Comprehensive genomic profiling and clinical outcomes in patients (pts) with fibroblast growth factor receptor rearrangement-positive (FGFR2+) cholangiocarcinoma (CCA) treated with pemigatinib in the fight-202 trial

Background Fight-202 is a phase 2 study (NCT02924376) of pemigatinib (INCB054828), a selective, potent, oral inhibitor of FGFR1, 2, and 3 in pts with advanced CCA. Interim results from the first 47 FGFR2+ CCA pts with ≥8 months (mo) of follow-up demonstrated an objective response rate (ORR) of 40.4%, disease control rate (DCR) of 85%, median progression-free survival (mPFS) of 9.2 mo, and median overall survival (mOS) of 15.8 mo, based on independent central review. Here we report the frequency of FGFR2 rearrangement partners and co-occurring alterations and their impact on clinical outcomes. Methods Comprehensive genomic profiling was performed in all pts prescreened and/or enrolled in fight-202 using FoundationOne. Clinical data were reported previously. Results Among 118 FGFR2+ pts identified, 54 unique FGFR2 rearrangement partners were observed, of which 74.1% (n = 40) were unique to a single patient. BICC1 was the most frequent FGFR2 rearrangement partner (29.7% [n = 35]). FGFR2+ pts had fewer genomic alterations (3.36 alterations/pt) than unaltered pts (4.6 alterations/pt). The most frequently co-altered gene, BAP1, was altered in 39.8% (n = 47) of FGFR2+ pts. As of the data cutoff date (July 24, 2018), 47 FGFR2+ pts were treated with pemigatinib and followed for ≥8 mo. There were no meaningful differences in ORR (42.9% vs 39.4%), mPFS (8.9 mo vs 9.6 mo), or mOS (not reached [NR] vs 15.8 mo) in patients with FGFR2-BICC1 (n = 14) versus other FGFR2 rearrangements. Similarly, no meaningful difference in ORR (53.3% vs 34.4%), mPFS (8.9 mo vs NR), or mOS (NR vs 15.8 mo) was observed in pts with BAP1 loss-of-function mutations (n = 15). Among other co-occurring genomic alterations, pts with TP53 alterations (n = 5) had no objective responses (0% vs 45.2%) and shorter mPFS (6.2 mo vs NR) and mOS (10.5 mo vs NR). Conclusions Despite myriad FGFR2 rearrangement partners identified in the study, an interim analysis did not indicate a difference in ORR, mPFS, or mOS between the most common rearrangement partner (BICC1) and other partner genes. Alterations in TP53, but not BAP1, were associated with decreased clinical benefit. Editorial acknowledgement Simon J. Slater, PhD, CMPP, of Envision Pharma Group (Philadelphia, PA), funded by Incyte Corporation. Legal entity responsible for the study Incyte Corporation. Funding Incyte Corporation. Disclosure A. Hollebecque: Consulting/Advisory Role, Travel/Accommodation/Expenses, Courses/Trainings: Amgen; Consulting/Advisory Role: Spectrum Pharmaceuticals; Consulting/Advisory Role, Travel/Accommodation/Expenses: Lilly; Consulting/Advisory Role, Travel/Accommodation/Expenses: Debiopharm; Travel/Accommodation/Expenses: Servier; Travel/Accommodation/Expenses: Incyte; Courses/Trainings: Bayer; Courses/Trainings: Eisai; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Janssen Cilag; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Sanofi. I.M. Silverman: Shareholder / Stockholder / Stock options, Full / Part-time employment: ): Incyte Research Institute, Incyte Corporation. S. Owens: Shareholder / Stockholder / Stock options, Full / Part-time employment: ): Incyte Research Institute, Incyte Corporation. L. Feliz: Shareholder / Stockholder / Stock options, Full / Part-time employment: Incyte Corporation. C.F. Lihou: Shareholder / Stockholder / Stock options, Full / Part-time employment: Incyte Corporation. H. Zhen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Incyte Corporation. R.C. Newton: Shareholder / Stockholder / Stock options, Full / Part-time employment: ): Incyte Research Institute, Incyte Corporation. T.C. Burn: Shareholder / Stockholder / Stock options, Full / Part-time employment: ): Incyte Research Institute, Incyte Corporation. D. Melisi: Research Grants (Institution), Advisory/Consultancy Role: Shire; Research Grants (Institution), Advisory/Consultancy Role: Incyte; Research Grants (Institution), Advisory/Consultancy Role: Evotec; Research Grants (Institution): Celgene; Advisory/Consultancy Role: Eli Lilly; Advisory/Consultancy: Baxter. All other authors have declared no conflicts of interest.