Invest New Drugs. 2026 Feb 12. doi: 10.1007/s10637-026-01602-6. Online ahead of print.
ABSTRACT
Cholangiocarcinoma (CCA) is a rare and aggressive biliary tract cancer with a poor prognosis. Despite recent advancements in molecularly targeted therapies for patients with IDH1 mutations and FGFR2 fusions, the efficacy of integrating these agents with first-line chemotherapy has not been established. This multicenter, Phase Ib dose de-escalation study, conducted prior to the establishment of chemoimmunotherapy as the standard first-line therapy, evaluated the safety and preliminary efficacy of combining ivosidenib or pemigatinib with gemcitabine and cisplatin in patients with advanced CCA. Eligible patients with no disease progression after three cycles of standard chemotherapy were assigned to receive either ivosidenib or pemigatinib based on their mutation status and chemotherapy. The primary endpoints were to evaluate safety, tolerability, the maximum tolerated dose, and the recommended Phase II dose. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and best response profile. The study opened in January 2020 and closed early in November 2022, enrolling eight patients – seven in the ivosidenib arm (Arm A) and one in the pemigatinib arm (Arm B). Enrollment in Arm B was constrained due to challenges in identifying FGFR2 fusion/rearrangement-positive patients in the first-line setting. Treatment-related toxicities of grade 3 or higher occurred in four patients (66.7%) in Arm A. Regarding efficacy, one patient (16.7%) in Arm A achieved a partial response, while the remaining five had stable disease, with a median progression-free survival (PFS) of 15.4 months in Arm A and a median overall survival (OS) of 22.9 months. Given the selection bias and small sample size, these efficacy analyses must be interpreted with caution. Adding ivosidenib to gemcitabine and cisplatin in this study demonstrated a challenging safety profile in advanced CCA. Further research and dose optimization are warranted to confirm these findings and optimize the integration of targeted therapies into first-line regimens.
PMID:41678089 | DOI:10.1007/s10637-026-01602-6
