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Ref Type Journal Article
PMID (33218975)
Authors Silverman IM, Hollebecque A, Friboulet L, Owens S, Newton RC, Zhen H, Féliz L, Zecchetto C, Melisi D, Burn TC
Title Clinicogenomic Analysis of FGFR2-Rearranged Cholangiocarcinoma Identifies Correlates of Response and Mechanisms of Resistance to Pemigatinib.
Journal Cancer discovery
Vol 11
Issue 2
Date 2021 Feb
URL
Abstract Text Pemigatinib, a selective FGFR1-3 inhibitor, has demonstrated antitumor activity in FIGHT-202, a phase II study in patients with cholangiocarcinoma harboring FGFR2 fusions/rearrangements, and has gained regulatory approval in the United States. Eligibility for FIGHT-202 was assessed using genomic profiling; here, these data were utilized to characterize the genomic landscape of cholangiocarcinoma and to uncover unique molecular features of patients harboring FGFR2 rearrangements. The results highlight the high percentage of patients with cholangiocarcinoma harboring potentially actionable genomic alterations and the diversity in gene partners that rearrange with FGFR2. Clinicogenomic analysis of pemigatinib-treated patients identified mechanisms of primary and acquired resistance. Genomic subsets of patients with other potentially actionable FGF/FGFR alterations were also identified. Our study provides a framework for molecularly guided clinical trials and underscores the importance of genomic profiling to enable a deeper understanding of the molecular basis for response and nonresponse to targeted therapy. SIGNIFICANCE: We utilized genomic profiling data from FIGHT-202 to gain insights into the genomic landscape of cholangiocarcinoma, to understand the molecular diversity of patients with FGFR2 fusions or rearrangements, and to interrogate the clinicogenomics of patients treated with pemigatinib. Our study highlights the utility of genomic profiling in clinical trials.This article is highlighted in the In This Issue feature, p. 211.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR2 ACLY FGFR2 - ACLY fusion unknown FGFR2-ACLY results from the fusion of FGFR2 and ACLY (PMID: 33218975). FGFR2-ACLY has been identified in cholangiocarcinoma (PMID: 33218975), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Aug 2022).
FGFR2 AFF4 FGFR2 - AFF4 fusion unknown FGFR2-AFF4 results from the fusion of FGFR2 and AFF4 (PMID: 33218975). FGFR2-AFF4 has been identified in cholangiocarcinoma (PMID: 33218975), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Aug 2022).
FGFR2 ARHGAP22 FGFR2 - ARHGAP22 fusion unknown FGFR2-ARHGAP22 results from the fusion of FGFR2 and ARHGAP22 (PMID: 33218975). FGFR2-ARHGAP22 has been identified in cholangiocarcinoma (PMID: 33218975), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Nov 2021).
FGFR2 ATAD2 FGFR2 - ATAD2 fusion unknown FGFR2-ATAD2 results from the fusion of FGFR2 and ATAD2 (PMID: 33218975). FGFR2-ATAD2 has been identified in cholangiocarcinoma (PMID: 33218975), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Aug 2022).
FGFR2 CCDC170 FGFR2 - CCDC170 fusion unknown FGFR2-CCDC170 results from the fusion of FGFR2 and CCDC170 (PMID: 33218975). FGFR2-CCDC170 has been identified in cholangiocarcinoma (PMID: 33218975), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Jun 2021).
FGFR2 CDC42BPB FGFR2 - CDC42BPB fusion unknown FGFR2-CDC42BPB results from the fusion of FGFR2 and CDC42BPB (PMID: 33218975). FGFR2-CDC42BPB has been identified in cholangiocarcinoma (PMID: 33218975), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Jul 2022).
FGFR2 GOPC FGFR2 - GOPC fusion unknown FGFR2-GOPC results from the fusion of FGFR2 and GOPC (PMID: 33218975). FGFR2-GOPC has been identified in cholangiocarcinoma (PMID: 33218975), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Jul 2022).
FGFR2 KIAA1217 FGFR2 - KIAA1217 fusion gain of function - predicted FGFR2-KIAA1217 results from the fusion of FGFR2 and KIAA1217 (PMID: 30745300), which leads to transformation in culture (PMID: 35176488), and therefore, is predicted to lead to a gain of protein function. FGFR2-KIAA1217 has been identified in cholangiocarcinoma (PMID: 34250419, PMID: 31109923, PMID: 33218975).
