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SAN FRANCISCO -- First-line nivolumab (Opdivo) plus cabozantinib (Cabometyx) continued to demonstrate clinically meaningful survival benefits in advanced renal cell carcinoma (RCC).

An update of the , which compared the immune checkpoint inhibitor/tyrosine kinase inhibitor (TKI) doublet with the TKI sunitinib (Sutent), showed that after 44 months of median follow-up, median progression-free survival (PFS) was 16.6 months versus 8.4 months, respectively (hazard ratio 0.58, 95% CI 0.48-0.71, P<0.0001). Overall survival (OS) at data cut-off was 49.5 months versus 35.5 months, respectively (HR 0.70, 95% CI 0.56-0.87, P=0.0014), reported Mauricio Burotto, MD, of the Bradford Hill Clinical Research Center in Santiago, Chile.

These survival benefits were mostly sustained regardless of patient risk classification, Burotto observed. "These results continue to support [nivolumab/cabozantinib] as a first-line treatment for patients with advanced or metastatic RCC," Burotto said at the ASCO Genitourinary Cancers Symposium (GuCS).

At the 2022 GuCS, Burotto and colleagues reported that at a median follow-up of , median OS with nivolumab/cabozantinib was 37.7 months. The latest reported OS, with its increase of 11.8 months, "is remarkable...we had probably not expected that much when looking at the last data," said GuCS discussant Manuela Schmidinger, MD, of the Medical University of Vienna. "So the initially reported results remain robust after longer follow-up and, like wine, is getting better with age."

The open-label, randomized, phase III trial was conducted in 125 hospitals and cancer centers across 18 countries, with 651 patients with previously untreated advanced or metastatic clear-cell RCC; a Karnofsky performance status of ≥70; measurable disease according to RECIST version 1.1 assessed by the investigator; and available tumor tissue for PD-L1 testing. Patients' median ages ranged from 56-63 and the vast majority were men. Most had a tumor PD-L1 expression of <1% or indeterminate.

Patients were randomized 1:1 to IV nivolumab (240 mg) every 2 weeks plus cabozantinib (40 mg) orally once daily, or oral sunitinib (50 mg) once daily (4 weeks per 6-week cycle).

In addition to the overall PFS results, the investigators found that when patients were stratified into subgroups according to International Metastatic RCC Database Consortium (IMDC) prognostic risk categories, PFS was:

• Favorable risk: 21.4 months (95% CI 13.1-24.8) with nivolumab/cabozantinib vs 13.9 months (95% CI 9.6-18.5) with sunitinib (HR 0.75, 95% CI 0.60-1.13)
• Intermediate risk: 17.5 months (95% CI 12.3-20.3) vs 8.5 months (95% CI 7.0-10.4), respectively (HR 0.61, 95% CI 0.48-0.79)
• Intermediate/poor risk: 16.4 months (95% CI 11.2-19.3) vs 7.1 months (95% CI 5.7-8.9; HR 0.55, 95% CI 0.45-0.69)
• Poor risk: 9.9 months (95% CI 5.9-17.7) vs 4.2 months (95% CI 2.9-5.6; HR 0.38, 95% CI 0.25-0.58)

The OS benefit was, for the most part, sustained when patients were stratified according to IMDC risk scores. For example, in the intermediate/poor risk group, the median OS was 49.5 months (95% CI 34.9-not evaluable) with the combination versus 29.2 months (95% CI 23.7-36.0) with sunitinib (HR 0.65, 95% CI 0.51-0.83). However, there was no difference in OS between the two arms in the favorable risk group (HR 1.07, 95% CI 0.63-1.79).

The overall response rate was 55.7% in the nivolumab/cabozantinib group versus 28.4% in the sunitinib group, with complete responses in 12.4% and 5.2% of the groups, respectively. The median duration of response was 23.1 months and 15.2 months, respectively.

Treatment-related adverse events (TRAEs) of any grade occurred in 97% and 93% of the nivolumab/cabozantinib and sunitinib groups, respectively, with grade ≥3 TRAEs occurring in 67% and 55% of patients, respectively.

In the nivolumab/cabozantinib arm, any TRAEs leading to discontinuation occurred in 27.5% of patients, with 9.7% discontinuing nivolumab only, 9.7% discontinuing cabozantinib only, 6.6% discontinuing both nivolumab and cabozantinib, and 1.6% discontinuing the combination sequentially. TRAEs leading to discontinuation occurred in 10.6% of patients in the sunitinib arm.

How might the updated results affect treatment choices in this patient population? Schmidinger noted that while PFS and OS superiority was particularly pronounced in the IMDC intermediate- and poor-risk populations, "I think, otherwise, at the moment, there is no additional data that will facilitate treatment choices between other strategies that are available."

"I think there are still serious gaps of knowledge when we use immunotherapy/TKI combinations," she added. "I'm pretty sure the choice of TKI matters in such combinations, and we need to know more about the spectrum of target activity of the different involved TKIs, and their pharmacological potency. But this data needs to be studied along with individual molecular properties of the tumor."

In any event, "to make the next big step in kidney cancer, we also need new agents," she concluded.

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