Chemoimmunotherapy in Biliary Tract Cancers: Data From TOPAZ-1

Transcript:

Milind Javle, MD: Laura, perhaps for the benefit of those who don’t treat cancer every day, like you and I do, would you briefly outline the study, the study design, the goals of the study, and the results?

Laura W. Goff, MD: This was a straightforward study of advanced biliary tract cancer, which is an umbrella term. Patients with advanced biliary tract cancer who had never received chemotherapy before were randomized to gemcitabine-cisplatin with placebo, or gemcitabine-cisplatin with durvalumab. As you know, there’s a bit of a split of how long patients receive chemotherapy in biliary cancers. The historical study on which the gemcitabine-cisplatin regimen was based was the ABC-02 trial. In that trial, patients were treated for 6 months with chemotherapy and then followed. In some parts of the world, that’s the standard. In the United States, oftentimes we treat as long as patients are tolerating, or there’s not a reason to come off the regimen.

In the TOPAZ-1 trial, they followed the historical precedent, treating patients with chemotherapy for 6 months and then stopping. Patients treated with the triplet regimen gemcitabine-cisplatin-durvalumab continued on durvalumab alone, and patients who were on the control arm continued on placebo alone. The goal was to look at whether there was improvement in overall survival and progression-free survival. They did show an improvement in both of these outcomes.

Milind Javle, MD: What do you make of the 3 different biliary cancer types? Does that guide your choice of first-line therapy with gemcitabine-cisplatin-durvalumab with gallbladder extrahepatic cholangiocarcinoma?

Laura W. Goff, MD: That’s a good question. At this point, I’m treating them all with the triplet regimen. We’re obviously very interested in being able to determine the patients who would respond better to the triplet combination or those we can spare from immunotherapy. But I haven’t seen enough evidence to guide me to not offer patients the opportunity to benefit from the combination. The tolerability seems to be pretty good overall. Right now, I’m offering the triplet as my standard.

Milind, remind us of the mechanism of action of durvalumab and why it may combine with chemotherapy.

Milind Javle, MD: We feel that the cancer cells have an immune-suppressed tumor microenvironment, where immune recognition is lost and leads to a phenomenon scientists like to call T-cell exhaustion and high PD-L1 expression. Durvalumab is a specific inhibitor of PD-L1, and the belief was that because the chemotherapy makes these cancer cells more immunogenic, the chemotherapy may help to counter the mechanisms that circumvent immune recognition. Giving chemotherapy and immunotherapy made sense. This has been attempted in several cancer types with variable success. It was attempted in biliary [cancer] because the effects of stimulation of PD-1 and PD-L1 inhibitor are very modest at best. That’s the loose rationale that went into this combination. I’m very happy that it led to significant clinical benefit and now 2 studies in the frontline setting.

I also noticed in these trials—because you and I have participated in other immunotherapy trials before—this phenomenon of progression. Some people call it hyperprogression. For some reason, I don’t see that with this combination. Is that your experience as well?

Laura W. Goff, MD: Yes. For biliary cancers, chemotherapy works for a lot of patients. We’ve known for a long time that this is a disease where we can see significant tumor shrinkage and, in rare cases after dramatic responses, some pathologic complete responses. Chemotherapy really helps. I don’t know if that’s the reason we’re not seeing hyperprogression. The chemotherapy is taking care of things in the beginning of the treatment, and the immunotherapy kicks in down the road. That’s my working theory, but I haven’t seen hyperprogression or pseudoprogression in my patients thus far.

Transcript edited for clarity.