Abstract 3472: Clinical outcomes and genomic evolution of FGFR2 fusions/rearrangements in intrahepatic cholangiocarcinoma
Authors: Cham Brent B. , Lee Sunyoung S. 
Published: June 2022

Abstract
Background: Fibroblast growth factor receptor 2 (FGFR2) alterations are commonly found 14-20% patients with intrahepatic cholangiocarcinoma. FGFR inhibition has been investigated for more than 7 years on clinical trials. More recently, pemigatinib and infigratinib, tyrosine kinase inhibitors of FGFR 1, 2, and 3 received approval from the FDA in patients with advanced cholangiocarcinoma with FGFR2 fusions/rearrangements in the second-line setting. There are limited data about evolution of mutational profiles post progression from FGFR2 inhibition.
Methods: Clinical outcomes data and mutational profiles were obtained from a retrospective database collected via an institutional DNA sequencing panel including tissue sequencing and cell free DNA (cfDNA), Foundation One, Guardant360, and Tempus. A total of 102 patients treated at UT MD Anderson Cancer Center from 2013 - 2021 with intrahepatic cholangiocarcinoma harboring FGFR2 fusions (91 patients) and rearrangements (11) were analyzed.
Results: Female 55 (54%) and male 47 (46%) patients; 99 patients had stage IV, 3 patients with stage IIIB at initiation of FGFR inhibition; median age, 59. Out of 91 patients with FGFR2 fusions, there were 52 different fusion partners: BICC1, AHCYL1, TACC2, and NOL4 with 24, 5, 4, and 3 patients, respectively. Forty two (42) patients with FGFR2 fusions and 9 patients with FGFR2 rearrangements received FGFR inhibitors: these include infigratinib (13), pemigatinib (17), futibatinib (14), derazantinib (5), and zoligratinib (2). Out of 51 patients, 14 (28%) patients received FGFR inhibition in the front-line setting, 15 (29%) and 22 (43%) received one prior, two/more (2 - 6), respectively. The median progression-free survival in 51 patients was 8.8 months (95% CI, 7.2 - 10.3), and median overall survival was 24.7 months (95% CI, 15.9 - 33.2). Eighteen (18) patients with FGFR2 fusions have mutational profiles before and post-progression on FGFR2 inhibition: 15 (83%) patients showed no more FGFR2 fusions; 3 patients showed the same fusions after progression. New FGFR alterations post-progression included FGFR1_K139I, FGFR2_N549K (2 patients), FGFR2_N549H, FGFR2_V564F, FGFR2 fusion with SYNPO2. New gene mutations that did not exist before FGFR inhibition but developed post progression included PIK3CA (2 patients), APC (2 patients), BRAF V600E/A694T, NRAS, BAP1, GNAS, TP53, and other mutations.
Conclusion: The genomic evolution post-progression on FGFR inhibition involves acquired resistance in multiple pathways. Targeting co-alterations acquired post-progression with drug combination may overcome these resistance mechanisms and potentiate the efficacy of FGFR inhibition.
Citation Format: Brent B. Cham, Sunyoung S. Lee. Clinical outcomes and genomic evolution of FGFR2 fusions/rearrangements in intrahepatic cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3472.