Expert hematologist/oncologists consider the potential role for adjuvant immunotherapy in patients with advanced clear cell renal cell carcinoma.
Brian Rini, MD: We have a little bit of time left. Maybe we can touch on some sort of newer topics; one would be adjuvant pembrolizumab. I have 2 questions around this. So, we know that the KeyNote data from the adjuvant pembrolizumab was fairly cleanly positive. It has a ratio for disease-free survival in the update that I believe was 0.63, if I have it right. No survival signal yet, but it’s fairly early and the hazard ratio is trending in the right direction. So fairly clean. That was the first study reported. But we’ve gotten wind, at least by press release, of some upcoming negative trials for other adjuvant immune therapies.
My questions to both of you, and I’ll start with Monty because he’s smiling, is: Do you think this is going to change people’s perception of the pembrolizumab data? The opposite happened with TKIs [tyrosine kinase inhibitors]. It was a bunch of negative trials, and then suddenly stuff tracked positive with sunitinib, which I think caught us all off guard. But it definitely colored our perception of those data, among other reasons. So here it’s kind of the opposite, where the first trial is positive, and trials 2, 3, and 4 are negative, and there’s still at least one more out there. Do you think this is going to change people’s perception? Will it change your own perception in practice?
Sumanta Pal, MD, FASCO: I don’t think so. I’ll tell you why, Brian. I think we’re going to really garner some important information from the setting in which these trials were conducted and the differences in methodology. For instance, among these negative trials that you have mentioned, one of those is PROSPER, which uses a perioperative approach. Maybe the presence of negative data in PROSPER but positive data in KEYNOTE-564 tells us that perioperative therapy isn’t a reasonable strategy. Again, just by way of example I’m using PROSPER, but I think each one of the studies is going to carefully help us distill the setting in which adjuvant I/O [immuno-oncology] may not be helpful. I still think that the benefits seen in KEYNOTE-564 will stand.
Brian Rini, MD: Hans, what do you think?
Hans Hammers, MD, PhD: First of all, I think it’s still unclear, to be honest with you, if you need to be [INAUDIBLE] immune checkpoints in the adjuvant space. That space was developed with cytotoxic chemotherapy where it was clear you could not cure anyone once you had microscopic recurrence of cancer¼breast cancer, for example. Cures in the adjuvant setting don’t mean cures in the microscopic recurrence setting. That was the primary rationale, and that’s why the space is heavily an adjuvant space. For immune checkpoints, I cure patients routinely who have overt recurrent microscopic disease. So it’s not clear yet, to be honest with you, that they cure more patients in the adjuvant setting. I think what we do is, we do expose more patients who don’t need it to therapy, and with it, to toxicity and death. So that’s something to keep in mind. Patient selection is critical in that setting, and we do cause a lot of irreversible side effects. Nobody died on that study, but we all know that, clearly, this is not an innocent drug.
The other thing with overall survival [OS] that we need to keep in mind is that this study was not perfectly designed in terms of access to subsequent immunotherapy in certain areas of the world. One-third of patients will probably never get access to immunotherapy. Versus the melanoma trial, also from Merck, Keytruda (pembrolizumab), was perfectly designed because it guaranteed everybody access to pembrolizumab if they progressed. And interestingly, with years ahead, there’s still no OS benefit. Now they use it more avidly. Why? Because recurrent melanoma is a devastating process. It’s just a very fast, devastating occurrence typically for patients with metastases widespread in the brain and everywhere else. So I think, in that disease setting, it may make more sense. But again, there is no OS benefit so far.
I would say, right now, that patients will select themselves. They’re nervous, they want to do it, I give it to them. I also tell them I don’t think you’re going to make a major mistake by just being under the microscope and being watched. And I think that is supported by the negative trials. Not as a reason against it, but as one where I think it’s clear that it’s not a no-brainer to give with adjuvant therapy. It’s a complicated discussion. We need to study the data carefully. But it’s not like, here’s the data, and now we all need to rush into the adjuvant space, and everybody should have it. That is certainly not the case, and I think the negative trials give us enough warning.
Brian Rini, MD: Yes.
Sumanta Pal, MD, FASCO: You got me, Brian. I was not going to answer that question. I was going to plead the Fifth. No matter how many times I was asked, I was going to plead the Fifth until after ESMO [European Society for Medical Oncology’s annual meeting]. Even if they asked 440 times, I was still going to plead the Fifth.
Brian Rini, MD: I think that was well stated. And again, in fairness, we haven’t seen all the data. There’s a whole lot of differences in detail, but I think it’s the beginning of the conversation. Certainly not the end.
Transcript edited for clarity.