Dr. Harrison on the Investigation of Combination Strategies in Frontline RCC

Michael R. Harrison, MD, associate professor of medicine, member, Duke Cancer Institute, discusses several ongoing or upcoming studies that may change the treatment paradigm in renal cell carcinoma (RCC).

Clarifying the best use of dual immunotherapy vs immunotherapy and tyrosine kinase inhibitor (TKI) combinations in the frontline setting is an area of high interest in RCC, Harrison begins.

Several ongoing studies aim to maximize responses with existing immuno-oncology (IO)–based doublets by exploring the use of triplet regimens in the frontline setting, he states.

The phase 3 COSMIC-313 trial (NCT03937219) was the first trial comparing a triplet combination with a standard IO doublet in frontline RCC. Initial findings were presented at the 2022 ESMO Congress, Harrison says. In the trial, the addition of cabozantinib (Cabometyx) to nivolumab (Opdivo) and ipilimumab (Yervoy) was compared with nivolumab and ipilimumab in patients with intermediate- or poor-risk advanced or metastatic RCC. Results demonstrated that the trial met its primary end point of improved progression-free survival. Investigators also reporteddecreased progressive disease as best response with the triplet, he details. However, no significant overall survival benefit was observed for the triplet regimen, and longer-follow up data are necessary to clarify the exact role of this therapy.

Other studies in this space may help contextualize results from COSMIC-313 and are set to present their own initial data in the next few years, Harrison continues. These include the phase 3 PDIGREE study (NCT03793166), which attempts to determine the optimal sequencing of therapies in RCC. The unique trial design allows patients who progress on the initial treatment of ipilimumab and nivolumab to switch to cabozantinib at week 12, while those achieving complete responses will continue with standard-of-care nivolumab monotherapy. Individuals with stable disease or partial responses will be randomly assigned to either group. Although this study is not directly comparable to COSMIC-313, it may provide more data on the best use of these combinations, Harrison concludes.