Dr. Laurence Albiges on Results of Arm B5 of KEYMAKER-U03B for Belzutifan Plus Lenvatinib in accRCC

Laurence Albiges, MD, PhD, Gustave Roussy Cancer Institute, details what previous research has suggested about belzutifan in pretreated RCC prior to KEYMAKER-U03B, what KEYMAKER-U03B hopes to accomplish, what the outcomes were for patients in arm B5, and what the next line of research may be for belzutifan for patients with progressive RCC.

What has previous research suggested about belzutifan in pretreated RCC prior to KEYMAKER-U03B?

Dr. Albiges: Up until a few years ago, we had basically a few mechanisms of action being VEGF-TKI inhibitors, one we being PD-1/PD-L1 inhibitors, and now we’re waiting for a new class of drug.

One HIF inhibitor is currently being clearly investigated: belzutifan. We’ve seen data from phase 1/2 with single-agent belzutifan being active in patients who previously failed standard of care.

We’ve seen belzutifan data in patient with VHL disease, but that is another story and is FDA approved. But the question is, is single-agent already approved in the setting? The response is, for all comers TSLRCC, we are waiting from an important randomized phase-3 that is comparing belzutifan with everolimus in patient who previously failed standards of care, meaning pretreated patients. We are still waiting for the results of this 005 study. So, as of now, we don’t yet have access to belzutifan in previously treated patients.

What does KEYMAKER-U03B hope to accomplish? What is the “adaptive umbrella” design and what are the patient inclusion criteria?

Dr. Albiges: What we’ve seen is combination therapy, our standard of care with a PD-1/PD-L1 inhibitor in frontline setting. What we are looking for is, what should we do in patients who fail prior immune checkpoint inhibitor? There is a need to develop new combinations, or at least to explore new combinations.

KEYMAKER-U03B is a randomized phase 1/2 multi-center, multi-arm, open-label umbrella study. It has been built to investigate several types of combinations in patient treated for clear cell RCC, who have failed immune checkpoint-based regimens in the past. There are several arms in this study, and it’s a very large phase 1. The idea is to explore safety and efficacy of combination therapy in patients who have previously progressed under PD-1/PD-L1 inhibitor, as well as VEGF-TKI. This study aimed to enroll about 50 patients per arm, with a reference arm of lenvatinib plus pembrolizumab.

Among these different arms that are being explored as part of the umbrella U03B study, the new data reported involves the combination of lenvatinib plus belzutifan. Therefore, the combination of the potent VEGF-TKI lenvatinib, plus the HIF1/HIF2-alpha inhibitor belzutifan. That is new, because this is the first time we are reporting on this activity of this regimen.

What were the outcomes for patients in arm B5, and what do these data suggest?

Dr. Albiges: At the time of data presentation, about 150 patients had been enrolled in this randomized phase 1/2. With regard to arm B5, which is the one reported, belzutifan plus lenvatinib, 32 patients have been assigned and 30 treated. Basically, we are reporting on those 30 patients treated with belzutifan plus lenvatinib. This is, of course, an early report because we have for now a median time from randomization to the data phase cutoff of 6.9 months, so these are very early data.

About 12 patients were enrolled in the safety run-in phase, and then the expansion, although, to those 30 treated patients treated with the lenvatinib plus belzutifan, what we can say is that these patients were pretreated per definition in this trial, and heavily pretreated. Basically, about 20% were in second line and about 50% in third line. Approximately 34% of patients were treated in later lines. So, clearly we’re talking about heavy pretreated patients, all of which we received prior ICI.

The response rate, which after safety is the endpoint that we will be focusing on, was assessed in all the patients who had the opportunity to have 2 postbaseline scans. Given the follow-up, we only have 24 patients that received 2 postbaseline CT scans.

A key finding in the study is the response rate of 50%, meaning 1 patient out of 2 had an objective response. This is very important data because we stress the fact that those patients were previously treated, and therefore having a response rate of 50% is absolutely encouraging, and we would like to have more data to further develop this approach. It’s too early to see complete response, so all those responses were partial response, and we had very limited number of upfront PD. Only one patient out of the 24 had upfront PD.

It’s also too early to see the median duration of response, but at the time of the analysis, 3 patients out of 4 were still responding with the follow-up that we had. Therefore, it’s clearly a very strong signal of activity, and this regimen is currently being assessed in a randomized phase 3 against cabozantinib. This combination is prospectively assessed in phase 3 at this very moment.

Among the other key findings is, of course, the question of safety. As anticipated, the combination, meaning a potent VEGF-TKI associated with high blood pressure and diarrhea, is combined with our HF2 inhibitor belzutifan, which is associated mostly with anemia. High blood pressure and anemia are the two toxicities that were anticipated and that are confirmed in this combination trial, with no new safety signal found. In other words, we saw the toxicity expected from each of those two drugs.

What is the next line of research for belzutifan for patients with progressive RCC? What are the ongoing clinical trial efforts?

Dr. Albiges: What is important to the community is our ability to bring new classes of drug to our patients. That means assessing the activity in all comers, but ultimately being able to pick the winners, meaning developing translational work to assess who in our patients are more likely to respond to a belzutifan, for instance.

I would be tempted to say that we need to develop the biomarker piece, and we need to assess this regimen earlier on in the disease. I will also mention the fact that in the frontline setting, there is currently an ongoing phase 3, the 012 study, looking at the combination of standard of care lenvatinib plus pembrolizumab versus the same regimen plus belzutifan, meaning the we add the HIF inhibitor, or a regimen where a CTLA-4 inhibitor is added.

We are aiming at really making a change with this three-plex strategy. We have to have in mind that the safety may be an issue. We have to be able to select the patients that are eligible for treatment, and those three-plex approaches needs to provide a significant change in outcomes for our patients, either in response rates, CR rates, or long-term overall survival benefits. That should be our goal.

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