February 23, 2023

Trial seeks to expand therapies for biliary cancers

A Vanderbilt clinical trial seeks to optimize the effect of immunotherapies for patients with biliary tract cancers who have already progressed on first-line therapy.


by Tom Wilemon

A Vanderbilt physician is leading a clinical trial that aims to unleash the full potential of immunotherapies against biliary tract cancers (BTC), which include cholangiocarcinoma and gallbladder cancer.

Treatment options have been limited for BTC, which have low survival rates similar to pancreatic cancer. However, after a decade, there has been a paradigm shift in treating patients with BTC who are not eligible to have their cancer surgically removed.

In September 2022, the Food and Drug Administration cemented the first role for an immunotherapy in BTC by approving the addition of the immune checkpoint inhibitor, durvalumab, to standard chemotherapy as the new first line systemic therapy for patients with BTC. The decision was based on the phase 3 TOPAZ-1 study, which showed that the combination of standard chemotherapy (gemcitabine and cisplatin) and durvalumab extended survival rates compared to chemotherapy alone.

Thatcher Heumann, MD, MPH

Now that a clear role for immunotherapy has been established for patients with BTC, the next step is trying to figure out how to make immunotherapy more effective for patients with these cancers.

Thatcher Heumann, MD, MPH, assistant professor of Medicine, is co-national principal investigator of the clinical trial by the National Cancer Institute that seeks to optimize the effect of immunotherapies for patients with BTC who have already progressed on first-line therapy.

The nationwide trial, which is now recruiting patients, is testing two new treatment combinations: 1) Patients in one arm will receive a triplet combination of an experimental immune stimulating medication, varlilumab (a CD-27 immune agonist), combined with atezolizumab (an immune checkpoint inhibitor that is similar to durvalumab and approved for use in multiple other type cancers), plus a third anti-cancer drug, the targeted therapy cobimetinib (a MEK inhibitor); 2) Patients in arm two will receive the two immunotherapies but not the targeted therapy.

“We already know that single-agent immune checkpoint inhibition is, unfortunately, not effective for the vast majority of biliary tract cancers,” Heumann said. “The results are not much better with using two different kinds of immune checkpoint inhibitors. Varlilumab, on the other hand, is an immune stimulant, so the idea here is we are lifting off the brakes with atezolizumab and pressing on the gas with varlilumab to supercharge the immune system to recognize and kill the cancer cells.”

The oral targeted therapy, cobimetinib, which is most often used as a melanoma treatment, as part of treatment for BRAF-mutated cancers, has been shown in both human and mice studies to make biliary tract cancer more sensitive and potentially more responsive to immunotherapy, Heumann said.

The trial is open to adult patients with biliary tract cancer (cholangiocarcinoma or gallbladder cancer) who are not eligible for surgery. Patients must have received one, but no more than two lines of systemic therapy in the advanced disease setting. Patients whose tumors harbor a FGFR2 fusion/rear-rangement or IDH-1 mutation, which makes them eligible for an FDA-approved targeted therapy, must receive these respective medications prior to enrollment.

“This study builds upon a previously successful clinical trial of two of these drugs together — atezolizumab and cobimetinib — in biliary tract cancers,” Heumann said. “That study showed the combination of the two medications prolonged the time it took for biliary tract cancers to grow compared to immunotherapy (atezolizumab) alone. However, we did not see that benefit in delayed cancer growth necessarily mean better overall survival. Essentially, it showed promise but only to a point. We needed to find a way to break through the ceiling.

“When we looked at research samples from this clinical trial and accompanying mice experiments, we saw the combination was helping, but if we added an immune stimulator like varlilumab to the mix, it really improved responses to this treatment regimen. What makes us hopeful about our current trial, ETCTN-NCI 10476, is that it represents the next iteration of a previously positive clinical trial and is based in strong correlative/lab studies that support its scientific rationale,” Heumann said.