Combined first-line treatment with nivolumab and cabozantinib significantly improved outcomes over single-agent sunitinib in patients with advanced clear cell renal cell carcinoma (RCC), according to study results presented at the ESMO Virtual Congress 2020.

The combination was well tolerated, exhibiting an adverse-event profile consistent with the known safety profiles of each individual drug.

Nivolumab, an immune checkpoint inhibitor, and cabozantinib, a tyrosine kinase inhibitor, are both used individually as treatments for patients with advanced RCC. Because of the immunomodulatory properties associated with cabozantinib that can counteract tumor-induced immunosuppression, researchers hypothesized that combination therapy with nivolumab might be effective.

The phase 3 CheckMate 9ER clinical trial recruited 651 patients with advanced RCC, whom the researchers randomly assigned to treatment with nivolumab (240 mg intravenous flat dose every 2 weeks) plus oral cabozantinib (40 mg daily) or oral sunitinib (50 mg daily for 4 weeks). Treatment continued in 6-week cycles until disease progression or unacceptable toxicity.

Progression-free survival (PFS) by blinded independent central review served as the primary endpoint. Overall survival (OS) and objective response rate (ORR) served as secondary endpoints.

The majority of patients (57.6%) had intermediate-risk disease; 22.6% had favorable-risk disease, and 19.7% had high-risk disease. PD-L1 expression of 1% or higher was observed in 24.9% of the study population.

Median follow-up was 18.1 months. The researchers observed a significant improvement in PFS with nivolumab plus cabozantinib (median, 16.6 months vs. 8.3 months; hazard ratio [HR], 0.51; 95% CI, 0.41-0.64; P < .0001).

Patients assigned the combination also had significantly improved OS (medians not reached; HR, 0.6; 98.89% CI, 0.4-0.89; P = .0010) and a higher ORR (55.7% vs. 27.1%; P < .0001). Complete responses were observed in 8% of patients assigned nivolumab plus cabozantinib and in 4.6% of patients assigned sunitinib.

The median duration of response for patients assigned the combination was 20.2 months, compared with 11.5 months for patients assigned sunitinib.

“The results with combination therapy were statistically significant and clinically meaningful,” said Toni K. Choueiri, MD, director, Lank Center for Genitourinary Oncology and director, Kidney Cancer Center, Dana-Farber Cancer Institute. “The risk of progression or death was cut by almost 50%, death was cut by 40% and the response rate doubled.”

Treatment-related adverse events of any grade occurred in 96.6% of patients assigned nivolumab plus cabozantinib and 93.1% of patients assigned sunitinib. The rates of grade 3 or higher treatment-related adverse events were 60.6% and 50.9%, respectively.

One treatment-related death occurred in the combination cohort; two deaths occurred in the sunitinib cohort.

Treatment discontinuation due to adverse events occurred in 8.8% of the sunitinib cohort and 3.1% of the combination cohort. In addition, 15.3% of patients discontinued nivolumab or cabozantinib, 5.6% discontinued nivolumab only and 6.6% discontinued cabozantinib only.

“This will become an important treatment option to choose from,” said Choueiri. “The various combinations will unlikely be compared head-to-head, but I think quality of life could differentiate this new therapy, as there was a statistical significance favoring the combination arm with both questionnaires we used. Another factor to consider is that clinicians are familiar with both of these drugs.”

Dominik Berthold, MD, head, specialized consultation for urological cancers medical oncology service, Lausanne University Hospital, cautioned that some questions remain unanswered by these results.

“The 18 months of follow-up is still quite short,” Berthold said in a press release. “The question is whether the responses to treatment are durable or patients progress at some point. It would also be useful to learn whether the combination of cabozantinib and nivolumab is effective in non–clear cell carcinoma. This is a minority of patients with advanced kidney cancer which are not well studied and were excluded from this trial.”