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. 2024 Nov 1;30(21):4943-4956.
doi: 10.1158/1078-0432.CCR-24-1834.

Understanding and Overcoming Resistance to Selective FGFR Inhibitors across FGFR2-Driven Malignancies

Francesco Facchinetti  1 , Yohann Loriot  1   2   3 , Floriane Brayé  1 , Damien Vasseur  4   5 , Rastislav Bahleda  2 , Ludovic Bigot  1 , Rémy Barbé  6 , Catline Nobre  1 , David Combarel  7   8 , Stefan Michiels  9   10 , Antoine Italiano  2   11 , Cristina Smolenschi  2   3 , Lambros Tselikas  12 , Jean-Yves Scoazec  13 , Santiago Ponce-Aix  1   3 , Benjamin Besse  1   3 , Fabrice André  1   3 , Ken A Olaussen  1 , Antoine Hollebecque  2   3 , Luc Friboulet  1
Affiliations

Understanding and Overcoming Resistance to Selective FGFR Inhibitors across FGFR2-Driven Malignancies

Francesco Facchinetti et al. Clin Cancer Res. .

Abstract

Purpose: Understanding resistance to selective FGFR inhibitors is crucial to improve the clinical outcomes of patients with FGFR2-driven malignancies.

Experimental design: We analyzed sequential ctDNA, ± whole-exome sequencing, or targeted next-generation sequencing on tissue biopsies from patients with tumors harboring activating FGFR2 alterations progressing on pan-FGFR-selective inhibitors, collected in the prospective UNLOCK program. FGFR2::BICC1 Ba/F3 and patient-derived xenograft models were used for functional studies.

Results: Thirty-six patients were included. In cholangiocarcinoma, at resistance to both reversible inhibitors (e.g., pemigatinib and erdafitinib) and the irreversible inhibitor futibatinib, polyclonal FGFR2 kinase domain mutations were frequent (14/27 patients). Tumors other than cholangiocarcinoma shared the same mutated FGFR2 residues, but polyclonality was rare (1/9 patients). At resistance to reversible inhibitors, 14 residues in the FGFR2 kinase domain were mutated-after futibatinib, only the molecular brake N550 and the gatekeeper V565. Off-target alterations in PI3K/mTOR and MAPK pathways were found in 11 patients, often together with on-target mutations. At progression to a first FGFR inhibitor, 12 patients received futibatinib or lirafugratinib (irreversible inhibitors), with variable clinical outcomes depending on previous resistance mechanisms. Two patients with TSC1 or PIK3CA mutations benefited from everolimus. In cell viability assays on Ba/F3 and in pharmacologic studies on patient-derived xenografts, irreversible inhibitors retained better activity against FGFR2 kinase domain mutations, with lirafugratinib active against the recalcitrant V565L/F/Y.

Conclusions: At progression to FGFR inhibitors, FGFR2-driven malignancies are characterized by high intra- and interpatient molecular heterogeneity, particularly in cholangiocarcinoma. Resistance to FGFR inhibitors can be overcome by sequential, molecularly oriented treatment strategies across FGFR2-driven tumors.

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Conflict of interest statement

