Impact of FGFR2-rearrangements in treatment response to systemic therapies in cholangiocarcinoma

The role of FGFR2 fusions and rearrangements and its impact on treatment responses to systemic therapy in cholangiocarcinoma (CCA) patients remains uncharacterised. A post-hoc analysis of the phase II FIGHT-202 study of pemigatinib therefore evaluated progression-free survival (PFS) to standard systemic therapy before FIGHT-202 study enrolment, in patients with CCA harbouring FGFR2 fusions or rearrangements.

Cholangiocarcinoma (CCA) is the most common primary malignancy of the bile duct. CCA is classified according to anatomical position, and includes intrahepatic (iCCA) or extrahepatic (including perihilar and distal) CCA. Most patients are diagnosed with advanced disease and are therefore ineligible for surgery. The standard of care (SoC) first-line treatment for these advanced/metastatic patients who are ineligible for surgery consists of gemcitabine plus cisplatin chemotherapy. For patients with disease progression on this first line treatment there is currently no SoC second-line systemic therapy. The current chemotherapies that are being used in this second-line setting are associated with a short overall survival.

Pemigatinib, a selective oral FGFR1-3 inhibitor, has been approved in the US, Japan and Europe for patients with previously treated, unresectable locally advanced or metastatic CCA harbouring FGFR2 fusions or rearrangements, following the results of the pivotal FIGHT-202 trial. FGFR2 fusions or rearrangements are oncogenic drivers of CCA and are almost exclusive to iCCA, with a prevalence of 10-15%. However, the role of these fusions and rearrangements and how they impact patient response to systemic therapy remains largely unknown. Therefore, a post-hoc analysis evaluated progression-free survival (PFS) to standard systemic therapy before FIGHT-202 study enrolment in patients with CCA harbouring FGFR2 fusions or rearrangements.

FIGHT-202 trial and post-hoc analysis design

FIGHT-202 was a phase II study that enrolled patients with locally advanced or metastatic CCA with or without FGF/FGFR genomic alterations who progressed on at least one prior therapy to receive pemigatinib (13.5 mg daily; 21-day cycle, 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent or physician decision. Patients were categorised into three cohorts based on their FGFR2 mutational status (Cohort A: FGFR2 fusions or rearrangements, Cohort B: other FGF or FGFR alterations and Cohort C: no FGF or FGFR alterations). For this analysis, electronic case report forms from patients with FGFR2-positive CCA enrolled in FIGHT-202 (Cohort A) were reviewed to determine the disease history of patients and their exposure to prior lines of systemic cancer therapies (LOSCT) in the advanced setting before receiving pemigatinib. Only patients with sufficient data on prior LOSCT were included in this analysis. Median PFS was calculated using the Kaplan-Meier method, defined as the date of initiation of LOSCT until the date of progression.

Results

For the 108 FGFR2-positive CCA patients included in the analysis, the median age was 55.5 years and 61% were female. The most common systemic therapy before receiving pemigatinib were pyrimidine analogues (99.1%) and platinum compounds (96.3%). Ninety-nine percent of patients had iCCA. The median PFS on first-line therapy prior to FIGHT-202 enrolment was 5.6 months (N= 104). The median PFS on second-line therapy received prior to enrolment was shorter at only 4.4 months (N= 40). In patients who progressed on just one line of therapy before receiving pemigatinib in a second-line setting during FIGHT-202, the median PFS was 7.0 months (N= 65). Median PFS on third-line therapy received prior to enrolment was 6.6 months (N= 13). For patients who progressed after second-line treatment and subsequently received pemigatinib in third-line during FIGHT-202, the median PFS was 8.9 months (N= 30).

Conclusion

This post-hoc analysis provides insight into the median PFS of CCA patients with FGFR2 fusions or rearrangements on standard systemic treatment prior to receiving pemigatinib. Importantly, the short PFS on standard therapies in these patients highlight the need for targeted therapies that improve survival outcomes. The median PFS observed with second- or third-line pemigatinib was longer than second- or third-line systemic therapy received prior to FIGHT-202 enrolment.

Reference

Abou-Alfa G, et al., Progression-free survival in patients with cholangiocarcinoma with FGFR2 fusions or rearrangements: A FIGHT-202 post-hoc analysis of prior systemic therapy response. Presented at the 2021 ESMO World Congress on Gastrointestinal World Cancer; Abstract SO-4.