Effect of FGFR2 Alterations on Overall and Progression-Free Survival in Patients Receiving Systemic Therapy for Intrahepatic Cholangiocarcinoma

Abstract

Background First-line standard-of-care therapy for advanced cholangiocarcinoma is gemcitabine plus cisplatin; there is no established second-line systemic therapy. Fibroblast growth factor receptor (FGFR)-2 fusions/rearrangements can be oncogenic drivers, occurring almost exclusively in intrahepatic cholangiocarcinoma, but little is known about whether FGFR2 status affects the response to systemic chemotherapy. Objective We aimed to evaluate the effects of FGFR2 status on survival outcomes in patients receiving systemic therapy for intrahepatic cholangiocarcinoma. Methods In this retrospective analysis, patients treated with systemic therapy at Memorial Sloan Kettering Cancer Center for intrahepatic cholangiocarcinoma were categorized into three cohorts: FGFR2 fusions; other FGFR2 alterations; no FGFR2 alterations. Endpoints were overall survival and progression-free survival per therapy line. Results In total, 132 patients with intrahepatic cholangiocarcinoma were included ( FGFR2 fusions, n = 15; other FGFR2 alterations, n = 2 [data not reported]; no FGFR2 alterations, n = 115). First-line therapy was platinum based in 93% of patients; 80% received platinum/pyrimidine-based second-line therapy. For patients with FGFR2 fusions and no FGFR2 alterations, respectively, median overall survival from diagnosis was 31.3 months (95% confidence interval [CI] 5.8–not estimable months) [ n = 9] and 21.7 months (95% CI 16.1–26.6) [ n = 109]; median progression-free survival in first-line therapy was 6.2 months (95% CI 2.0–16.8) [ n = 15] and 7.2 months (95% CI 5.0–8.3) [ n = 107], and median progression-free survival in second-line therapy was 5.6 months (95% CI 2.8–10.3) [ n = 8] and 3.7 months (95% CI 2.6–5.6) [ n = 81]. Conclusions Patients with intrahepatic cholangiocarcinoma and FGFR2 fusions may have a better prognosis than those without FGFR2 alterations in terms of overall survival, and progression-free survival on second-line, but not first-line systemic therapy. Progression-free survival improvement on second-line chemotherapy may imply an important impact of prior chemotherapy as first line.

Are FGFR and IDH1-2 alterations a positive prognostic factor in intrahepatic cholangiocarcinoma? An unresolved issue

“…Another important question is to rule out whether the presence of FGFR alteration could affect response to systemic therapies. Several trials agree that there is not impact on response to first-line chemotherapy ( 18 , 19 ). However, this is less clear for further lines of treatment, with one trial suggesting a slightly longer PFS for second-line chemotherapy, although with the strong bias of a retrospective descriptive analysis only ( 19 ).…”

“…Several trials agree that there is not impact on response to first-line chemotherapy ( 18 , 19 ). However, this is less clear for further lines of treatment, with one trial suggesting a slightly longer PFS for second-line chemotherapy, although with the strong bias of a retrospective descriptive analysis only ( 19 ). Regarding the effect of FGFR target therapies on OS, two trials confirmed the positive prognostic role of FGFR alterations on their subset of patients, even after censoring those who had received targeted drugs ( 16 , 17 ), thus suggesting that the prognostic role of these molecular changes could be independent to the administered targeted treatments.…”

“…A retrospective study ( 19 ) on the effect of first-line chemotherapy on FGFR2 altered patient showed that, although OS was longer for altered patients (31.3 vs 21.7 months), this was not due to a better response to first-line treatment (93% of cases platinum based) with a PFS of 6.2 months for altered cases vs 7.2 months for wild-type cases. Interestingly, even after excluding patients who had received an FGFR inhibitor, a slightly longer PFS for second-line treatment was observed (5.6 months for 8 mutated patients vs 3.7 months for 81 wild-type cases).…”

“…Interestingly, even after excluding patients who had received an FGFR inhibitor, a slightly longer PFS for second-line treatment was observed (5.6 months for 8 mutated patients vs 3.7 months for 81 wild-type cases). It should be noted however that size sample was small and that only descriptive statistics was employed (p-values were not provided) ( 19 ).…”

Intrahepatic Cholangiocarcinoma—Where Are We Now and Where Are We Going to?

“…According to the studies carried out so far, it is believed that lesions positive for EGFR, ERBB2 or KRAS mutations in their cells are associated with a more aggressive course of the disease, which obviously worsens the prognosis of patients [6]. One of the most recent discoveries, which may be of great importance in iCCA-targeted therapies, is genetic FGFR2-G3BP2 fusion [11][12][13]. This is why, now, due to the identification of numerous genetic abnormalities in iCCA cells, there are many potential opportunities for the use of new drug molecules that remain in clinical trials (pemigatinib, futibatinib or ivosidenib) [1,7,12].…”