The Evaluation of Novel Agents and Combination Regimens in the First-Line Setting in RCC

The panel elaborates on novel agents and combination treatments that are currently being evaluated for the first-line setting in advanced RCC.

Tian Zhang, MD: We’d love to move on to some novel agents and combination strategies being evaluated. I’ll kick it off by highlighting that we did see some activity about a year ago with belzutifan and cabozantinib in the treatment-refractory cohort that was enrolled. Dr [Toni] Choueiri presented this at GU ASCO [American Society of Clinical Oncology Genitourinary Cancers Symposium] a year ago. It showed some good objective responses. Of note, [there was an] almost 90% disease control rate in that treatment-refractory population. That’s a promising combination for us as we go forward. Hopefully we’ll also see that pan out in the frontline setting in ongoing trials.

In addition, I’m a bit biased, but we’ve been enrolling across the country to PDIGREE, an adaptive phase 3 trial, particularly IMDC [International Metastatic RCC Database Consortium] intermediate porous disease with induction ipilimumab-nivolumab followed by nivolumab—like in the CheckMate 214 regimen—or the combination of nivolumab with cabozantinib. The primary end point is hedged on 3-year overall survival [OS], an event-driven end point, and secondary end points around progression-free survival [PFS] of 1-year complete response rates and prospective discontinuation. Many of you have opened or are in the process of opening the study, which is halfway accrued. It’s great to see across the country.

We’d love to hear about the novel triplet regimens in development and in ongoing trials. Dr Barata, can you summarize for us the COSMIC-313 trial?

Pedro C. Barata, MD, MSc: Yes, we can highlight it. By the way, PDIGREE is doing great so congratulations for that. Just to quickly highlight COSMIC-313. It’s a superimportant trial. It asks the question for the first time. We’ll see the role of a treatment therapy, so as a reminder of the design: it’s a phase 3 trial taking 840 patients or so with advanced RCC [renal cell carcinoma] and clear cell to ipilimumab-nivolumab plus cabozantinib. For the first time, we’re testing the combination of TKI [tyrosine kinase inhibitor] to a backbone of 2 checkpoint inhibitors, nivolumab and ipilimumab. A primary end point was progression-free survival, and a secondary end point was overall survival. That’s important because it’s the first leverage on interesting data from Dr Andrea Apolo proving the safety of these treatment combinations. We’re all very curious to see the results of this trial. It obviously depends on events, but it’s planned to be out later this year, so it’s a very important study.

Tian Zhang, MD: Wonderful. These triplets are very exciting. Let’s move on to the other triplet open, the triplet that I recently understood was the “light spark” series of trials. Dr Bilen, talk us through the other triplet that’s ongoing.

Mehmet A. Bilen, MD: This is another important triplet open and enrolling multiple sites around the country and internationally. It has similar eligibility: advanced metastatic clear cell RCC, no prior therapy. This is a 3-arm trial. The control arm is pembrolizumab plus lenvatinib, but in this clinical trial pembrolizumab is given 400 mg IV [intravenous] every 6 weeks. This will be easier for our population in terms of the number of infusions. There are 2 experimental arms. One is HIF2-alpha plus PD-1 plus TKI, which is belzutifan, pembrolizumab, and lenvatinib. The other experimental arm is a CTLA4, PD-1, TKI combination, which is MK-1308A. This is a core formulation of pembrolizumab plus Merck CTLA4, which is every 6 weeks infusion plus lenvatinib 20 mg once a day. Patients stratify based on IMDC and region. The primary end point is PFS and OS, and the secondary end points will be objective response rate, duration of response, and safety and tolerability.

Tian Zhang, MD: Wonderful summary. Thanks so much, Dr Bilen. We’re all looking forward to both of these triplet trials.

This transcript has been edited for clarity.

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