F. Facchinetti reports personal fees from BeiGene outside the submitted work. Y. Loriot reports personal fees, nonfinancial support, and other support from Janssen during the conduct of the study, as well as personal fees, nonfinancial support, and other support from MSD, Pfizer, Merck KGaA, Astellas, Gilead, Bristol Myers Squibb, and Roche, nonfinancial support and other support from Incyte, other support from Exelixis, and personal fees and other support from Taiho outside the submitted work. S. Michiels reports personal fees from DSMB or scientific committee study membership for Kedrion, Biophytis, Servier, IQVIA, Yuhan, and Roche outside the submitted work. A. Italiano reports grants and personal fees from Bayer, IPSEN, Roche, and Bristol Myers Squibb and grants from MSD, Merck, AstraZeneca, and BeiGene outside the submitted work. C. Smolenschi reports personal fees from Servier and Merck, nonfinancial support from Astellas and Bristol Myers Squibb, and grants from Pierre Fabre outside the submitted work. L. Tselikas reports personal fees from Incyte during the conduct of the study, as well as personal fees from GE Healthcare, Quantum Surgical, and Boston Scientific outside the submitted work. B. Besse reports other support from AbbVie, BioNTech SE, Bristol Myers Squibb, Chugai Pharmaceutical, CureVac AG, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, PharmaMar, Regeneron, Sanofi-Aventis, Turning Point Therapeutics, Eli Lilly and Company, Ellipses Pharma Ltd, Genmab, Immunocore, Janssen, MSD, Ose Immunotherapeutics, Owkin, Taiho Oncology, AstraZeneca, BeiGene, GlaxoSmithKline, Roche-Genentech, Takeda, Hedera Dx, and Springer Healthcare Ltd during the conduct of the study. F. André reports grants from AstraZeneca, Guardant Health, Novartis, Owkin, Pfizer, Eli Lilly and Company, Roche, and Daiichi Sankyo, other support from Boston Pharmaceutics, Gilead, and Servier, and grants and other support from N-Power Medicine outside the submitted work. A. Hollebecque reports personal fees and nonfinancial support from Amgen, personal fees from Basilea, Bristol Myers Squibb, Servier, Relay Therapeutics, Taiho, MSD, Seagen, grants and personal fees from Incyte, and nonfinancial support from Pierre Fabre outside the submitted work, as well as reports being a PI of the TransThera (Tinengotinib) phase III trial. L. Friboulet reports grants from Relay Therapeutics during the conduct of the study, as well as grants from Nuvalent and Sanofi outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
Molecular findings at resistance to reversible FGFR inhibitors. A, Patients suffering from intrahepatic cholangiocarcinoma. B, Patients suffering from other tumor types. C, Molecular findings of patient ST1056, suffering from a lung adenocarcinoma harboring a FGFR2::TACC2 fusion, at acquired progression to erdafitinib. D, Clinicoradiologic and molecular evolution of patient ST238, suffering from a FGFR2 C383R–driven triple-negative breast cancer. The ctDNA findings are reported, and ctDNA findings are reported as VAF (%). BOR, best objective response; CR, complete response; CUP, cancer of unknown primary; Dera, derazantinib; Erda, erdafitinib; HGSOC, high-grade serous ovarian cancer; LUAD, lung adenocarcinoma; PD, progressive disease; Pemi, pemigatinib; PR, partial response; SD, stable disease; TBNC, triple-negative breast cancer.
Figure 2.
Figure 2.
Molecular findings at resistance to the irreversible FGFR inhibitor futibatinib. A, Patients suffering from intrahepatic cholangiocarcinoma. B, Molecular evolution of patient MR553, suffering from an intrahepatic cholangiocarcinoma harboring a FGFR2::ERC1 fusion. C, Clinicoradiologic and molecular evolution of patient MR332, suffering from an intrahepatic cholangiocarcinoma driven by a FGFR2::BICC1 fusion. D, Patients suffering from other tumor types. The ctDNA findings are reported as VAF (%). BOR, best objective response; HGSOC, high-grade serous ovarian cancer; PD, progressive disease; PDAC, pancreatic ductal adenocarcinoma; PR, partial response; SD, stable disease.
Figure 3.
Figure 3.
Global view on candidate resistance mechanisms to FGFR inhibitors across FGFR2-driven malignancies. A, Spectrum of FGFR2 kinase domain mutations detected across patients progressing to reversible inhibitors and futibatinib. B, Overview of the molecular alterations found at progression to reversible inhibitors in cholangiocarcinoma and other tumor types (top), and pooled across all cases. C, Overview of the molecular alterations found at progression to the irreversible inhibitor futibatinib in cholangiocarcinoma and other tumor types (top), and pooled across all cases.
Figure 4.
Figure 4.
Clinical and molecular evolution of patients with FGFR2-driven intrahepatic cholangiocarcinoma receiving sequential targeted treatments including futibatinib and everolimus. A, Three patients received a sequential treatment of futibatinib and everolimus, with the latter administered given the molecular finding of alterations in the PI3K/mTOR pathway. B, Molecular evolution of patient MR379, suffering from an FGFR2::BICC1–driven disease, with a concomitant pathogenic TSC1 frameshift mutation. C, Molecular evolution of patient MR422, suffering from a FGFR2-rearranged disease, with a concomitant PIK3CA H1047R mutation. D, Additional five patients received a sequence of reversible FGFR inhibitor followed by futibatinib. E, Clinicoradiologic and molecular evolution of patient MR174, suffering from a FGFR2 C383R–driven disease. The ctDNA findings are reported as VAF (%). BOR, best objective response; Chemo, chemotherapy; PD, progressive disease; PR, partial response; SD, stable disease.
Figure 5.
Figure 5.
Clinical and molecular evolution of patients receiving a first FGFR inhibitor followed by the irreversible, highly selective FGFR2 inhibitor lirafugratinib. A, Four patients harboring a FGFR2 fusion received lirafugratinib as a second FGFR inhibitor. None received intercurrent treatment between the FGFR inhibitors. B, Clinicoradiologic and molecular evolution of patient ST3470, with a cholangiorcarcinoma driven by FGFR2::BICC1 progressing on pemigatinib. C, Patient MR1271 had duodenal cancer progressing on futibatinib with emergence of FGFR2 V565L mutation that was cleared by lirafugratinib. The ctDNA findings are reported as VAF (%). BOR, best objective response; PD, progressive disease; PR, partial response; SD, stable disease.
Figure 6.
Figure 6.
In vitro and in vivo evaluation of the activity of selective FGFR inhibitors against FGFR2 kinase domain mutations. A, IC50 values of seven reversible FGFR inhibitors (and their average) against parental Ba/F3, FGFR2::BICC1 Ba/F3 (wild-type, WT), and 17 mutants. B, Graphical representation of the IC50 values of the two irreversible FGFR inhibitors futibatinib and lirafugratinib (and their average) against parental Ba/F3, FGFR2::BICC1 Ba/F3 (WT), and 17 mutants. We created two different cut-off thresholds, given the lower potency of zoligratinib, derazantinib, and rogaratinib against WT FGFR2::BICC1 Ba/F3. In A and B, IC50 values (nmol/L) are reported as means of ≥3 independent datasets. C, Tumor growth kinetics in PDX models established from patients with cholangiocarcinoma, exposed to four FGFR inhibitors. # MR332 PDX was established from the liver tissue biopsy harboring FGFR2 V565F, whereas the bone lesion harbored FGFR2 V565L (see Fig. 2C). q.d.: quaque die (i.e., daily).
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