TOPAZ-1: Chemotherapy + Durvalumab in Biliary Tract Cancers


Centering discussion on the TOPAZ-1 trial of chemotherapy in combination with durvalumab, panelists consider how this regimen has impacted clinical practice.


Milind M. Javle, MD: One of the most impressive trials in recent time for biliary cancer was the TOPAZ-1 trial. I want to remind the audience that this was a multicenter phase 3 trial, based on a very nice signal in a phase 2 setting in South Korea by Dr Do-Youn Oh, M.D. This trial randomized 685 patients to gemcitabine, cisplatin, and durvalumab given for 6 months, followed by durvalumab maintenance vs the same chemotherapy and placebo. There was a median overall survival improvement ... There’s also a significant improvement in progression-free survival and response rate. Somewhat more impressive, long-term survival was 2 years, which was 10% vs 24% in the gemcitabine-cisplatin-placebo vs gemcitabine-cisplatin-atezolizumab. There seems to be a tail in those curves. Dr Shroff, we’ve been using this regimen in our practice for the last 5 months, since its approval. What has your experience been so far?

Rachna Shroff, MD: At the end of the day, the best part about it is that it’s a well-tolerated regimen. There was a lot of conversation when the data first came out because there was this tail, and it seemed only a small percentage of patients were durably benefiting. But the truth is that it’s hard to know who those may be. The gemcitabine-cisplatin-durvalumab regimen is so well-tolerated that it has been implemented into my practice as my go-to frontline regimen unless there’s a contraindication to immunotherapy.

The other nice thing is that in the United States, we haven’t traditionally followed the ABC pattern of 6 months of gemcitabine-cisplatin and then stopping. We do that in select patients, but it’s been a patient-by-patient conversation about whether we feel comfortable fully stopping therapy. With the durvalumab maintenance option, after 6 months of a hard regimen—gemcitabine-cisplatin wears on a patient—this is a wonderful option to offer because it’s a maintenance approach but also a break from cytotoxics.

Milind M. Javle, MD: You touched on a very important point. If I were in the situation, I certainly wouldn’t want to get lifelong chemotherapy. This regimen offers an opportunity for a chemotherapy-free interval. I want to remind the audience that when they looked at toxicity and AE [adverse effect] profile between the durvalumab-placebo and gemcitabine-cisplatin-containing arms, there was no striking difference between the 2. You would think that there was a higher incidence of diarrhea or liver problems, or some traditional effects associated with checkpoint inhibitors. But that hasn’t happened much in the trial or in our practice. The regimen requires close follow-up, guidelines to monitor thyroid function, and actions to specialists if they develop autoimmune colitis or pneumonitis or other diseases, which are rare but do need some specialty management. Dr Shroff, we extrapolate all the time now in our practice. What’s your practice if somebody isn’t a candidate for the cisplatin therapy or develops an allergic reaction to cisplatin?

Rachna Shroff, MD: There are a lot of varying approaches that are not really data driven. There are often questions. Is there another platinum option? If there’s an issue with cisplatin, could you offer them oxaliplatin vs gemcitabine alone with durvalumab added? There are no clear guidelines. To me, it’s always been a case-by-case approach to these patients. As long as there isn’t an autoimmune condition or something that prevents us from durvalumab, the nice thing about is that there aren’t a lot of patients who don’t feel comfortable or can’t tolerate durvalumab. Gemcitabine plus durvalumab or gemcitabine with a different platinum would typically be my approach.

Milind M. Javle, MD: This brings up an important point. What do you do in the case of autoimmune disease? Patients who have ulcerative colitis, Crohn disease, or PSC [primary sclerosing cholangitis] weren’t included in TOPAZ-1, and we can’t recommend this regimen in that setting. We hope that there will be some clinical trials conducted in this space. There’s an NCI [National Cancer Institute] trial ongoing for immunotherapy in the patient in the face of underlying autoimmune disease. Remember, these patients get chemotherapy and steroids. Exceptions can be made, but this has to be done carefully and by people who have a lot of experience in this setting.

There have been several subsets and subgroups analyzed following the publication of the TOPAZ-1 regimen. One of the earlier analyses was in quality of life. As you know, there was some quality of life improvement. There was no deterioration despite additional durvalumab…but we were all looking forward to the next-generation sequencing [NGS]. The company and the sponsors have done a wonderful job, because two-thirds of the patients, 440 of 685, had next-generation sequencing. Some of these data were presented at ESMO [European Society for Medical Oncology Congress], where they presented some of the information. The data seem to indicate underlying HRD [homologous recombination deficiency] genotype with BRCA mutations, and patients who are long-term survivors seem to be enriched with those mutations. What’s your impression of the NGS profile, Dr Shroff? How would that impact your administration of the TOPAZ-1 regimen?

Rachna Shroff, MD: I agree. I want to applaud the investigators and the sponsors for being committed to doing a deep dive into the biomarkers. A lot of us were eagerly awaiting that information to better understand if there were molecular subsets of patients who were deriving that added benefit from durvalumab. It’s interesting to see some of these signals emerge.

But it’s also important to point out, as in the ESMO data, that across the different alterations that we think of—BRCA, IDH, FGFR2—there was benefit to durvalumab. The hazard ratios continued to favor the addition of the immunotherapy. That was not as clear in the ERBB2 population, but even then, there were some higher response rates and things like that. What’s impressive is that with every subgroup analysis that we’ve looked at—the traditional ones of disease site, region, and stage, and now you layer in biomarker analyses—you feel comfortable. You don’t necessarily need to stop and think, when you see a patient who’s eligible for gemcitabine-cisplatin-durvalumab, to offer it to them. You don’t need to pause and say, “Let me check to see if they have certain biomarkers that are making us not favor it.”

Milind M. Javle, MD: The study had shown a somewhat more favorable signal in Asian patients vs Western patients. But that hazard ratio was still in favor of durvalumab, even in Western patients. There’s a lot to learn, especially in the setting of NASH [nonalcoholic steatohepatitis] and checkpoint inhibition, and that work will continue.

Transcript edited for clarity.

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