Abstract 4114: Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in FGFR2 fusion-positive cholangiocarcinoma patients

Abstract

Genetic alterations in the fibroblast growth factor receptor (FGFR) pathway are promising therapeutic targets in a broad range of cancers and occur in ~20% of ICCs. As seen with other targeted therapies, however, acquired resistance has limited the efficacy of selective FGFR kinase inhibitors such as BGJ398. In a phase II trial of patients with advanced refractory cholangiocarcinoma harboring an FGFR gene alteration, BGJ398 displayed an overall response rate of 22%, but the durability of response was short in some patients. We report the molecular basis of acquired resistance in 4 patients with advanced FGFR2-fusion positive ICC via integrative genomic characterization of cell-free circulating tumor DNA (cfDNA), the primary tumor, and metastases. Each patient enjoyed an initial response, but all subsequently progressed within 10 months. Serial analysis of cfDNA revealed multiple point mutations in the FGFR2 kinase domain at progression (Table 1). The gatekeeper mutation, p. V564F, sterically hinders drug binding and was identified in 3 of 4 patients. In patient #1, five different FGFR2 mutations were detected in the post-progression cfDNA but only one, p. K641R, was identified in the post-progression biopsy. A rapid autopsy was performed, and genomic characterization of 12 metastatic lesions revealed marked inter- and intra-lesional heterogeneity, with different FGFR2 mutations in individual resistant clones. Molecular modeling and in vitro studies indicated that each mutation lead to BGJ398 resistance that was surmountable by structurally distinct FGFR inhibitors. Thus, our report provides the first genetic evidence of clinical acquired resistance to FGFR inhibitor therapy in patients and informs future strategies for detecting mechanisms of resistance and promoting more durable remissions. Clinical and Molecular Data on Patients with Advanced Refractory CCA treated with BGJ398Patient IDSexAge at Diagnosis (years)FGFR2 Fusion partnerMaximum ResponseProgression Free Survival on BGJ398 (months)Overall Survival since Diagnosis (months)FGFR2 Mutations on cfDNA at progression1F47OPTN28%3.632V564F, N549H, K641R, E565A, L617V2F59ZMYMY450%5.631V564F, N549H/K, E565A, K659M3F69SORBS168%12.650K659M, K714R4M43BICC137%7.418V564F Note: This abstract was not presented at the meeting. Citation Format: Lipika Goyal, Supriya K. Saha, Leah Y. Liu, Giulia Siravegna, Ignaty Leshchiner, Leanne G. Ahronian, Jochen K. Lennerz, Phuong Vu, Benedetta Mussolin, Stephanie Reyes, Pascal Furet, A. John Iafrate, Gad Getz, Diana G. Porta, Ralph Tiedt, Alberto Bardelli, Dejan Juric, Ryan B. Corcoran, Nabeel Bardeesy, Andrew X. Zhu. Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in FGFR2 fusion-positive cholangiocarcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4114. doi:10.1158/1538-7445.AM2017-4114

Acquired Resistance to FGFR Inhibitor in Diffuse-Type Gastric Cancer through an AKT-Independent PKC-Mediated Phosphorylation of GSK3β

“…In a recent study, the acquisition of a gatekeeper mutation, p.V564F, in FGFR2 was found to confer resistance in three cholangiocarcinoma patients with acquired clinical resistance to BGJ398 (43). This study highlights the first clinical occurrence of the FGFR2 V564F gatekeeper mutation as a mechanism of acquired resistance, which had been previously investigated in preclinical studies (28,29).…”

The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients

“…As such, a portion of this database has been included in the Blood Profiling Atlas in Cancer, a National Cancer Moonshot Initiative (34). Improved detection of resistance mutations may facilitate enrollment in clinical trials and enable the development of more accurate biomarkers of response to therapy (21,35,36). Therefore cfDNA, and other minimally invasive techniques, address a real and unmet need, as it is essential to provide realtime tumor genotyping at the time of progression to guide subsequent therapeutic strategies.…”

“…Further, 24% of those resistance-harboring samples (91/381) had >1 alteration associated with resistance to the same therapy, suggesting independent evolution in distinct tumor lesions (20) or sequential treatment with distinct therapies targeted to the same gene. For example, one NSCLC patient had an EML4-ALK fusion (VAF of 7.1%) and ALK SNVs reported to confer resistance to crizotinib (L1196M, 2.5%), crizotinib/alectinib (I1171T, 0.1%), and crizotinib/ceritinib/alectinib (G1202R, 5% relative to the original driver alteration and many were missed by single-metastatic-site tissue biopsy but confirmed by repeat biopsy or biopsy of multiple metastases at autopsy (21,22,25).…”

The Irreversible Covalent Fibroblast Growth Factor Receptor Inhibitor PRN1371 Exhibits Sustained Inhibition of FGFR after Drug Clearance

“…Some of the challenges facing the clinical development of FGFR inhibitors include selecting the right patient that will benefit from an FGFR inhibitor which may vary with different tumor types, managing the toxicity profile of on-target hyperphosphatemia, predicting the mechanisms of acquired resistance that may emerge and designing a rational combination strategy to abrogate this. The first report of a genetic mechanism driving clinical acquired resistance to FGFR inhibition was recently published (15). In a phase II trial of BGJ398 in cholangiocarcinoma patients exhibiting FGFR2 fusions, the initial efficacy was striking but not durable, as driven by the emergence of FGFR2 resistance mutations, including a gatekeeper mutation, V564I.…”