Ongoing Trials Investigate Intensified Frontline Therapy for RCC


Bradley A. McGregor, MD, discusses new trials of intensified combination regimens for frontline treatment of patients with intermediate- or poor-risk advanced renal cell carcinoma.

Bradley A. McGregor, MD, clinical director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and instructor in medicine at Harvard Medical School, discusses new trials of intensified combination regimens for frontline treatment of patients with intermediate- or poor-risk advanced renal cell carcinoma (RCC).

The current frontline therapy for intermediate- and poor-risk patients is a choice between immunotherapy (IO) and tyrosine kinase inhibitor (TKI) combinations or the IO/IO combination of ipilimumab (Yervoy) plus nivolumab (Opdivo). Ipilimumab/nivolumab tends to offer more durable responses but a lower objective response rate than IO/TKIs.

McGregor says some randomized trials are attempting to improve on the outcomes of IO/IO and IO/TKI combinations through intensified therapy. This includes the COSMIC-313 trial (NCT03937219) comparing cabozantinib (Cabometyx), nivolumab, and ipilimumab versus nivolumab/ipilimumab alone. Additionally, the 3-arm MK-6482-012 trial (NCT04736706) will evaluate lenvatinib (Lenvima)/pembrolizumab (Keytruda) versus lenvatinib, pembrolizumab and belzutifan (Welireg), versus pembrolizumab/lenvatinib plus quavonlimab, a novel anti­–CTLA-4. The PDIGREE trial (NCT03793166) will add cabozantinib after an initial treatment of nivolumab/ipilimumab.

For now, McGregor feels that if a patient needs a response in the first line, an IO/TKI would be used. But if he thought a patient could continue to be treated, if they do not respond to frontline therapy, he would choose ipilimumab/nivolumab and then a second-line TKI.


0:08 | When we look at intermediate/poor-risk disease, obviously I think therapy is indicated. There are trials ongoing to see: Can we improve upon the IO/TKI doublets or nivolumab/ipilimumab? So COSMIC-313 has accrued; this was limited in intermediate/poor disease and looked at combination of cabozantinib and nivolumab/ipilimumab versus nivolumab/ipilimumab. So can we get the increased response rate on the TKI/IO combinations with the durability of nivolumab/ipilimumab? We look forward to those results.

There's an ongoing trial with lenvatinib and pembrolizumab versus lenvatinib, pembrolizumab and CTLA-4 versus lenvatinib, pembrolizumab, and belzutifan that is currently accruing. So I think it'd be really important to think about this idea of intensification.

0:57 | Until we know if intensification is going to be important, we're left with IO/IO versus IO/TKI. And that's where, if I have a patient who I feel that they have progressive disease as their best response, they can likely go on to a TKI. I'm going to think about nivolumab/ipilimumab. I strongly support the ongoing PDIGREE trial, which starts with nivolumab and ipilimumab, and then based on response, will look at adding cabozantinib to nivolumab versus nivolumab alone, so this [would be an] adaptive approach. I think those are going to be really important data to help us further improve care for our patients.

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