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In Cholangiocarcinoma, New Targets, New Therapies, and Some Old Ones, Too


Last year, pemigatinib, the first targeted therapy in cholangiocarcinoma was approved for previously treated patients with FGFR2 fusions or rearrangements.

It’s been a year of big news in cholangiocarcinoma. Also called bile duct cancer, this is an aggressive disease of the narrow tubes that carry bile through the liver. Historically, there had been little success with systemic therapy.

But about 4 years ago, research in the disease began to bear fruit, and a breakthrough came a year ago when the FDA granted accelerated approval for pemigatinib. This first targeted therapy in cholangiocarcinoma was approved for previously treated patients with FGFR2 fusions or rearrangements. Other new options, including immunotherapy, have been added to the National Comprehensive Cancer Network guidelines.

At this week’s Cholangiocarcinoma Foundation Annual Conference, an extended session on Thursday covered how genomics are driving research into therapeutics for cholangiocarcinoma (CCA). A series of speakers offered updates on the better-known mutations, FGFR and IDH1/IDH2, as well as novel targets such as BAP1, CDK, and ARID1A.

Ghassan K. Abou-Alfa, MD, of Memorial Sloan Kettering Cancer Center and lead author of the FIGHT-202 trial for pemigatinib, said approval based on the phase 2 study helped patients. Findings showed 107 patients the overall response rate was 36% including 3 complete responses. The median durable response was 9.1 months, with responses lasting at least 6 months in 24 of the 38 patients responding patients (63%) and at least 12 months in 7 (18%) patients.

New targeted therapies are on the horizon; attendees gathered online amid word that FDA had granted Breakthrough Therapy designation to futibatinib, an investigational therapy to treat FGFR2 gene rearrangements, including gene fusions. (A poster on the FOENIX-CCA2 study on futibatinib was presented later in the day).

But the session also shows how work in other BRCA-mutated cancers is paying dividends in cholangiocarcinoma, with much of the progress coming with familiar drugs, including immunotherapy and PARP inhibitors.

Timothy Yap, MD, associate professor at The University of Texas MD Cancer Center, discussed how the use PARP inhibitors in pancreatic cancer is informing the development of treatments in cholangiocarcinoma. Sarinya Kongpetch, PhD, assistant professor at Khon Kaen University, Thailand, discussed the potential for CDK4/6 inhibitors, which are already FDA-approved in metastatic breast cancer. The “ubiquitous dependency” of cholangiocarcinoma on CDK4/6 activity, Kongpetch said, suggests that the that the CDK4/6-pRB pathway could be a treatable target.

One theme from the speakers and during a panel discussion that followed: the precision medicine approach that is the future of cholangiocarcinoma care demands next-generation sequencing; some called for every patient to be tested for microsatellite instability-high (MSI-H). Challenges going forward will involve developing effective drug combinations: targeted therapies with chemotherapy (and in what order), immunotherapy and PARP inhibitors. Some patients may have more than one druggable target, which will call for individualized care. Only 8000 new cases are diagnosed a year and 5-year survival rates have been low; 10% or less, depending on which type of bile-duct cancer.

Novel targets. While Kongpetch said that FGFR and IDH1 are “the best understood mutations to date,” more knowledge is being gained about new potential targets: epigenetic factors BAP1 and ARID1A. Next-generation sequencing is giving researchers new paths to pursue, she said. Said Kongpetch, “ARID1A-mutated cancers are sensitive to EZH2 methyltransferase inhibition,” referring to enhancer of zeste homolog 2, which is known to regulate gene expression and is involved in cell proliferation and apoptosis. Development of EZH2 inhibitors is a significant area of cancer research, and Kongpetch said early phase clinical trials said there is particular in interest in evaluating their use in cancers with loss of BAP1 function.

DNA damage response (DDR). Yap spoke about bringing knowledge gained from other cancers to the fight against cholangiocarcinoma; in particular, he called for deploying PARP inhibitors in combination with immuno-oncology. He outlined a half-dozen classes of DDR inhibitors that have been studied, of which PARP inhibitors have several FDA approvals. He also discussed DDR cell-cycle targets, and what investigators have learned about BRCA-mutated cancers over the 15 years.

“We have learned a lot from pancreatic cancer and use that to apply learnings to every cancer,” he said. The POLO trial involving the use of the PARP inhibitor olaparib for maintenance therapy was “certainly setting the stage for the development of similar agents in biliary cancers,” he said. The challenge is to think about applying inhibitors beyond the BRCA scenario, and during them in combinations since drug resistance “is nearly inevitable in patients who do respond initially.”

He showed a chart with PARP inhibitors as the centerpiece of multiple combinations, including radiation. Because of toxicity, however, Yap predicts a move away from chemotherapy combinations to those with PD-1 or PD-L1, or targeted agents and radiation.

Options at last. After years of not having options, it appears doctors and patients will have several. In his remarks, Abou-Alfa said accelerated approvals after phase 2, as was done for pemigatinib, are appropriate, given the high level of need, “rather than wait for those elaborate long, pretty evolved studies, or even joined them all in one study, because it will take the same time.”

Otherwise, he said, regulators “really will be missing the point—and missing on the opportunity that we provide for patients.”

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