Key opinion leaders reflect on novel treatment modalities still under investigation for the management of advanced renal cell carcinoma.
Ulka N. Vaishampayan, MBBS: What are some of the novel pathways or new treatments being developed in kidney cancer?
Moshe Ornstein, MD: That’s interesting. As we look forward to the next steps in research in developing the next regimens for patients with kidney cancer, there’s 2 main ways I think about this: Are we going to develop novel agents? Then I think about studies [such as] LITESPARK or PIVOT-09, [in which] we’re trying to incorporate belzutifan, [which is] an HIF-2α [hypoxia-inducible factor-2α] inhibitor, or some form of an agent that’s going to work along the cytokine/IL-2 [interleukin-2] pathway using novel agents. In the other category are trials such as PDIGREE [NCT03793166] and CheckMate 8Y8, which are telling us more about how we use the agents we currently have. [For instance], in PDIGREE, [having a risk-adapted approach] for patients getting ipilimumab and nivolumab up front [and knowing when to stop therapy for patients] who have disease progression. Or in CheckMate 8Y8, understanding [whether] there is a need for ipilimumab and nivolumab or [whether] we can give nivolumab alone. I tend to split the trials into those categories of novel agents vs optimizing our current regimens. But what about commenting on the triplets that are ongoing and some [that have] been reported? What are your thoughts about those?
Ulka N. Vaishampayan, MBBS: One of the triplets that was recently reported [was cabozantinib with ipilimumab and nivolumab in]the COSMIC-313 trial [NCT03937219]. The study met its primary end point, which was progression-free survival [PFS], and the triplet showed a significant improvement in PFS as compared [with] ipilimumab and nivolumab. The study is an important one because it did show that, with the new control arm of [ipilimumab and nivolumab], the triplet did add value. However, when balanced with the toxicities for a small PFS advantage, is it really going to be used and translated into clinical practice? I think we will need overall survival data to be sure of considering that in the frontline setting. There are other triplets that are currently in clinical trials, 1 of which is lenvatinib [and] pembrolizumab with belzutifan, which is an HIF-2α inhibitor. That’s a novel agent that is being incorporated into the triplet up front to see [whether] that is better than lenvatinib and pembrolizumab as a control.
Moshe Ornstein, MD: I agree. It’s nice to see that we’re saying because 2 agents have traditionally been better than 1 in kidney cancer, we’re trying to push the envelope with 3. I think it’s ultimately going to come down to a balance of efficacy and toxicity. Right now, the gold standard is overall survival, given the IO [immuno-oncology]-based therapies we have. So until we see that, it’s going to be hard to move a triplet into the frontline setting.
Ulka N. Vaishampayan, MBBS: Especially if sequential is similar. The adaptive method in PDIGREE was explored, [and] if that turns out to be similar to the doing the triplet up front, [then] that may be another reason. Although the adaptive method hasn’t been terribly successful for ipilimumab and nivolumab, [there were very modest response rates when] starting with nivolumab up front and then adding ipilimumab. For that regimen, it’s become clear through multiple trials that you need to use that combination up front, and adding ipilimumab later does not give you similar types of benefits.
Transcript edited for clarity.