Effect of FGFR2 alterations on survival in patients receiving systemic chemotherapy for intrahepatic cholangiocarcinoma.

Abstract

303 Background: Most patients (pts) with cholangiocarcinoma (CCA) are diagnosed with advanced disease and are ineligible for surgery. FGFR2 fusions/rearrangements are oncogenic drivers and are present almost exclusively in pts with intrahepatic CCA (iCCA; 10–16% of pts); however, little is known about the effects of FGFR2 status on response to systemic chemotherapy. Memorial Sloan Kettering (MSK) obtains genomic sequencing data from almost all iCCA pts treated at the institution. This provides a unique, rich database from which genomic profiling data can be overlaid with clinical data to facilitate a meaningful understanding of pt outcomes, and to suggest potential therapeutic options. This retrospective analysis evaluated progression free survival (PFS) and overall survival (OS) in pts receiving standard systemic chemotherapy (CXT) for iCCA harboring FGFR2 fusions/rearrangements ( FGFR2 +), or harboring wild-type FGFR2 ( FGFR2wt). Methods: Clinical and genomic data were obtained from the MSK database for all iCCA pts to determine disease history and exposure to prior lines (PL) of CXT in the advanced setting. Only pts with complete data for PL of CXT were analyzed. Median PFS and OS were calculated using the Kaplan-Meier method. OS was calculated from diagnosis until death; PFS was calculated from first dose of first line of CXT until progression, death, last visit, relevant dates of later CXT lines; pts with unconfirmed outcomes were censored at last known follow-up date. Results: One-hundred-thirty-two pts were included in this analysis (median age at diagnosis: 62.0 y; 54.5% female; FGFR2+, n = 15; FGFR2wt, n = 115; other FGFR2 alterations, n = 2). Among pts receiving first-line CXT, median PFS was 7.1 months (95% CI: 5.0–8.3) for all pts (n = 124), 6.2 months (2.0–16.8) for FGFR2+ pts (n = 15), and 7.2 months (5.0–8.3) for FGFR2wt pts (n = 107). Among pts with ≥2 PL of CXT (n = 90), median PFS on second-line chemotherapy was 5.6 months (95% CI: 2.8–10.3) for FGFR2+ pts, and 3.7 months (2.6–5.6) for FGFR2wt pts. Median OS was numerically longer in FGFR2+ pts compared with FGFR2wt pts (31.3 months [95% CI: 5.8–not estimable] vs 21.8 months [16.7–26.6]). Conclusions: Among pts receiving standard systemic chemotherapy for iCCA, median PFS was similar in pts harboring FGFR2+ vs FGFR2wt receiving first-line chemotherapy, and relatively longer in pts harboring FGFR2+ receiving second-line chemotherapy. Median OS was longer in FGFR2+ vs FGFR2wt pts. Compared with recently published data in molecularly unselected CCA pts (Lowery. Cancer. 2019; 125: 4426), PFS was similar in pts receiving first-line chemotherapy, and slightly longer for second-line chemotherapy. Data interpretation is limited by the retrospective nature of this analysis of investigator-reported data, the study size, and by the possibility that the analysis population may not reflect the general population of pts with CCA.

Progression-Free Survival in Patients With Cholangiocarcinoma With or Without FGF/FGFR Alterations: A FIGHT-202 Post Hoc Analysis of Prior Systemic Therapy Response

“…In a retrospective analysis of patients with iCCA receiving first-line chemotherapy at Memorial Sloan Kettering, the median PFS was 6.2 months for patients with FGFR2 fusions or rearrangements and 7.2 months for patients with no FGFR2 alterations. 20 The retrospective study by Jain et al reported that the median PFS in patients with FGFR alterations receiving first-line chemotherapy for CCA was numerically longer compared with those without FGFR alterations (33.9 v 25.4 weeks); however, this difference did not reach statistical significance ( P = .07). 13 Another retrospective, observational study based on real-world data from 571 patients with advanced CCA compared OS in patients with FGFR2 fusions/rearrangements versus those without FGFR2 alterations.…”

“…In the retrospective analysis of patients with iCCA receiving second-line chemotherapy at Memorial Sloan Kettering, the median PFS was 5.6 months for patients with FGFR2 fusions or rearrangements and 3.7 months for patients with no FGFR2 alterations. 20 Various systemic chemotherapy regimens have been investigated in the second-line setting for molecularly unselected advanced BTC, in both retrospective studies 6,9,[24][25][26] and prospective clinical trials. 7,8 A systematic review of second-line chemotherapy in advanced BTC reported a weighted mean PFS of only 3.2 months and a weighted mean OS of 7.2 months 27 ; another systematic review and meta-analysis of second-line treatments for advanced BTC reported a weighted median PFS of 2.6 months and a weighted median OS of 6.5 months.…”

“…In the retrospective analysis of patients with iCCA receiving second-line chemotherapy at Memorial Sloan Kettering, the median PFS was 5.6 months for patients with FGFR2 fusions or rearrangements and 3.7 months for patients with no FGFR2 alterations. 20 …”

Equipoise, drug development, and biliary cancer

“…11 Although validated mutations in these targets are found for each in only a small subset of sequenced tumors, their presence could lead to alternative therapies that may eventually reshape the nature and sequence of first-line therapy for this select subset of patients who could cumulatively constitute a third to one-half of all biliary cancers once all target and treatment pairs are identified. 14 A second path forward is the development of novel chemotherapy options. One example is the addition of nabpaclitaxel to the gemcitabine-cisplatin backbone, a regimen initially used in pancreatic cancer.…”

Biliary Tract Cancers: Treatment Updates and Future Directions in the Era of Precision Medicine and Immuno-Oncology

“…However, for patients whose tumors harbor targetable mutations, targeted therapy is preferred over chemotherapy in the second line. These include pemigatinib and infigratinib for fusions or mutations in fibroblast growth factor receptor-2 (FGFR2), larotrectinib and entrectinib for neurotrophic tropomyosin receptor kinase (NTRK) fusions, and ivosidenib for isocitrate dehydrogenase 1 (IDH1) (10)(11)(12)(13)(14). Pembrolizumab, an immune checkpoint inhibitor (ICI), is recommended for patients with microsatellite instability-high (MSI-H) (15).…”