Expanding Treatment Options for Patients with Advanced Cholangiocarcinoma

Wayne Kuznar

August 2019, Vol 10, No 4 | Payers’ Perspectives In Oncology: ASCO 2019 Highlights - Cholangiocarcinoma, Liver Cancer


Chicago, IL—A greater understanding of the biology of cholangiocarcinoma, including differences between intrahepatic versus extrahepatic cholangiocarcinoma, is driving the development of new therapeutic options that have shown promising results in advanced stages of this difficult-to-treat cancer.

Patients whose disease progressed while receiving first-line treatment with gemcitabine (Gemzar) and cisplatin (Platinol) have few treatment options. The median overall survival (OS) with first-line treatment of this combination is up to 12 months, and the median OS when gemcitabine and cisplatin is used as a second-line treatment is a maximum of 6.7 months.

Disease Relapse Is Common

According to Milind M. Javle, MD, Professor, Gastrointestinal (GI) Medical Oncology, M.D. Anderson Cancer Center, Houston, “Most cholangiocarcinomas are diagnosed at a very advanced stage. Overall survival with gemcitabine and cisplatin, the current standard of care in the first-line setting, is 11.7 months. After this treatment fails, there is no standard treatment,” Dr Javle said at his presentation at ESMO 2018.

Surgical resection is currently considered the gold standard for patients with advanced cholangiocarcinoma, but only 20% to 40% of the patients are eligible for surgery, and the 5-year survival is less than 10%. Furthermore, the disease relapse rate after surgery approaches 60%.

The combination of gemcitabine plus cisplatin is used as a postoperative adjuvant treatment for patients with cholangiocarcinoma, but the evidence is insufficient to support this strategy.

New Treatment Options in Clinical Trials

New treatment options are currently being investigated in clinical trials. A phase 2 clinical trial of gemcitabine, cisplatin, and nab-paclitaxel (Abraxane) in patients with advanced biliary tract cancers was presented at the ESMO 2018 Congress. The results showed a median progression-free survival (PFS) of 12.9 months among the patients with intrahepatic cholangiocarcinoma and 6 months among patients with extrahepatic cholangiocarcinoma. The median OS was also greater for the gemcitabine plus cisplatin combination than for historical data (19.2 months vs <12 months, respectively).

A phase 3 clinical trial of the triplet of gemcitabine, cisplatin, and nab-­paclitaxel as a treatment option for newly diagnosed biliary tract cancers is currently recruiting patients.

Adjuvant Treatment

Recently, adjuvant treatment with capecitabine (Xeloda) was found to improve OS in patients with resected biliary tract cancer, and it may now be considered a standard of care in this population.

In a randomized, controlled phase 3 clinical trial in patients with cholangiocarcinoma or with muscle invasive gallbladder cancer who underwent surgical resection, the median OS was 17 months longer in the capecitabine arm compared with patients in the observation arm: 53 months versus 36 months, respectively (adjusted hazard ratio [HR], 0.75; P = .028) in a per-protocol analysis.

However, the study did not meet its primary end point of an improvement in median OS in the intent-to-treat population. The OS was 51.1 months in the capecitabine arm versus 36.4 months in the observation arm (HR, 0.81; P = .097).

Targeted Agents: FGFR Inhibitors

Fibroblast growth factor receptor (FGFR) translocations are driver mutations in cholangiocarcinoma and have been found to be present in approximately 17% of intrahepatic disease. At the ESMO 2018 Congress, 2 phase 2 clinical trials demonstrated promising antitumor activity of FGFR inhibitors in patients with cholangiocarcinoma and FGFR translocations.

The investigative agent infigratinib is an ATP-competitive FGFR1-3 selective oral tyrosine kinase inhibitor. In patients with cholangiocarcinoma whose disease progressed while receiving treatment with platinum-based chemotherapy, infigratinib was associated with a confirmed objective response rate (ORR) of 26.9%, a median PFS of 6.8 months, and a median OS of 12.5 months. Overall, 60% of the patients had received 2 or more previous lines of therapy.

Pemigatinib, a potent, selective oral inhibitor of FGFR1, FGFR2, and FGFR3, was studied in an open-label, multicenter phase 2 clinical trial of patients with cholangiocarcinoma whose disease had progressed despite at least 1 previous treatment. In a cohort of patients with FGFR translocations, pemigatinib elicited an ORR of 40%, a median PFS of 9.2 months, and a median OS of 15.8 months.

The disease control rate exceeded 80% in both studies. In comparing the patient populations of the 2 phase 2 clinical trials, approximately 30% more patients in the infigratinib study had stage IV cholangiocarcinoma at the time of enrollment than those in the pemigatinib study. In addition, the infigratinib study included almost twice as many patients who received at least 3 lines of therapy as did the patients in the pemigatinib study.

On the Horizon: The PROOF Study

Based on the promising preliminary response data from a phase 2 clinical trial presented by Dr Javle at ESMO 2018, the phase 3 clinical trial PROOF is designed to compare the efficacy of infigratinib versus treatment with gemcitabine and cisplatin in the front-line setting in patients with advanced (relapsed or refractory) cholangio­carcinoma and FGFR2 fusions or translocations. Dr Javle is the principal investigator of the PROOF study.

Patients are eligible for enrollment in the PROOF study if they have advanced, metastatic, or inoperable cholangiocarcinoma, according to Dr Javle. Enrolled patients are randomized in a 1:1 ratio to oral infigratinib once daily for 21 days of a 28-day treatment cycle or to intravenous gemcitabine (1000 mg/m2) plus cisplatin (25 mg/m2) on days 1 and 8 of a 21-day cycle. The treatment will continue until disease progression, treatment intolerance, withdrawal of informed consent, or death.

The primary end point is PFS per RECIST v1.1, as confirmed by central review. Secondary end points include investigator-assessed PFS, OS, ORR, disease control rate, duration of response, and safety. Quality-of-life evaluations will also be conducted.

The PROOF study was initiated in February 2019; the investigators hope to enroll 350 patients with cholangiocarcinoma and confirmed FGFR2 gene fusions or translocations.