Chemotherapy Combinations and Novel Treatments in Advanced Biliary Tract Cancer

Web Exclusives - Cholangiocarcinoma

New cytotoxic chemotherapy regimens and novel combinations are being evaluated in clinical trials in an effort to improve the outcomes of chemotherapy in the adjuvant and palliative settings in patients with biliary tract cancer, including cholangiocarcinoma (CCA), said Angela Lamarca, MD, PhD, MSc, Consultant, Medical Oncology, the Christie NHS Foundation Trust, Manchester, United Kingdom. She discussed the future of cytotoxic chemotherapy for this patient population at the 2020 Cholangiocarcinoma Summit.

In the adjuvant setting, the current gold standard for the treatment of patients with CCA is capecitabine. Developing more effective cytotoxic chemotherapy regimens are needed, because not all patients have adequate tissue for molecular profiling that would allow selection of targeted therapy, she said.

“Almost 1 of every 4 patients [with CCA] that were referred for molecular profiling didn’t have enough tissue in that biopsy,” Dr Lamarca explained. “The second problem we are facing is that even for those patients where we do have enough tissue from molecular profiling, around 60% of them will not have a targetable finding. Therefore, we need better options for this 60% of patients with CCA,” she said.

The ACTICCA 1 study is a multicenter, prospective, randomized phase 3 clinical trial designed to compare the efficacy and safety of adjuvant gemcitabine plus cisplatin versus capecitabine after resection of CCA and muscle-invasive gallbladder cancer.

“Until we have the results, capecitabine remains the standard of care,” said Dr Lamarca.

Triple-Drug Combinations

Triple-drug chemotherapy with gemcitabine, cisplatin, and S1 (an oral fluoropyrimidine prodrug) improved median progression-free survival versus gemcitabine plus cisplatin alone (7.4 vs 5.5 months, respectively) and overall survival (13.5 vs 12.6 months, respectively) in a randomized phase 3 clinical trial of patients with advanced biliary tract cancer.

Nevertheless, these benefits may not be enough to justify the added toxicity of S1, Dr Lamarca noted. Still, the higher response rate with the triplet regimen (41.5%) than with the doublet therapy (15%) may make the triplet regimen beneficial in the neoadjuvant setting or for patients with locally advanced disease.

“Not all the triple combinations have been successful,” Dr Lamarca pointed out. For example, a modified FOLFIRINOX regimen did not improve progression-free survival versus cisplatin and gemcitabine in patients with advanced biliary tract cancer.

Novel Approaches

Approximately 17% of patients with biliary tract cancer have a DNA damage repair (DDR) gene mutation, indicating a potential role for platinum-based chemotherapy in this patient population. Although some studies report longer survival with such regimens in patients with DDR mutations, others do not.

The investigational compound NUC-1031 is designed to overcome key resistance mechanisms to gemcitabine, resulting in increased intracellular levels of the anticancer metabolite gemcitabine triphosphate. In a phase 1b study, the combination of NUC-1031 and cisplatin as first-line therapy for advanced biliary tract cancer led to responses in 4 patients, including 3 partial responses, among 8 patients with locally advanced or metastatic disease. A phase 3 study of NUC-1031 plus cisplatin versus cisplatin plus gemcitabine is underway.

Novel treatment targets that have been identified in biliary tract cancer, mainly in patients with intrahepatic CCA, include fusion proteins. Fusion proteins are likely oncogenic drivers, because the use of tyrosine kinase inhibitors (TKIs) has induced clinically meaningful responses in patients with intrahepatic CCA harboring FGFR2 fusions.

Although immunotherapy monotherapy for the treatment of CCA has shown disappointing results, combining immunotherapy with chemotherapy has resulted in response rates superior to those obtained with immunotherapy alone, said Dr Lamarca.

“Because of that, there are at least 3 randomized phase 3 clinical trials in the first-line setting combining immunotherapy compounds with gemcitabine, and comparing the outcomes to cisplatin and gemcitabine alone,” Dr Lamarca pointed out.

Finally, combining immunotherapy with TKIs is a rational strategy that has shown promising early results in patients with advanced biliary tract cancer. Combinations with early data to support their efficacy include the combination of immunotherapy with the PD-1 inhibitor toripalimab plus the multikinase inhibitor lenvatinib (Lenvima) and oxaliplatin plus gemcitabine, as well as the combination of the TKI imatinib (Gleevec) plus the PD-1 inhibitor pembrolizumab (Keytruda).

Related Items
GemCis with or without CPI-613 as First-Line Treatment for Patients with Advanced Biliary Tract Cancers
TOP - November 2022 Vol 15, No 6 published on November 9, 2022 in Cholangiocarcinoma
First-Line Chemoimmunotherapy Regimen Prolongs Survival in Advanced Biliary Tract Cancer
TOP - September 2022 Vol 15, No 5 published on September 15, 2022 in Cholangiocarcinoma
The International Cholangiocarcinoma Research Network Program Initiatives
TOP - May 2022 Vol 15, No 3 published on May 6, 2022 in Cholangiocarcinoma
Update on Emerging Systemic Therapies in Cholangiocarcinoma
TOP - May 2022 Vol 15, No 3 published on May 6, 2022 in Cholangiocarcinoma
The Drug Pipeline for Cholangiocarcinoma
Erin Burns, PhD
TOP - March 2022 Vol 15, No 2 published on February 28, 2022 in Cholangiocarcinoma
Resistance Mechanisms and Adverse Events Associated with Targeted Therapy in Cholangiocarcinoma
TOP - March 2022 Vol 15, No 2 published on February 28, 2022 in Cholangiocarcinoma
Next-Generation Sequencing and Interventional Oncology in Cholangiocarcinoma
Erin Burns, PhD
TOP - March 2022 Vol 15, No 2 published on February 28, 2022 in Cholangiocarcinoma
The Latest Research in Biliary Tract Cancers Presented at ASCO GI 2021
Web Exclusives published on December 9, 2021 in ASCO, Biliary Tract Cancer, Cholangiocarcinoma, Pancreatic Cancer
Truseltiq (Infigratinib) New Targeted Therapy FDA Approved for Advanced or Metastatic Cholangiocarcinoma Harboring FGFR2 Alterations
Loretta Fala, Medical Writer
TOP - September 2021 Vol 14, No 5 published on September 7, 2021 in Drug Updates, Cholangiocarcinoma
Ivosidenib Extends Survival in Patients with Cholangiocarcinoma and IDH1 Mutation
William King
TOP - May 2021 Vol 14, No 3 published on May 14, 2021 in Cholangiocarcinoma
Last modified: July 11, 2023