Rohit Kumar, MD, assistant professor, the Department of Medicine, the University of Louisville, discusses the benefits of combining immunotherapy agents with each other or with TKIs in patients with renal cell carcinoma (RCC) and the unmet needs that remain for patients with RCC who do not respond to immunotherapy.

Dr. Kumar on TKI/Immunotherapy Doublets in RCC

TKIs are an established therapeutic option for patients with RCC, and adding immunotherapy to the armamentarium has changed the RCC treatment landscape, Kumar says. Patients with RCC who receive immunotherapy, even those with stage IV disease, are experiencing years-long progression-free survival, as well as overall survival of up to 5 years, meaning some of these patients are likely cured, Kumar explains. The addition of immunotherapy agents to TKIs or to other immunotherapy agents is a step forward for RCC treatment, Kumar highlights.

Many patients with clear cell RCC are responding to immunotherapy doublets, even those with advanced disease, Kumar notes. However, there is still an unmet need for treatment options after patients have progressed on TKI/immunotherapy or immunotherapy/immunotherapy combinations, Kumar says. In the frontline setting, immunotherapy/immunotherapy combinations have an 18% primary progression rate, meaning 18% of patients progress while on this treatment, Kumar explains. Since an unspecified subgroup of patients with RCC does not respond to immunotherapy, more research to develop more effective options is crucial, Kumar emphasizes.

Ongoing trials are investigating genetics and mutation genomics to determine which patients with RCC do not respond to immunotherapy and why, Kumar notes. Research is evaluating whether this primary progression on immunotherapy can be predicted, and whether other treatment options, such as triplet therapies or novel agents, may disproportionately benefit a subgroup of patients, Kumar says. Successful outcomes from this research may fulfill this large unmet need in patients with RCC who progress on immunotherapy, Kumar concludes.

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Rohit Kumar, MD, discusses the benefits of combining immunotherapy agents with each other or with TKIs in patients with renal cell carcinoma and the unmet needs that remain for patients with RCC who do not respond to immunotherapy.

Dr. Kumar on Immunotherapy Combinations in RCC

Rohit Kumar, MD, assistant professor of Medicine, University of Louisville, medical oncologist, University of Louisville Health, Brown Cancer Center, discusses the current and future uses of triplet combinations in metastatic renal cell carcinoma (RCC).

Immuno-oncology (IO)–based doublet combinations with other IO agents or TKIs have become the standard of care in the frontline setting for patients with metastatic RCC, and these combinations include ipilimumab (Yervoy) plus nivolumab (Opdivo) or nivolumab plus cabozantinib (Cabometyx).

TKI and IO combinations have been established across clinical trials, and NCCN guidelines currently recommend axitinib (Inlyta) plus pembrolizumab (Keytruda), cabozantinib plus nivolumab, and Lenvatinib (Lenvima) plus pembrolizumab, Kumar explains.

Although these doublet combinations have an established role in the treatment of RCC, triplet combinations could represent the next logical step for investigators, Kumar notes. Specifically, Kuman ponders if an IO-IO combination could become a triplet with the addition of a TKI.

For example, the phase 3 COSMIC-313 trial (NCT03937219) examined the combination of cabozantinib with nivolumab and ipilimumab, and the study met meet its primary end point of progression-free survival (PFS). Additionally, the ongoing phase 3 PDIGREE study (NCT03793166) is examining different ways of combining and sequencing cabozantinib plus ipilimumab and nivolumab.

Although COSMIC-313 had a PFS positive outcome, it is vital to be vigilant for overall survival data the further determine the possible benefit, along with any additional adverse effects (AEs) associated with the triplet, Kumar says. A key for investigators will be to weigh the risk of safety vs the survival benefits, Kumar says.

Although there was a PFS benefit in COSMIC-313, the response rates for the triplet also left something to be desired, Kumar says, adding that the results were similar to what is seen with just an immunotherapy-based doublets. Triplet therapy remains potential way to improve the treatment landscape in RCC; however, more research is still needed, Kumar concludes.

Rohit Kumar, MD, discusses the current and future uses of triplet combinations in metastatic renal cell carcinoma.

Rohit Kumar, MD

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