Targeted Agents Show Promise in Cholangiocarcinoma

Cholangiocarcinoma is both rare and aggressive, and the current systemic standard of care, gemcitabine plus cisplatin, produces only modest results.

Aiwu Ruth He, MD, PhD

Cholangiocarcinoma (CCA) is both rare and aggressive, and the current systemic standard of care, gemcitabine plus cisplatin, produces only modest results. However, targeted agents such as the FGFR inhibitors pemigatinib and infigratinib (BGJ398), and the IDH1 inhibitor ivosidenib (Tibsovo) have shown encouraging activity in clinical trials and may represent the future of care in this disease with a high unmet need, said Aiwu Ruth He, MD, PhD.

He, an associate professor of hematology at Georgetown-Lombardi Comprehensive Cancer Center, reviewed treatment options for cholangiocarcinoma during a presentation at the 5th Annual School of Gastrointestinal Oncology (SOGO®).

“CCA is a rare tumor. It doesn't have a very high prevalence, but it is very interesting,” she said. “It is very genetically heterogeneous and in more than 70% of CCAs, we can identify up to 1 molecular or genetic aberration.”

Pemigatinib, a selective a selective oral inhibitor of FGFR1, 2, and 3, is currently under FDA priority review for patients with previously treated, locally advanced or metastatic CCA with FGFR2 fusions or rearrangements.1 Data from the open-label, single-arm phase II FIGHT-202 trial presented at 2019 ESMO Congress showed a strong, durable response in this patient population.2

Eligible patients had locally advanced or metastatic CCA despite at least 1 line of prior therapy. Patients were segregated in 3 cohorts. Cohort A included 107 patients with FGFR2 fusion/rearrangements, cohort B included 20 with other FGF/FGFR alterations, and cohort C included 18 with no FGFR2 alterations. All patients received 13.5 mg oral pemigatinib using a 2 weeks on/1 week off schedule. The study was not designed to make statistical comparisons between the 3 cohorts.

The objective response rate (ORR) in cohort A was 35.5% (95% CI, 26.5-45.4) and the median duration of response was 7.5 months (95% CI, 5.7-14.5). In contrast, there were no responses observed in the other cohorts.

The higher ORR translated into a median progression-free survival (PFS) of 6.9 months in cohort A compared with 2.1 months in cohort B and 1.7 months in cohort C.

“The disease control rate is quote impressive at over 80%,” He said. “The majority of patients with FGFR2 fusion or rearrangements had some sort of tumor shrinkage.”

Overall survival (OS) data were not yet mature at the time March 22, 2019 data cutoff, but with a median duration of follow-up of 15.4 months and a median duration of treatment of 7.2 months, the median OS was 21.1 months in the cohort with FGFR2 fusions/rearrangements. Median OS was only 6.7 months among patients with other FGF/FGFR alterations after a median follow-up of 19.9 months, and only 4.0 months in patients without FGFR2 mutations after a median follow-up of 24.2 months.

Infigratinib is being evaluated in the ongoing phase III PROOF trial (NCT03773302). Patients with advanced cholangiocarcinoma with FGFR2 gene fusions or translocations will be assigned to infigratinib at 125 mg or standard of care gemcitabine with cisplatin. The primary end point of the study is PFS. Secondary end points include OS and the percentage of investigator-assessed PFS in patients treated with infigratinib versus gemcitabine/cisplatin.

In January 2020, the FDA granted infigratinib a Fast Track Designation for the treatment of CCA in adults with first-line advanced or metastatic disease based on results from a phase II trial (N = 71) first presented at the 2018 ESMO Congress.3,4,5

In those findings, the confirmed and unconfirmed ORR among all FGFR2-fusion—positive patients was 31.0% (95% CI, 20.5-43.1). Investigators observed no complete responses and 18 (25.4%) partial responses. The median PFS was 6.8 months (95% CI, 5.3-7.6) with a median OS of 12.5 months (95% CI, 9.9-16.6).

He said approximately 11% of patients with intrahepatic CCA have FGFR aberrations, so these agents could have a major impact on the treatment of this disease.

Targeting IDH1

Up to 20% of patients with CCA harbor IDH1 mutations and the mutation is associated with poorer prognosis, He said. Investigators are evaluating ivosidenib, a first-in-class, oral, small-molecule inhibitor of mutant IDH1, as a potential targeted therapy. Based on findings from the pivotal phase III ClarIDHy study (NCT02989857) presented at the ESMO Congress 2019, the drug could represent a practice-changing advance in treatment.6

In the trial, 185 patients with advanced cholangiocarcinoma and IDH1-mutant cholangiocarcinoma were randomly assigned to 500 mg oral ivosidenib daily (n = 124) or matched placebo (n = 61). Crossover from the placebo arm to ivosidenib was permitted following signs of radiographic progression.

Prior to study entry, patients had received up to 2 prior therapies, including 1 gemcitabine- or 5-fluorouracil—containing regimen.

Ivosidenib induced superior median PFS compared with placebo (2.7 vs 1.4 months; HR, 0.37; 95% CI, 0.25-0.54; P <0.001). Despite more than half of patients crossing over (57%), there was a 31% trend toward reduction in the risk for death with ivosidenib (HR, 0.69; 95% CI, 0.44-1.10; P = 0.06).

At 6 months, 32% of patients in the ivosidenib arm remained alive and progression-free, compared with 0% in the placebo group. By month 12, the PFS rate was 22% in the investigational arm. “In IDH1-mutated CCA, usually the tumor progresses very quickly,” He said.

OS rates favored the ivosidenib arm at 6 months (67% vs 48%) and 12 months (59% vs 38%). He added that ivosidenib resulted in a numerical improvement in OS compared with placebo based on the intent-to-treat population. The agent induced a significant improvement in OS when adjusting for crossover using the rank-preserving structural failure time method (HR, 0.46; 95% CI, 0.28-0.75; P <0.001).


  1. Incyte announces acceptance and priority review of NDA for pemigatinib as a treatment for patients with cholangiocarcinoma [news release]. Wilmington, DE: Incyte; November 27, 2019. Accessed March 23, 2020.
  2. Vogel A, Sahai V, Hollebecque A, et al. FIGHT-202: a phase 2 study of pemigatinib in patients (pts) with previously treated locally advanced or metastatic cholangiocarcinoma (CCA). Presented at: 2019 ESMO Congress; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA40.
  3. BridgeBio Pharma’s QED therapeutics receives fast track designation for infigratinib in adults with first-line advanced or metastatic cholangiocarcinoma and orphan drug designation for infigratinib for treatment of cholangiocarcinoma [news release]. San Francisco, California: BridgeBio Pharma Inc; January 6, 2020. Accessed March 23, 2020.
  4. Javle M, Lowery M, Shroff RT, et al. Phase II study of BGJ398 in patients with fgfr-altered advanced cholangiocarcinoma. J Clin Oncol. 2018;36(3):276—282. doi:10.1200/JCO.2017.75.5009
  5. Javle M, Kelley RK, Roychowdhury S, et al. A phase II study of infigratinib (BGJ398), an FGFR-selective tyrosine kinase inhibitor (TKI), in patients with previously-treated advanced cholangiocarcinoma containing FGFR2 fusions. In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract 3652.
  6. Abou-Alfa GK, Maraculla TM, Javle M, et al. ClarIDHy: A global, phase 3, randomized, double-blind study of ivosidenib (IVO) vs placebo in patients with advanced cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation. Presented at: 2019 ESMO Congress; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA10_PR.