FGFR2 MACF1 FGFR2 - MACF1 fusion unknown FGFR2-MACF1 results from the fusion of FGFR2 and MACF1 (PMID: 33218975). FGFR2-MACF1 has been identified in cholangiocarcinoma (PMID: 33218975), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Jul 2022).
FGFR2 NRBF2 FGFR2 - NRBF2 fusion unknown FGFR2-NRBF2 results from the fusion of FGFR2 and NRBF2 (PMID: 33218975). FGFR2-NRBF2 has been identified in cholangiocarcinoma (PMID: 33218975), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Aug 2022).
FGFR2 PAWR FGFR2 - PAWR fusion unknown FGFR2-PAWR results from the fusion of FGFR2 and PAWR (PMID: 33218975). FGFR2-PAWR has been identified in cholangiocarcinoma (PMID: 33218975, PMID: 31392046), salivary duct carcinoma (PMID: 31609094), and pancreatic adenocarcinoma (PMID: 34250383), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Mar 2022).
FGFR2 RABGAP1L FGFR2 - RABGAP1L fusion unknown FGFR2-RABGAP1L results from the fusion of FGFR2 and RABGAP1L (PMID: 33218975). FGFR2-RABGAP1L has been identified in cholangiocarcinoma (PMID: 33218975), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Jul 2022).
FGFR2 RASSF4 FGFR2 - RASSF4 fusion unknown FGFR2-RASSF4 results from the fusion of FGFR2 and RASSF4 (PMID: 33218975). FGFR2-RASSF4 has been identified in cholangiocarcinoma (PMID: 33218975), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Jul 2022).
FGFR2 SPICE1 FGFR2 - SPICE1 fusion unknown FGFR2-SPICE1 results from the fusion of FGFR2 and SPICE1 (PMID: 33218975). FGFR2-SPICE1 has been identified in cholangiocarcinoma (PMID: 33218975), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Apr 2022).
FGFR2 TRIM8 FGFR2 - TRIM8 fusion unknown FGFR2-TRIM8 results from the fusion of FGFR2 and TRIM8 (PMID: 33218975). FGFR2-TRIM8 has been identified in cholangiocarcinoma (PMID: 33218975), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Aug 2022).
FGFR2 USH2A FGFR2 - USH2A fusion unknown FGFR2-USH2A results from the fusion of FGFR2 and USH2A (PMID: 33218975). FGFR2-USH2A has been identified in cholangiocarcinoma (PMID: 33218975), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Jul 2022).
FGFR2 WDHD1 FGFR2 - WDHD1 fusion unknown FGFR2-WDHD1 results from the fusion of FGFR2 and WDHD1 (PMID: 33218975). FGFR2-WDHD1 has been identified in cholangiocarcinoma (PMID: 33218975), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Mar 2022).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 - ATAD2 cholangiocarcinoma predicted - sensitive Pemigatinib Case Reports/Case Series Actionable In a Phase II trial (FIGHT-202), Pemazyre (pemigatinib) treatment in a cholangiocarcinoma patient harboring FGFR2-ATAD2 resulted in stable disease with a decrease in tumor size of 13% and progression-free survival of 8.8 months (PMID: 33218975; NCT02924376). 33218975
FGFR2 - NRBF2 FGFR2 N549K cholangiocarcinoma predicted - resistant Pemigatinib Case Reports/Case Series Actionable In a Phase II trial (FIGHT-202), a cholangiocarcinoma patient harboring FGFR2-NRBF2 experienced disease progression after 13.1 months of treatment with Pemazyre (pemigatinib), and was found to have acquired FGFR2 N549K (PMID: 33218975; NCT02924376). 33218975
FGFR2 - CCDC170 cholangiocarcinoma predicted - sensitive Pemigatinib Case Reports/Case Series Actionable In a Phase II trial (FIGHT-202), Pemazyre (pemigatinib) treatment in a cholangiocarcinoma patient harboring FGFR2-CCDC170 resulted in a partial response with a decrease in tumor size of 58.2% and progression-free survival of 6.9 months (PMID: 33218975; NCT02924376). 33218975
FGFR2 - WDHD1 cholangiocarcinoma predicted - sensitive Pemigatinib Case Reports/Case Series Actionable In a Phase II trial (FIGHT-202), Pemazyre (pemigatinib) treatment in a cholangiocarcinoma patient harboring FGFR2-WDHD1 resulted in a partial response with a decrease in tumor size of 63.6% and progression-free survival of 8.8 months (PMID: 33218975; NCT02924376). 33218975
