Key opinion leaders in the field of biliary tract cancers highlight mainstay systemic therapy regimens within the treatment paradigm.
Milind M. Javle, MD: I’m going to move on to systemic therapy for advanced and resectable disease. Dr Shroff, you led the SWOG S1815 trial. It was a pioneering trial because it was the first randomized phase 3 trial in this space. We’ve been eagerly anticipating the result. You gave a presentation [at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, ASCO GI]. Before we get into the results, could you discuss the challenges of systemic therapy trials for biliary tract cancer? What are the challenges when you find patients with this rare disease? What was involved in your particular case for S1815?
Rachna Shroff, MD: The reason S1815 was pioneering is that it’s the first randomized phase 3 trial we’ve been able to do successfully in the United States. Historically, the UK team has led the charge in terms of developing standards of care until the TOPAZ-1 trial. There’s concern that this is a rare tumor. As we were discussing earlier, I don’t necessarily think it’s rare. Other randomized phase 3 trials in rare tumors have been done and have been completed. We needed proof of principle to demonstrate that we could do this. The challenges that remain, in terms of developing effective systemic therapies, are that we continue to lump them together. S1815 did this, along with ABC-02 and TOPAZ-1.
As we keep saying, these are completely different diseases. The concern remains: are you able to do a large, randomized trial if you start to parse it out and do a gallbladder trial, an intrahepatic trial, and an extrahepatic cholangiocarcinoma trial? We need to be smarter and a little more strategic as we start to think through what these next trials need to look like in terms of trial development and shared controlled arms. We talk about this a lot. We don’t necessarily need multiple trials that have gemcitabine-cisplatin—now gemcitabine-cisplatin-durvalumab—as the standard-of-care arm. All those strategies will help us be a little smarter as we plan what subsequent trial should look like. Hopefully, we’ve been able to demonstrate between TOPAZ-1 and S1815 and a lot of other trials that have been in the frontline space, like KEYNOTE-966, that we can do a large prospective randomized trial to ask important questions and develop and find new systemic therapies.
Milind M. Javle, MD: I want to remind the audience that this trial enrolled at a rapid rate, which is not common for cooperative groups. They’re usually quite sluggish in enrollment, unfortunately. The trial accrued 441 patients in 20 months.
Rachna Shroff, MD: Correct.
Milind M. Javle, MD: It’s something like 20 patients a month.
Rachna Shroff, MD: Yes. The accrual rate was about 18 patients a month.
Milind M. Javle, MD: That’s striking. Dr Shroff, could you discuss the results and your take on them? It didn’t meet the overall survival boundary. However, there were some subtleties. I’d like to get your take on those.
Rachna Shroff, MD: S1815 was a randomized trial of 441 patients for newly diagnosed biliary tract cancer, so intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer. It was designed before TOPAZ-1. The standard-of-care arm was gemcitabine-cisplatin, and we were looking at the gemcitabine-cisplatin nab-paclitaxel triplet arm, or GAP. Patients were randomized in a 2:1 fashion. The triplet regimen is a tough regimen in terms of primarily hepatologic toxicities that we had seen in phase 2. Dosing was developed based on our phase 2 experience. The primary end point was overall survival [OS] with a target ratio of 0.7. The median OS was 14 months on the triplet arm vs 12.7 months on the gemcitabine-cisplatin arm. It numerically improved, but it was not statistically significant. Similar improvements were noted but they were not significant improvements in median PFS [progression-free survival]. The overall response rate was 31% in the triplet. That’s a reasonable response rate vs 22% in the gemcitabine-cisplatin arm. This goes back to starting to look at things, and subtleties and nuances in these diseases.
There were some prespecified stratification factors, including disease site. In gallbladder cancer, for instance, there did seem to be a signal in terms of better survival, with a doubling of the overall response rate to 44%. Similar subtle trends were noted in the locally advanced patient population vs the metastatic patients. The tricky part is that those were small numbers, so it’s hard to draw any strong conclusions. There was an interest in seeing what that means and whether we can explore that. Of course, there were prospectively collected specimens of blood and tissue. Hopefully, there will be some biomarker analyses that we can do to see if there are subsets of patients who may benefit from GAP [gemcitabine-cisplatin nab-paclitaxel].
At the end of the day, this didn’t meet its primary end point. It’s not going to be the standard of care for all patients. Everybody at this table has used it. Some patients truly benefit from GAP [gemcitabine-cisplatin nab-paclitaxel]. We’ve also figured out to give it in a way that’s probably a little more tolerable and to mitigate some of grade 3/4 AEs [adverse events] that we saw with anemia, neutropenia, and thrombocytopenia.
Milind M. Javle, MD: This study was very informative in many ways. As Dr Shroff mentioned, these patients can handle multiagent chemotherapy. Randomized studies are possible through the cooperative group mechanism. We’re hoping that this will be a predecessor of several efforts in the future. In terms of other systemic therapies discussed at ASCO GI, we also had the IMbrave 151 study, which was gemcitabine-cisplatin with atezolizumab-bevacizumab vs gemcitabine-cisplatin and atezolizumab with placebo. This study wasn’t powered to compare 1 arm with another. There was no standard of care in that arm. The progression-free survival, to my recollection, was around 8 months. There doesn’t seem to be any great difference between these arms, in terms of what we know now, although overall survival wasn’t quite reached. I want to reflect at a very high level, Dr Shroff. Are you considering this regimen in your practice right now?
Rachna Shroff, MD: I’d be hard-pressed to consider it right now. OS data will be important to see, but it was a phase 2 trial. It was not a comparator trial, and we have gemcitabine-cisplatin-durvalumab. It’s not as if we don’t have cytotoxic with an immunotherapy option. To me, a data purist, the level 1 evidence remains with gemcitabine-cisplatin-durvalumab. I don’t necessarily think IMbrave 151 would make me change my practice pattern.
Milind M. Javle, MD: Thank you, Dr Shroff.
Transcript edited for clarity.