Transcript:Daniel J. George, MD: I want to switch gears again and get back to clinical trials. Nizar, you brought these up earlier—there are some , I think, really important ongoing clinical trials now in the metastatic setting. I thought maybe we could highlight a few of these for people to be aware of. So, the CheckMate 9ER study—Joe, what’s that one about?

Chung-Han Lee, MD, PhD: The CheckMate 9ER study is a randomized clinical trial of cabozantinib plus nivolumab versus sunitinib in the first-line setting. It’s a study that has already completed accrual and we’re just kind of waiting to see what the results may end up being for that.

Daniel J. George, MD: Any idea when that might read out?

Chung-Han Lee, MD, PhD: My sense is, it’s probably going to be sometime next year. For us, it’s a very exciting sort of study because cabozantinib by itself has been shown to be superior than sunitinib in the intermediate and poor-risk patients, so whether or not the addition of a checkpoint inhibitor could further enhance that, is something that will be very interesting to see.

Daniel J. George, MD: These are potential other targets in these multi-targeted ones like MET and AXL that Bob, you mentioned earlier. And then there’s the study with lenvatinib as well.

Nizar M. Tannir, MD, FACP: That’s the CLEAR study.

Daniel J. George, MD: That’s the CLEAR study.

Nizar M. Tannir, MD, FACP: Or 307 study and it’s a 3-arm study.

Daniel J. George, MD: Yes.

Nizar M. Tannir, MD, FACP: And it’s pembrolizumab plus lenvatinib versus lenvatinib plus everolimus versus sunitinib. Again, the vast majority of these phase III trials have used sunitinib for comparator, so this is still unknown. CheckMate 9ER has reached its total accrual, but the 307 study, or CLEAR study is still ongoing. I believe it should be completing its accrual this year, maybe third quarter of this year. And, and again, like CheckMate 9ER, I think the CLEAR study will probably read out next year 2020. It started as a 750-patient phase III trial, but then they powered it to really have OS [overall survival] as well as PFS [progression-free survival] as primary endpoints, and it’s now a 1050-patient phase III trial.

What we will have to see is, will CheckMate 9ER and CLEAR 307 studies meet or achieve an OS like KEYNOTE-427, KEYNOTE-426 and nivolumab-ipilimumab, or will because of the availability of all these immune checkpoint inhibitors and other therapies, will they not have an OS and the regulatory agencies approve these therapies with just a PFS and higher response rate. What do you think, Dan?

Daniel J. George, MD: Well, it seems to me if they’re going to find an OS it’s going to have to come early. Because if you don’t see that signal early, then these patients are going to be crossing over, particularly the ones that have access to crossover therapies, multiple therapies. And the likelihood is they’re going to get exposed to all the different therapeutic lines and classes. It’s less and less likely you’re going to see a survival signal 3 years out than you are 1 year out.

Nizar M. Tannir, MD, FACP: It’s going to be very hard to show OS in renal anymore now, right? I think we will have to design trials with different endpoints or not have OS as primary endpoint. Again, maybe treatment-free survival will be an endpoint but maybe aim for a high CR [complete response] rate as the most relevant or helpful surrogate for benefit rather than just OS because it’s going to be very hard to show OS.

Daniel J. George, MD: And that’s a little bit what we’re trying to do with PEDIGREE.

Nizar M. Tannir, MD, FACP: Yes.

Daniel J. George, MD: PEDIGREE is a cooperative group study that’s just opened. We see this around the country now opening up over the next year or so, and this is a randomized study where everybody is treated with sort of a lead-in of nivolumab-ipilimumab. These are intermediate and poor-risk patients—1,000 patients—getting nivolumab-ipilimumab for 4 cycles, 3 months or if they stop early because of toxicity, they get 6 months to recover from that toxicity. They are then randomized at that point to either just nivolumab, which is really the standard of care for those patients, or nivolumab-cabozantinib. The randomization is for the patients that haven’t achieved a CR and don’t have clear progressive disease. There’s sort of that large intermediate group that has some minor responses, some partial response, they’re not a CR yet but maybe they’re on their way. How do we get a higher percentage of patients there? And then that study stops all therapy at a year. To answer that second question, is time-off treatment a new endpoint for some of these studies?

Nizar M. Tannir, MD, FACP: It’s a beautiful design.

Daniel J. George, MD: Time-off treatment.

Nizar M. Tannir, MD, FACP: Very intelligent design.

Daniel J. George, MD: And short-term OS in the first 3 years. Those are the endpoints of that study.

Nizar M. Tannir, MD, FACP: Beautiful design. I think it answers a lot of questions. I mean, the addition of a TKI [tyrosine kinase inhibitor], cabozantinib, in this instance for patients who have stable disease and PR [partial response], not CR or not progressive disease, and then duration of therapy for the CRs. Do you think this trial will finish its target accrual? I think it is ambitious, more than 1000 patients.

Daniel J. George, MD: Well, so the interesting thing is 1000 patients for the lead-in. The actual number of patients needed to randomize is about 650.

Nizar M. Tannir, MD, FACP: OK.

Daniel J. George, MD: It’s not as big as it sounds, but we recognize we’re going to lose some patients in that induction period. Some patients will have significant toxicity that they don’t recover from. Others may have the CR or the PD [progressive disease]. We’re thinking about 70% of the patients will actually get there. Some might screen and fail, and if we can get that 600, 650 through that randomization, we should be able to answer that question.

Nizar M. Tannir, MD, FACP: I hope the trial will reach its targeted accrual and we’ll have results in the near future because I think this is going to answer a lot of questions. It’s relevant. I just hope that you’ll have a lot of the community physicians, oncologists where patients are seen enrolling on the trial or refer patients for enrollment.

Daniel J. George, MD: That’s right. Cooperative group studies are really written for the community. Bob, maybe you can speak a little bit about what it’s like giving nivolumab-ipilimumab in the community. Has that been a struggle or you’ve been able to do that?

Robert S. Alter, MD: It’s very hard. So 15 years ago, 20 years ago when we were giving high-dose IL [interleukin]-2, we were seeing every patient in the community. I think over the course of the last 10 years, physicians feel a little reluctant starting TKI therapies, and they have gotten the sense of accomplishment. They went from sunitinib to pazopanib. They felt a lot more comfortable sequencing therapies. But we used to see these patients in these academic centers as a third or fourth-line targeted therapy. Now what do you do?

Oncologists have been using ipilimumab-nivolumab before GU [genitourinary] oncologists have. They’ve been using it for melanoma non—small–cell lung cancer, so we’re the third kid on the block when it came down to using the combination. They feel very comfortable using it. I think that the development of using an IO/TKI is going to be a little bit of a push. I think they’ll adapt to it relatively soon. It is unfortunate that we cannot get more physicians to refer patients to us to get tested to cooperate with clinical trials in the community, but I think that they have a strong sense to abide by the NCCN [National Comprehensive Cancer Network] Guidelines. It gives them a sense that they can take care of these patients, and they most probably could, but it does decrease our accrual into clinical trials because physicians are feeling a lot more adept to taking care of these patients.

Transcript Edited for Clarity