Tian Zhang, MD: Last but not least, we’re going back to an oldie but a goodie—ipilimumab [Yervoy] and nivolumab [Opdivo]. Dr Braun, would you please give us an update of CheckMate 214?

David Braun, MD, PhD: Sure. Absolutely. CheckMate214 is really a pivotal phase 3 trial. It was the one that really brought immunotherapy into the frontline setting for advanced RCC [renal cell carcinoma]. And just as a refresher, it was nivolumab 3 mg, ipilimumab 1 mg in combination for 4 doses given every 3 weeks. And then followed by nivolumab continuation. That’s compared to sunitinib [Sutent], which was standard of care at the time. The coprimary end points were IMDC [International Metastatic RCC Database Consortium risk score] intermediate and poorest populations looking at overall survival, [OS] progression-free survival [PFS], and objective response rate. It really was superior to sunitinib on all those accounts and at the time it was originally published the landmark New England Journal of Medicine articlein 2018, there was a median of around 2 years, 25 months of follow-up. Now there’s an update given by Dr R.J. Motzer [MD, at Memorial Sloan Kettering Cancer Center] and colleagues at ESMO [European Society for Medical Oncology meeting] this past year that had a minimum of 5 years of follow-up. Thus, I think this is actually a really important update because it tells us a lot about the durability of these new therapies. Something that we’re hoping not just a response but long-lasting response. Sometimes, responses might last indefinitely. This really provides a window into that. At ASCO [American Society of Clinical Oncology] GU [Genitourinary Cancers Symposium], Dr … in his talks brought up the idea how it started and how it’s going and look at this for CheckMate 214. How it started in 2018 and how it’s going at ASCO 2021. We have the updated follow-up. I think for some of the IO [immuno-oncology]/TKI [tyrosine kinase inhibitor] combinations there’s at least the question of whether that durability holds up to the same degree. I know some people have been following the hazard ratios for OS or PFS and maybe they start to trend up a little bit. I think that’s an open question. But here’s a situation where we really have pretty extensive follow-ups so we can really see how things compare over time. I think biologically there’s a rationale for thinking that this additional agent, ipilimumab, a CTLA-4 blockade agent, really could add durability to these responses. If we go back again to 2018, to when it was reported then, the hazard ratio for overall survival for the intermediate poorest patients was 0.63. Now it’s 0.68. Thus, really stable. The median at the time wasn’t reached. Now, it’s 47 months, so just about 4 years for the intermediate poorest population, and 55 months, 6 years for the overall population. The PFS actually looks like it’s gotten better. Hazard ratio was 0.82 when it was first reported in 2018. Now it’s actually improved to 0.73 in favor of nivo [nivolumab] plus ipi [ipilimumab], again in that intermediate poorest population. I think that’s something to me that’s just [an] incredible statistic is what is the landmark 5-year survival. We think back to these awful not from that long ago to 2010 where the survival rate for stage IV kidney cancer was probably in the single digits or low double digits. Here at 5 years, 48% of the overall treated population was alive at 5 years and even in that intermediate poor risk group, 43% were alive. Nearly half of patients were alive at 5 years. Hence, I really think this inflection point for immunotherapy show that durability is possible. Just still not for enough patients. An additional interesting analysis that was done was a conditional analysis. It sort of plays with this idea of durability. The idea was if you’re in response at 1 year or 2 years or 3 years, what is your chance of still being a response 2 years later? Again, it gets at this sort of idea as to whether or not is this durable? If you’re responding 2 years in, are you very likely to still be responding 4 years in? The answer is overwhelmingly yes. For patients who made it to 2 years of response, there’s somewhere an 80% or 90% chance that they’d still be responding 2 years after that. Again, really hints at the potential durability of immunotherapy.

I think with these drugs though, there are all of these positives, I think we have to acknowledge the challenges and that is there are higher rates of immune-related adverse events, and those have to be monitored closely and managed appropriately. I think 1 thing that sort of people have started to think about is, do we use different starting doses or different regimens for this combination? I think personally in my practice I don’t. I think the nivo3 [nivolumab 3 mg]/ipi1 [ipilimumab 1 mg] combination is what’s really been shown and really has demonstrated efficacy. I stick to the every 3 weeks [regimen]. I will say there is some emerging data that’s interesting. There’s a trial now in the UK [United Kingdom], the PRISM study, which actually looked at an alternative dosing schedule. Not dose but dosing schedule for ipi [ipilimumab]. Rather than giving that every 3 weeks, giving that every 12 weeks and looking at whether it’s still as effective and whether there’s a decrease in toxicity. Again, CAUTION was a small study. It’s a phase 2. It’s around 120 patients randomized to this new schedule. Around 60 patients or so on the traditional ipi [ipilimumab] schedule. At least on these initial data, I think there is kind of a signal there. When we’re to look at the significant treatment-related adverse events, the grade 3 or 4 events, it was around 30% in this 12-week ipi [ipilimumab] schedule, whereas over 50% for the traditional 3-week ipi [ipilimumab] schedule, the efficacy seems to be pretty similar between the 2. Again, CAUTION is a small study, but I think it’s something that certainly merits further investigation because there are certainly those patients that go in that we’re nervous about the risk of immune-related adverse events. They have comorbid conditions, they might be frail, or might not be able to withstand toxicity and so at least, clean the possibility that one could diminish the toxicity without really significantly impacting the advocacy is really appealing. Something I hope is explored more in the future.

Tian Zhang, MD: Excellent. Thanks so much for that overview. I think what you highlighted about extending this overall survival and really showing those 5-year end points for CheckMate 214 and the durable responses. If people are responding at 2 years, they are most likely than not to be still responding 4 or 5 years later is really important for our study populations and patients in our clinics. You’re highlight of the ipilimumab typical dosing, a little bit more spaced out can help us manage these immune-mediated toxicities more since I do think that CTLA-4 blockade is somewhat associated with higher toxicities. Wonderful, David. Thank you so much.

This transcript has been edited for clarity.