Experts Discuss the RCC Landscape and Available Therapy for Patients

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.