Biliary Tract Cancers: Combination Strategies With Immune Checkpoint Inhibitors


An overview on novel treatment strategies in biliary tract cancers combining immune checkpoint inhibitors with various targeted agents.


Milind M. Javle, MD: At this [European Society for Medical Oncology Congress] meeting, there was an interesting abstract, which I was looking forward to, regarding antibiotic usage and the outcome with immunotherapy. There were some hypotheses that increased antibiotic usage may somewhat diminish the benefit from durvalumab. Fortunately, that wasn’t the case. As you know, we use antibiotics, especially for perihilar cholangiocarcinoma. Dr Koay, you’ve done some work in relation to immunotherapy and radiation. Do you see any prospective strategies, given the TOPAZ-1 regimen?

Eugene J. Koay, MD, PhD: There’s a lot of excitement about combining radiation with immunotherapy, in not only intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma but also many other disease. We’ve tried to conduct a phase 1 study with previous immunotherapy. Unfortunately, that 1 got taken off the shelf. But there may be some very interesting molecular correlations that we can learn from and hopefully derive and apply to other settings, where there are active investigations into durvalumab or other immunotherapies and checkpoint inhibitors.

Radiation as a way to expand the immune repertoire or the immune response to cancer and activate the effects of the immune checkpoint blockade is an exciting area for future direction. To build on what Dr Rocha was saying, liver failure is the proximate cause of death in patients who have advanced disease. This is an active area where it makes a lot of sense to combine a locoregional therapy, such as external-beam radiation or other locoregional therapies, with exciting systemic therapies like immunotherapy.

Milind M. Javle, MD: I’m looking forward to building on this regimen. Dr Shroff, this is a situation where perhaps we’d consider the TOPAZ-1 regimen plus novel therapies and targeted agents. Do you see the field going that direction?

Rachna Shroff, MD: Absolutely. The tolerability of adding durvalumab to gemcitabine-cisplatin makes it seem like an obvious thing that we could start to layer in, especially things that are rationally synergistic. The theme of yesterday’s oral abstract discussion was that more isn’t always better, and that’s an important point. But as you start to think about synergy, it’s absolutely something that can be thought through. For instance, there’s a lot of interest in the synergy between IDH-targeting therapy with immunotherapy and PARP inhibition. There’s a lot of work that has been looked at in the preclinical space. As you start to move through clinical trials, we think through what can be added to a relatively well-tolerated backbone.

Milind M. Javle, MD: I want to remind the audience that some of the subgroups that we looked at—investigators have done an amazing job looking at the various subgroups—weren’t necessarily statistically powered. For instance, the signal in perihilar cholangiocarcinoma cannot be compared with the signal in gallbladder cancer. That hazard ratio was somewhat less favorable in gallbladder cancer, but there were simply not that many patients. My take from the NGS [next-generation sequencing] finding of the long-term survivors is that this group of biliary tract cancer is enriched with DNA-repair mutations, much more than many other GI [gastrointestinal] cancers. There are opportunities there for all biliary tract cancers. Finally, Dr Rocha, in terms of surgical strategies, do you see the TOPAZ-1 regimen having an impact in terms of future with resection?

Flavio G. Rocha, MD, FACS, FSSO: I’m very excited about these options. A lot of the work with new agents gets done in the advanced setting, but my mission is to bring these up front in the treatment sequencing. Perhaps we can apply the exciting data in certain populations in the preoperative setting. We talked about subgroup analyses in the TOPAZ-1 and SWOG S1815 trials. There’s a suggestion that in locally advanced vs metastatic cancers, maybe there’s a signal. As we incorporate these regimens, we’ll want to think about moving them up the treatment sequencing, especially when you get the downstaging effect. As a surgeon, with immunotherapy there’s less of an issue with resection because unlike chemotherapy, you don’t have all the suppressed counts, so you can have a shorter window to surgery. The interesting piece will be how that relates to things like transplantation. Immunotherapy and transplantation are obviously a yin and yang, with competing interests. What’s encouraging is that that’s being investigated in the HCC [hepatocellular carcinoma] space. I’m assuming it will trickle down into cholangiocarcinoma.

Transcript edited for clarity.

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