Abstract LB-092: TAS120, a covalently-binding FGFR inhibitor (FGFRi), overcomes resistance to BGJ398 in patients with FGFR2 fusion positive cholangiocarcinoma

Abstract

Fibroblast growth factor receptor (FGFR) inhibitors are currently in clinical trials in a variety of cancers including lung, breast, urothelial, gastric, and uterine cancers and intrahepatic cholangiocarcinoma (ICC). The selective and potent ATP-competitive FGFRi BGJ398 has shown a 19% response rate in advanced refractory FGFR2-fusion positive ICC, but acquired resistance rapidly limits its efficacy. We previously reported the emergence of polyclonal FGFR2 kinase domain mutations in patients with ICC progressing on BGJ398. TAS120, a covalently-binding FGFRi, demonstrates in vitro activity against wildtype FGFR2 and multiple FGFR2 mutations shown to confer resistance to BGJ398. Here we report the ability of TAS120 to overcome resistance to BGJ398 in the clinic. Three patients with FGFR2 fusion positive ICC treated on a phase II trial of BGJ398 experienced a partial response, progressed, and 2 of 3 subsequently had a PR on a phase I trial of TAS120 (NCT02052778) and one had stable disease for 7.3 months. Baseline and post-progression plasma samples and tissue biopsies were obtained on BGJ398, and sequencing results from post-progression cell-free DNA (Guardant360) and tissue (whole exome sequencing or FoundationOne) were compared to results from baseline samples (see Table 1). In Patient #1, three of 5 mutations detected upon progression on BGJ398 (i.e. FGFR2 K659M, E565A, and N549H) became undetectable on Guardant360 during treatment with TAS120, as did the only 2 FGFR2 mutations – K659M and K714R - that emerged on BGJ398 in Patient #2. In vitro studies validated TAS-120's ability to suppress the activity of FGFR2-fusion alleles carrying these secondary FGFR2 mutations. In summary, TAS120 demonstrates preliminary activity in overcoming resistance to prior FGFRi, and it is currently under investigation in a clinical trial in this setting. Table 1: Clinical benefit and emergence of FGFR resistance on BGJ398 with subsequent clinical benefit on TAS120IDFGFR2 Fusion detected in tissueBOR on BGJ398PFS on BGJ398New FGFR2 Mutations Identified in post-BGJ398 ctDNANew FGFR2 Mutations Identified on post-BGJ398 biopsyIntervening therapies and Duration between last day of BGJ398 and first day of TAS120BOR on TAS120Time on TAS1201FGFR2-ZMYM4-49.9%5.6 monthsV564F N549K/H E565A K659MV564F K659MNone, 48 days+8.3%7.3 months2FGFR2-SORBS1-68.2%12.4 monthsK659M K714RNoneNone, 36 days-76.7%15.2+ months, ongoing3FGFR2-NRAP-40.0%7.1 monthsNot performedNot performedPembrolizumab, FOLFOX, 225 days-45.9%8.3+ months, ongoingBOR=Best Overall Response; PFS = Progression Free Survival Citation Format: Lipika Goyal, Leah Y. Liu, Jochen K. Lennerz, James J. Harding, Jerry Huang, Robert Winkler, Hirai Hiroshi, David T. Ting, Dejan Juric, Ryan B. Corcoran, Nabeel El-Bardeesy, Andrew X. Zhu. TAS120, a covalently-binding FGFR inhibitor (FGFRi), overcomes resistance to BGJ398 in patients with FGFR2 fusion positive cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-092.

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“…Futibatinib (TAS-120), a third-generation irreversible pan-FGFR inhibitor, has since been shown to be active against multiple mutations conferring resistance to infigratinib on assessment of serial tumour and liquid biopsies and patient-derived ICC cells [69]. As futibatinib has been shown to provide patients with disease control in an early-phase trial [70], phase II evaluation is underway (FOENIX 101, NCT02052778). It has also been proposed that FGFR2-independent mechanisms, such as phosphatase and tensin homolog (PTEN) loss-of-function mutations, may contribute to secondary resistance and provide a rationale for dual inhibition of FGFR2 and PI3K/PTEN signalling pathways [68].…”

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“…In a phase Ib/IIa study, a combination of 1 with either anastrozole or letrozole showed anti-tumor activity in advanced estrogen receptor-positive breast cancers resistant to aromatase inhibitors . In addition, a selective covalent FGFR inhibitor, 7 , has shown a tolerable safety profile and antitumor activity in patients with CCA harboring FGFR2 gene fusions and CCA patients with FGFR2 gene fusion resistance prior to the FGFR inhibitor 2 . ,, A phase II study of 7 with patients with intrahepatic CCA harboring FGFR2 gene fusions has been initiated. Despite the advances made in FGFR inhibitors, the road to clinical treatment of various diseases related to alterations of FGFR remains long and challenging.…”