Immunotherapy in BTC: The Future Is Now

Nilofer Azad, MD, a professor of oncology at Johns Hopkins University, gave a presentation on immunotherapy advancements in biliary tract cancers (BTC) at the 20th Annual Meeting of the International Society of Gastrointestinal Oncology.

The reality in the BTC world right now, she began, is that “things have changed dramatically in the past 5 years.” Multiple drugs have been approved for targetable mutations and abnormalities, as well as PD-L1. The PD-L1 approval of durvalumab came from the TOPAZ-1 study, which was a statistically significant, positive study, although median survival was under 13 months. The KEYNOTE-966 trial confirmed this positive but limited survival benefit.

Dr. Azad then moved on to anti-VEGF therapy. While these therapies have revolutionized care in hepatocellular cancer, does this approach have a role in BTC? The IMbrave151 study demonstrated improved (though not statistically significant) progression-free survival (PFS) with this approach. However, duration of response was statistically significant. “I do think we will continue to see anti-VEGF therapies tested in this setting in the future as one strategy,” she said, “and we we still need better drugs and to combine them in more rational ways.”

We are in the “hotbed” of immunotherapy right now, and there are “so many” immunomodulatory drugs available, she continued. However, the patient size of BTC is relatively low, which will require thoughtful trial design for immunotherapy.

Dr. Azad began advocating for personalized immunotherapy, explaining that BTC is uniquely set up for this approach because of the many targetable mutations. Data suggest that targeted modulation of an abnormality may lead us to an immune effect. She started with showcasing IDH1 in the phase 3 ClarIDHy trial, which led to the approval of ivosidenib. However, mouse models have shown that an intact immune system is needed to get the benefit of IDH1 inhibition. IDH1 inhibition combined with anti-CTLA4 inhibition provides a significant antitumor effect, Dr. Azad explained, and this approach should be the basis for further research.

Then, she discussed BRCA1/2 PARP inhibition with immunotherapy as an area worth exploring. CTLA4 inhibition in combination with PARP inhibitors has shown substantial benefit in ovarian cancer, she noted, and was further demonstrated in the PARPVAX trial for pancreatic cancer. “BTC could be amendable to this approach as well,” she said, while pointing to a poster study she and her colleagues presented earlier in the year. Ongoing and new clinical trials that are attempting to answer the question of whether there is benefit of PARP inhibitors plus immunotherapy in BTC, including NCT04042831, NCT03639935, and NCT04779151.

Lastly, Dr. Azad highlighted KRAS inhibition in BTC, including data on adagrasib leading to a response rate of 42% and a disease control rate of 92%. There is also a “whole slew” of KRAS inhibitors working their way down the pipeline in BTC.

In her concluding remarks, Dr. Azad spoke to some ongoing work she and her colleagues at Johns Hopkins are doing that looks at vaccine-based approaches, including a vaccine of the 6 most common KRAS mutations. The trial enrolled patients with pancreatic and metastatic colon cancer. The results are encouraging in pancreatic cancer, but in colon cancer responses are being seen in microsatellite-stable disease, which has led her team to consider it in BTC across multiple mutated cholangiocarcinomas. This latter trial is currently written and going through US Food and Drug Administration and Institutional Review Board approval. The idea is to add the vaccine after first-line therapy to improve PFS.

Finally, she mentioned cellular therapy as a strategy with proof-of-concept, but much more research is required before everyday use.