Jonathan Rosenberg, MD: I’m Dr. Jonathan Rosenberg. I’m a medical oncologist at Memorial Sloan Kettering Cancer Center, and I focus on the treatment of advanced urothelial cancer and other genome malignancies.
Aaron Tallent, Interviewer: Can you describe KEYNOTE-869 and the clinically significant findings that were presented at ESMO?
Dr. Rosenberg: KEYNOTE-869, otherwise known as EV-103, data was presented at ESMO in 2022. The data were presented from cohort K, which is a randomized phase 2 cohort testing enfortumab vedotin monotherapy or enfortumab vedotin and pembrolizumab combination therapy in cisplatin-ineligible patients who had not received treatment for metastatic urothelial cancer. The primary endpoint of this cohort was objective response rate, and secondary endpoints were safety, progression-free survival, and overall survival. The cohorts were not comparative, not designed to be compared. It was really designed to understand the contribution of components of enfortumab to the combination of enfortumab with pembrolizumab and untreated patients. The response rate for enfortumab and pembrolizumab was 64.5% in this cohort, which compares very favorably to the prior data that was recently published in EV103 cohort A, which looked at the same combination in a smaller cohort of patients where they found a 73% response rate.
EV monotherapy had a 45% response rate in this cohort, which is similar to what we've seen in other enfortumab data. The progression-free survival and overall survival data were quite immature. The progression free survival for EV pembro has not been reached. The median duration of response has not been reached, and the overall survival is about 22 months. Although, I expect that number to change dramatically because there's a lot of censoring still going on and there’s a lot of patients who haven’t reached that time point or beyond. The median follow up is only about 15 months, so it’s very impressive data, I think, in terms of responses and bladder cancer, kind of unprecedented compared to cytotoxic standard chemotherapy or even immunotherapy as monotherapy. And so, this is really may represent a big change.
Tallent: What were the side effects associated with this combination?
Dr. Rosenberg: The side effects of enfortumab, vedotin, and pembrolizumab in combination were not that different than either drug by itself. So they were mostly, I would say, additive. Although there were more skin rashes seen in the combination than you might expect with enfortumab or with pembrolizumab, and that’s not really a surprise because that’s an overlapping side effect of both drugs. But there weren’t any really serious, life-threatening skin reactions in this study, and enfortumab monotherapy also has a risk of early and severe skin reactions in a very small number of patients, and it did not seem to be increased in this clinical trial. Peripheral neuropathy was observed in the combination, and that was mostly, if not all, related to enfortumab. There was a very low rate of pneumonitis, again, potentially an overlapping toxicity of both drugs, but really not more than what you might expect from each drug by itself, potentially because most of the toxicity profiles are nonoverlapping.
Tallent: Are there any next steps for this research?
Dr. Rosenberg: There is a randomized phase three trial that’s going on right now that is occurring patients internationally called EV302, which is comparing enfortumab vedotin and pembrolizumab versus standard chemotherapy in all patients with metastatic urothelial cancer who are eligible for platinum. So, patients are randomized to EV and pembro or they’re randomized to gemcitabine and either cisplatin or carboplatin, depending on whether they’re cisplatin eligible or not. And that study will confirm the results of KEYNOTE-689, EV103 cohort K, and hopefully lead to full approval of the regimen worldwide for patients with metastatic urothelial cancer because we expect the median survival of patients treated with chemotherapy followed by maintenance to be somewhere between 16 and 20 months if you take all comers, maybe shorter, maybe a little longer.
Whereas, at least in cohort A, the overall survival was more than two years of the cisplatin ineligible patient population, where, historically, we’d expect between nine and 13 months, and so at least a doubling of overall survival in that patient population. So, I’m optimistic that we’re going to see these results be replicated in the randomized phase 3 trial. We won’t know that data for a little while. It is possible that EV and pembro will be submitted and receive an accelerated approval in the United States based on the results of KEYNOTE-689 cohort K, but that remains to be determined.
Tallent: How do these findings add to the information available on antibody drug conjugates in treating bladder cancer?
Dr. Rosenberg: The data that we have now suggests that antibody drug conjugates are highly active in urothelial cancer and bladder cancer. The data from ESMO in 2022 confirms that there is what appears to be at least an additive, if not synergistic, effect of enfortumab vedotin with pembrolizumab, probably based on the fact that enfortumab vedotin appears to cause what we call immunogenic cell death, which is the type of cell death where the cancer cells die in such a way that it stimulates the immune system. There are many ways to kill a cancer cell. Not all of them lead to immune recognition.
And then you have pembrolizumab which can add to the effects of enfortumab and really bring the immune system in. And so I think this confirms that this is probably what’s going on in with EV-pembro. And so I think we will see future data coming out around more translational science around this to try to understand it a little better and maybe think about ways this can be augmented in other contexts.
Tallent: Which other GU cancer studies presented at ESMO did you find most clinically significant?
Dr. Rosenberg: I think there were two that stand out in kidney cancer. One is the addition of cabozantinib to ipilimumab and nivolumab in first-line patients, and that study was positive for progression-free survival with a significant improvement. I think the question is going to be whether this addition will lead to improved overall survival and that data is not yet mature, but the regimen might end up being approved in the United States based on PFS data. We’ll see where the study ends up, but that I think was very significant that we can add a TKI to doublet immunotherapy and improve progression-free survival.
The other study that was important was the negative ipilimumab-nivolumab data in kidney cancer, the randomized adjuvant study, and then the other negative randomized adjuvant atezolizumab monotherapy study. At the moment, the only drug that’s effective and approved for adjuvant therapy is pembrolizumab for kidney cancer.
But why those two studies were negative, I think that remains not entirely clear. Perhaps the toxicity with a doublet immunotherapy reduced the amount of therapy patients were receiving, and perhaps the IMmotion study with atezolizumab, it may have been that the drug just wasn’t as good. Atezolizumab has had negative results in kidney cancer in general, and so I think a lot more work needs to be done to understand why. Maybe the pembrolizumab positive data was a fluke, but we’ll see the longer-term data from some of these trials to understand the differences between these randomized phase 3 studies.
