Tian Zhang, MD: I’d love to go now onto our next combination strategy with cabozantinib [Cabometyx] and nivolumab [Opdivo]. Dr Ornstein, I wonder if you can give us an update on CheckMate 9ER.

Moshe C. Ornstein, MD, MA: Sure. CheckMate 9ER was similar to the other trials. Phase 3 trial of an IO [immuno-oncology] and TKI [tyrosine kinase inhibitor] versus sunitinib [Sutent] and it was cabozantinib at a dose of 40 mg once per day and nivolumab 240 mg once every 2 weeks. The big picture results, which were published in the New England Journal of Medicine demonstrated superiority really across all end points and really across all risk groups as well. The PFS [progression-free survival] was superior at 16.6 months versus 18.3 months. The objective response rate 55.7% for the combination of cabozantinib and nivolumab versus 27.1% for the patients receiving sunitinib. The hazard ratio for overall survival came through very favorable at 0.6, which is a 40% risk reduction, and similar to the other trials there were of course grade 3 toxicities notable in both arms. But only about 19% of patients required high-dose steroids which is the equivalent of 40 mg of prednisone or its equivalent per day. And that’s particularly referring to the cabozantinib and nivolumab arm. Where we are concerned, as Dr Barata mentioned about, the immune-related adverse events. A couple things to highlight has to do with the dosing. The dosing in this combination for the cabozantinib, when we give it as a single agent in the relapse and refractory setting, we use 60 mg as the general starting dose based on the trials that led to its approval. But in combination with nivolumab, it’s given as a 40 mg dose which might lend it to be a little bit better tolerated in combination with nivolumab. What I would like to highlight is the update that we just saw at ASCO [American Society of Clinical Oncology] GU [Genitourinary Cancers Symposium]. They presented a 2-year final OS [overall survival] analysis with a median overall survival for the combination of cabozantinib and nivolumab at 37.7 months versus 34.3 months for patients receiving sunitinib. The median PFS really didn’t change. It was 16.6 months versus 8.3 months. But I do think looking at these landmark OS and PFS analyses, notably the 24-month mark, is important because it really gives you a sense when you’re facing a patient what can I tell the patient based on the trial to expect at 2 years for instance. And the 24-month OS was 70% for the combination of cabo [cabozantinib]/nivo [nivolumab] versus 60% for patients receiving sunitinib. And the 24-month PFS 39.5% versus 20.9%, again cabo [cabozantinib]/nivo [nivolumab] versus sunitinib, respectively. Another thing to point out is the CR [complete response] rate. The complete response rate, which we don’t know for sure what to make of it, but we do know that when there’s a complete response it’s good. And in the updated analysis the cabozantinib and nivolumab group had a 12.4% CR rate versus 5.2% for the sunitinib group. I think in summary what we see from the updated analysis is not only that these efficacy results are holding up but that it seems to be tolerable. The OS holds up at landmark analyses. Thus, does the PFS and the CR rates look very impressive for cabozantinib and nivolumab, and taken together really does establish it as 1 of the standards of care for patients for treatment-naïve metastatic RCC [renal cell carcinoma].

One thing to consider with really any of these regimens, but specifically with cabozantinib and nivolumab, is here’s a combination that has durable effect, but really these drugs tend to work only if we can get them to the patients. And with toxicities that differ between cabozantinib and nivolumab, but with toxicities that also sometimes have a little bit of overlap. It’s important to be able to manage these toxicities appropriately so that we can keep patients on therapy for their benefit. One thing I do is, and one way to go about this is, to first try to identify is the toxicity a classic immune-related adverse event? Sometimes a patient comes in with pneumonitis and you just know it’s from the immunotherapy. Or to figure out is this something that’s much more classically a TKI mediated adverse event. These drugs have been around now for a long time and some of them are easily recognizable like hand-foot syndrome. In those scenarios, you can address either 1 of those. Either you’re giving steroids for the immune-related adverse event or you’re giving supportive care, breaks in therapy, dose reductions, etc. for the TKI-mediated toxicity. For those that have potential overlap, say diarrhea or elevated liver enzymes, 1 option is to hold both agents, or especially the TKI, and to give it a couple of days to see if there’s resolution. I would say that I tend to be a little bit trigger-happy when it comes to giving steroids. If I think that I need to give steroids I give it, because in the short period of time it’s probably not going to impact the long-term outcome and I could potentially save someone who’s got a really rough adverse event. But I do think in a patient who’s nontoxic, holding both therapies to start to tease out whether the LFTs [liver function tests] are now going down without steroids and just being off the cabozantinib can really allow a physician to figure out which drug is the offending agent, and then to address it appropriately. Again, the general management for the immune-mediated adverse events is going to be steroids and other immunosuppressants, and then you’re faced with the question at what point if ever you can resume the immunotherapy, the nivolumab in this case. With TKIs, we’re well-versed with the general management of either dose reductions, dose interruptions, supportive care, preventative care, but I do think it’s important with all these combinations to really pay attention to the toxicity because we know that patients need to be on these drugs for longer period of time. I do think in some ways this plays into that starting dose that I mentioned earlier, 40 mg. Since we see this tremendous benefit of the combination at the lower dose, I think it’s wise to start at the dose that was in the trial, which is the cabozantinib at 40 mg. Then, if any toxicities show up to manage them accordingly and to consider dose reductions if they are recurrent and they are definitely related to the cabozantinib.

Tian Zhang, MD: That’s a really important point of making sure we start at those starting doses for trials. Certainly, if we’re starting at a lower dose, it’s really for patient comorbidities and frailty. This is a really wonderful discussion about those adverse event management. Thank you so much, Moshe.

That’s a wonderful summary, Moshe. Particularly, your highlight of overall survival—the recent update. Oftentimes, we’re thinking about whether combination strategy is better than sequential and in this particular case, I think we’re seeing good benefit from the combination.

This transcript has been edited for clarity.