ctDNA-detected co-occurring genomic alterations with response to futibatinib, and determination of patterns of acquired resistance following progression on futibatinib.
Among 300 patients treated with futibatinib, 226 were eligible for this analysis, including 139 (62%) with cholangiocarcinoma. Among patients with known FGFR2 fusions/rearrangements, FGFR1 fusions, FGFR3 fusions, or FGFR2 amplifications per tissue analysis, detection rates in ctDNA for these aberrations were 84%, 0%, 11%, and 59%, respectively.
Objective response rates on futibatinib were not significantly different between patients with TP53 altered versus unaltered solid tumours; progression-free survival was reduced in patients with CDKN2B altered versus unaltered cholangiocarcinoma (median 4.8 versus 11.0 months; p = 0.03). Acquired resistance to futibatinib was frequently polyclonal and driven by an array of mutations within the relevant FGFR kinase domain, predominantly V565L, V565F, and N550K variants.
The authors concluded that in this largest and most systematic analysis of acquired resistance to an FGFR inhibitor from prospective clinical trials, emergence of secondary FGFR2 kinase domain mutations was observed in most patients receiving clinical benefit to futibatinib. ctDNA analysis showed clinically relevant potential as a non-invasive method for assessing genomic profiles, identifying patients who may benefit from FGFR inhibitor treatment, and exploring acquired resistance mechanisms.
In another manuscript published also in the Annals of Oncology, Dr. Lipika Goyal and colleagues presented a comprehensive analysis of primary data from patients with FGFR-altered cholangiocarcinoma treated with an FGFR inhibitor at one of 10 cancer centres. The study employed a multimodal approach to investigating resistance, leveraging six interconnected strategies: cell-free DNA, tissue biopsy, rapid autopsy, statistical genomics, in vitro and in vivo studies, and pharmacologic analyses.
The researchers characterised the diversity, clonality, frequency, and mechanisms of acquired resistance to FGFR inhibitors in patients with FGFR-altered cholangiocarcinoma. Clinical samples were analyzed longitudinally as part of routine care. Among 138 patients evaluated, 77 met eligibility, yielding a total of 486 clinical samples. Patients with clinical benefit exhibited a significantly higher rate of FGFR2 kinase domain mutations compared to those without clinical benefit (65% versus 10%, p < 0.0001). A total of 26 distinct FGFR2 kinase domain mutations were identified, with 63% of patients harbouring multiple.
While IC50 assessments indicated strong potency of pan-FGFR inhibitors against common resistance mutations, pharmacokinetic studies revealed that low clinically achievable drug concentrations may underly polyclonal resistance. Molecular brake and gatekeeper mutations predominated, with 94% of patients with FGFR2 mutations exhibiting one or both, whereas mutations at the cysteine residue targeted by covalent inhibitors were rare. Statistical genomics and functional studies demonstrated that mutation frequencies were driven by their combined effects on drug binding and kinase activity rather than intrinsic mutational processes.
The authors commented that FGFR inhibitors should be small, high-affinity, and selective for specific FGFR family members. Tinengotinib, a novel small molecule inhibitor with these characteristics, exhibited preclinical and clinical activity against key resistance mutations. This integrative framework allowed to bridge clinical observations with preclinical insights, illuminating the essential characteristics of next generation inhibitors.
The researchers presented the preclinical rationale for the development of tinengotinib, the novel small molecule inhibitor currently being evaluated in the first registrational phase III trial of an inhibitor in the post-FGFR inhibitor setting for cholangiocarcinoma. The proof-of-concept of tinengotinib suggests that this model can effectively inform and guide drug development.
In an accompanied editorial article, Dr C. Benedikt Westphalen of the Comprehensive Cancer Center Munich & Department of Medicine III, University Hospital, LMU Munich in Munich, Germany and German Cancer Consortium (DKTK), partner site Munich, German Cancer Research Center (DKFZ) in Heidelberg, Germany wrote that this incredibly rich dataset was compiled in the setting of academic collaboration demonstrating a critical role for academia to contribute to the understanding of response and resistance to approved targeted therapies and driving the implementation and further evolution of precision cancer medicine.
Translational work in the FOENIX study was supported by Taiho Oncology, Inc., and Taiho Pharmaceutical Co., Ltd.
References
- Goyal L, DiToro D, Hollebecque A, et al. Genomic correlates of response and resistance to the irreversible FGFR1-4 inhibitor futibatinib based on biopsy and circulating tumor DNA profiling. Annals of Oncology; Published online 11 December 2024. DOI: https://doi.org/10.1016/j.annonc.2024.11.017
- Goyal L, DiToro D, Facchinetti F, at al. A Model for Decoding Resistance in Precision Oncology: Acquired Resistance to FGFR inhibitors in Cholangiocarcinoma. Annals of Oncology; Published online 18 December 2024. DOI: https://doi.org/10.1016/j.annonc.2024.12.011
- Westphalen CB. Unveiling Targets and Resistance in FGFR-Altered Cancers. Annals of Oncology; Published online 10 January 2025. DOI: https://doi.org/10.1016/j.annonc.2025.01.002