Dr Tykodi on the Selection Between IO/IO and IO/TKI Combinations in Frontline Advanced Clear Cell RCC

"The phenotype of the patient, how much disease they have, and how symptomatic they are [will] influence [treatment] choices."

Scott Tykodi, MD, PhD, an associate professor in the Clinical Research Division and an affiliate investigator in the Translational Science and Therapeutics Division at Fred Hutchinson Cancer Center, as well as an associate professor in the Division of Hematology and Oncology University at Washington School of Medicine, discussed key clinical considerations that inform selection between dual immuno-oncology (IO) combinations (IO/IO) vs combinations featuring IO plus a TKI (IO/TKI) in the frontline treatment of advanced clear cell renal cell carcinoma (RCC).

Patient phenotype, disease burden, and symptomatology are critical in guiding treatment strategy, Tykodi explained. The National Comprehensive Cancer Network Guidelines currently list the IO/IO combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) as a preferred regimen for patients with favorable- or poor/intermediate–risk disease; however, only the poor/intermediate–risk recommendation is listed as category 1. Regarding IO/TKI combinations, axitinib (Inlyta) plus pembrolizumab (Keytruda), cabozantinib (Cabometyx) plus nivolumab, and lenvatinib (Lenvima) plus pembrolizumab all have category 1 recommendations as preferred regimens, regardless of risk. Notably, cabozantinib monotherapy is also a preferred regimen in patients with poor/intermediate–risk disease.

Iniitally, data from the phase 3 CheckMate 214 trial (NCT02231749) initially indicated poorer outcomes for nivolumab plus ipilimumab in favorable-risk patients compared with sunitinib (Sutent) monotherapy, Tykodi said. As a result, use of this IO/IO combination in this population has traditionally been limited, he added; however, longer-term follow-up from the study has demonstrated a potential overall survival (OS) advantage with nivolumab plus ipilimumab in patients with favorable-risk disease, prompting updates to clinical guidelines.

Despite this, most clinicians remain cautious when using IO/IO combinations in patients with favorable. These individuals often present with small-volume, asymptomatic, and indolent disease—such as isolated pulmonary metastases years after nephrectomy, Tykodi said. In such cases, clinicians may favor nivolumab plus ipilimumab to maximize long-term disease control and potentially induce durable responses, accepting the lower initial response rate in exchange for the possibility of prolonged OS. For these patients, the availability of subsequent lines of therapy is a critical safety net should progression occur.

In contrast, patients with high-volume or symptomatic disease at diagnosis are more appropriately treated with IO/TKI combinations, Tykodi elaborated. These regimens are associated with higher initial overall response rates, improved disease control, and lower incidence of primary refractory disease. They provide more immediate tumor shrinkage and symptomatic relief, which is particularly important in patients with rapidly progressive or symptomatic disease, he said.

Tykodi emphasized the value of tailoring therapy based on clinical presentation, with the flexibility to sequence agents based on initial response and emerging therapeutic options.