FGFR2 - AHCYL1 FGFR2 L617V cholangiocarcinoma predicted - resistant Pemigatinib Case Reports/Case Series Actionable In a Phase II trial (FIGHT-202), a cholangiocarcinoma patient harboring FGFR2-AHCYL1 experienced disease progression after 6.8 months of treatment with Pemazyre (pemigatinib), and was found to have acquired FGFR2 L617V (PMID: 33218975; NCT02924376). 33218975
FGFR2 - TRIM8 cholangiocarcinoma predicted - sensitive Pemigatinib Case Reports/Case Series Actionable In a Phase II trial (FIGHT-202), Pemazyre (pemigatinib) treatment in a cholangiocarcinoma patient harboring FGFR2-TRIM8 resulted in a partial response with a decrease in tumor size of 46% and progression-free survival of 9.1 months (PMID: 33218975; NCT02924376). 33218975
FGFR2 - KIAA1217 cholangiocarcinoma predicted - sensitive Pemigatinib Case Reports/Case Series Actionable In a Phase II trial (FIGHT-202), Pemazyre (pemigatinib) treatment in a cholangiocarcinoma patient harboring FGFR2-KIAA1217 resulted in a partial response with a decrease in tumor size of 60.5% and progression-free survival of 15.9 months (PMID: 33218975; NCT02924376). 33218975
FGFR2 - PAWR cholangiocarcinoma predicted - sensitive Pemigatinib Case Reports/Case Series Actionable In a Phase II trial (FIGHT-202), Pemazyre (pemigatinib) treatment in a cholangiocarcinoma patient harboring FGFR2-PAWR resulted in a partial response with a decrease in tumor size of 39.8% and progression-free survival of 6.9 months (PMID: 33218975; NCT02924376). 33218975
FGFR2 - KIAA1217 FGFR2 K659M cholangiocarcinoma predicted - resistant Pemigatinib Case Reports/Case Series Actionable In a Phase II trial (FIGHT-202), a cholangiocarcinoma patient harboring FGFR2-KIAA1217 experienced disease progression after 15.9 months of treatment with Pemazyre (pemigatinib), and was found to have acquired FGFR2 K659M (PMID: 33218975; NCT02924376). 33218975
FGFR2 - NRBF2 cholangiocarcinoma predicted - sensitive Pemigatinib Case Reports/Case Series Actionable In a Phase II trial (FIGHT-202), Pemazyre (pemigatinib) treatment in a cholangiocarcinoma patient harboring FGFR2-NRBF2 resulted in stable disease with a decrease in tumor size of 15.7% and progression-free survival of 13.1 months (PMID: 33218975; NCT02924376). 33218975
FGFR2 - CCDC170 FGFR2 N549K FGFR2 K641R cholangiocarcinoma predicted - resistant Pemigatinib Case Reports/Case Series Actionable In a Phase II trial (FIGHT-202), a cholangiocarcinoma patient harboring FGFR2-CCDC170 experienced disease progression after 6.9 months of treatment with Pemazyre (pemigatinib), and was found to have acquired FGFR2 N549K and FGFR2 K641R (PMID: 33218975; NCT02924376). 33218975
FGFR2 - AHCYL1 cholangiocarcinoma predicted - sensitive Pemigatinib Case Reports/Case Series Actionable In a Phase II trial (FIGHT-202), Pemazyre (pemigatinib) treatment in a cholangiocarcinoma patient harboring FGFR2-AHCYL1 resulted in stable disease with a decrease in tumor size of 33.3% and progression-free survival of 6.8 months (PMID: 33218975; NCT02924376). 33218975
FGFR2 - ATAD2 FGFR2 N549H cholangiocarcinoma predicted - resistant Pemigatinib Case Reports/Case Series Actionable In a Phase II trial (FIGHT-202), a cholangiocarcinoma patient harboring FGFR2-ATAD2 experienced disease progression after 8.8 months of treatment with Pemazyre (pemigatinib), and was found to have acquired FGFR2 N549H (PMID: 33218975; NCT02924376). 33218975
FGFR2 - TRIM8 FGFR2 E565A FGFR2 L617V FGFR2 K659M cholangiocarcinoma predicted - resistant Pemigatinib Case Reports/Case Series Actionable In a Phase II trial (FIGHT-202), a cholangiocarcinoma patient harboring FGFR2-TRIM8 experienced disease progression after 9.1 months of treatment with Pemazyre (pemigatinib), and was found to have acquired FGFR2 E565A, FGFR2 L617V, and FGFR2 K659M (PMID: 33218975; NCT02924376). 33218975