Therapeutic Sequencing Strategies for Advanced Kidney Cancer - Episode 12

Immunotherapeutic Combinations for mRCC: IMmotion-151


Daniel George, MD: For this last segment, we’re going to talk about emerging concepts and combination strategies for metastatic renal cell carcinoma. Brad, why don’t you start us off with a little bit of the rationale for using immunotherapies in combination in renal cell carcinoma?

Bradley McGregor, MD: We look at this, and there have obviously been a lot of trials that looked at combining more immunotherapies. We had CheckMate-214 using ipilimumab with nivolumab, with the idea of using that CTLA-4 to enrich the T-cell population and then turn them on, if you will, with PD-1 blockade. And then, we’ve had multiple studies, phase I and phase II trials, that have already finished accrual looking at combinations of VEGF TKIs with immunotherapy and simplistically thinking, “Well, maybe I’m just killing the tumor cells to enrich the immune response.” But I think there’s probably a lot more to it than just that. There have been data by Dave McDermott that show these VEGF therapies are really doing more to the actual immune environment, changing the regulatory T-cell environment and enriching the cells for a better immune response. Clearly, it’s a synergistic effect when you start combining these drugs.

Daniel George, MD: I think that’s one of the really interesting things now, thinking about ways to create not just a little bit of additive effect but a synergistic effect. I think you’re right—mechanistically, it’s going to be hard to say we fully understand these patterns. I think we’re going to have to be careful to look at toxicity, because what we don’t want to see is synergy on the toxicity side, as well. But what’s nice about some of these really disparate mechanisms is that they may have the opportunity to play off of each other from an efficacy standpoint without necessarily overlapping toxicity too much. Great. Nick, do you want to tell us about the IMmotion-151 trial? That is one of the highlights here at ASCO GU 2018, and one that I think we’re going to be looking toward leading the field.

Nicholas J. Vogelzang, MD, FASCO, FACP: We’ve covered nivolumab/ipilimumab. I just want to make certain everybody has got that pretty clearly in mind. That was the first one out of the block, and it set a new standard, I think. We’re going to all look forward to it. I’m not sure I’m going to know how to give ipilimumab because I don’t give ipilimumab, but I’m going to have to learn. But I did participate pretty heavily in the development of the atezolizumab and Avastin, or bevacizumab, trial. We did the randomized phase II trial where atezolizumab actually beat sunitinib: not by a lot, but it wasn’t inferior. In the subset of patients, the atezolizumab/bevacizumab combination was quite good—about 14 months in the PD-L1—positive patients. That was a randomized phase II study. We’ve heard that presented by Mike Atkins last year at ASCO. Bob Motzer—“Iron Man Bob”—presented another randomized phase III study, this time of atezolizumab and Avastin, or bevacizumab, compared with sunitinib. The results were, I think, powered for the PD-L1–positive patients.

Daniel George, MD: Based on those phase II data.

Nicholas J. Vogelzang, MD, FASCO, FACP: Yes.

Daniel George, MD: It made sense based on what we saw.

Nicholas J. Vogelzang, MD, FASCO, FACP: It’s perfectly logical.

Daniel George, MD: We should look at it in a phase III in that group.

Nicholas J. Vogelzang, MD, FASCO, FACP: It was a low bar. It was greater than 1% or something like that, and the results were that PFS was 7.7 months for sunitinib and 11.2 months for atezolizumab/bevacizumab. It’s all right. The hazard ratio was 0.75 and the P value was 0.02. Toxicities were not significantly different. In fact, they were maybe a little better with the double combination. The duration of response was pretty respectable and not even reached yet in the doublet arm. The objective response rate was about 43%. So, I think as we see these data presented and analyzed, it’s a reasonable immunotherapy/VEGF combination. It’s certainly well tolerated. It’s IV every 3 weeks, which is convenient from the patient perspective, and probably a bit pricey, but it avoids the whole issue of TKI toxicities. I think it’s a reasonable contender against nivolumab/ipilimumab. Now, I don’t have any experience with nivolumab/ipilimumab, but I’ll let you guys tell me how this stacks up against nivolumab/ipilimumab.

Neeraj Agarwal, MD: I just heard you talking about progression-free survival of 11.4 months and the response rates of 43%. I don’t find them very different from the population—the intermediate- and poor-risk population or intention-to-treat (ITT) population—in the ipilimumab/nivolumab CheckMate-214 trial. If you just look at the cross-trial comparison with the caveat of different patient populations possibly happening, I see the progression-free survival and overall objective responses as fairly comparable.

Daniel George, MD: But that was in a PD-L1—positive population.

Nicholas J. Vogelzang, MD, FASCO, FACP: Yes, but the ITT populations were very similar, I think. I’ve got the ITT data here. IIT included all-comers, and it was 8.4 months for sunitinib and 11.2 months for atezolizumab/bevacizumab. The P value was identical, 0.02, and the objective response rate was very similar, so I think they powered it for the PD-L1—positive, but the ITT was spot-on in the same population.

Robert Alter, MD: I think it’s also impressive. Even though the response rate was 35% or 36%, there still was a 50% CR rate in the patients who were PD-L1—positive receiving the combination. I think that’s also important. It’s back to PD-L1 testing again.

Nicholas J. Vogelzang, MD, FASCO, FACP: It’s a contender, and certainly being every 3 weeks with 2 drugs that most medical oncologists are pretty comfortable with makes it a reasonable option.

Neeraj Agarwal, MD: I would be curious to see their use of corticosteroids in this trial, whereas the use of corticosteroids in the ipilimumab/nivolumab trial was close to 60%.

Nicholas J. Vogelzang, MD, FASCO, FACP: I think they presented that. I thought I had the data. They weren’t very high.

Neeraj Agarwal, MD: I think it was a very well-tolerated regimen.

Daniel George, MD: I think that’s good to know for the community, right? When we look into real-world experience with our patients, frequently we see toxicities are harder than what we see in the clinical trials reported.

Robert Alter, MD: I think they saw a little bit more hypertension, obviously because of the Avastin aspect, but again, it was mostly grade 1 and grade 2. We’ve been learning how to take care of hypertension, too.

Neeraj Agarwal, MD: It’s definitely a new option and a very valued option.

Transcript Edited for Clarity