As reported in The New England Journal of Medicine by Toni K. Choueiri, MD, and colleagues, the phase III CheckMate 9ER trial has shown that the combination of nivolumab and cabozantinib improved progression-free survival and overall survival vs sunitinib in first-line treatment of patients with advanced renal cell carcinoma.

The study supported the January 2021 approval of the combination as first-line treatment for patients with advanced renal cell carcinoma.

Toni K. Choueiri, MD

Study Details

In the open-label trial, 651 patients from sites in 18 countries were randomly assigned between September 2017 and May 2019 to receive nivolumab at 240 mg every 2 weeks plus cabozantinib at 40 mg once daily (n = 323) or sunitinib at 50 mg once daily for 4 weeks of each 6-week cycle (n = 328), with treatment continued until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival on blinded independent central review.

Progression-Free Survival

At a median follow-up of 18.1 months for overall survival, median progression-free survival was 16.6 months (95% confidence interval [CI] = 12.5–24.9 months) in the nivolumab/cabozantinib group vs 8.3 months (95% CI = 7.0–9.7 months) in the sunitinib group (hazard ratio [HR] = 0.51, 95% CI = 0.41–0.64, P < .001); 12-month rates were 57.6% vs 36.9%.

Subsequent anticancer treatment was received by 18.9% vs 32.9% of all patients, and by 43.0% of 142 patients in the nivolumab/cabozantinib group and 47.4% of 228 patients in the sunitinib group who discontinued study treatment.

Median overall survival was not reached in either group. The probability of overall survival at 12 months was 85.7% (95% CI = 81.3%–89.1%) in the nivolumab/cabozantinib group vs 75.6% (95% CI = 70.5%–80.0%) in the sunitinib group (HR = 0.60, 98.89% CI = 0.40–0.89, P = .001).

Objective response on independent review was observed in 55.7% vs 27.1% of patients (P < .001), with complete response in 8.0% vs 4.6%. Median time to response was 2.8 months vs 4.2 months. Median duration of response was 20.2 months vs 11.5 months, with response persisting at 12 months in 71.1% vs 40.9% of responders.

Adverse Events

Grade ≥ 3 adverse events occurred in 75.3% of the nivolumab/cabozantinib group vs 70.6% of the sunitinib group; the most common in the combination group were hypertension (12.5% vs 13.1% in the sunitinib group) and hyponatremia (9.4% vs 5.9%). Grade 3 or 4 increased alanine aminotransferase and aspartate aminotransferase occurred in 9.8% and 7.9% of the nivolumab/cabozantinib group vs 3.5% and 2.6% of the sunitinib group.

Adverse events led to discontinuation of treatment in 19.7% (both drugs in 5.6%) vs 16.9% of patients. A total of 19.1% of patients in the nivolumab/cabozantinib group received glucocorticoid treatment for immune-mediated adverse events. Death considered related to treatment occurred in one patient in the nivolumab/cabozantinib group (due to small intestine perforation) and two patients in the sunitinib group (due to pneumonia and respiratory distress).

As assessed by the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19), health-related quality of life was maintained in the nivolumab/cabozantinib group and steadily deteriorated in the sunitinib group through 91 weeks.

The investigators concluded, “Nivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal cell carcinoma.”

Disclosure: The study was funded by Bristol Myers Squibb in collaboration with Ono Pharmaceutical and with Exelixis, Ipsen Pharma, and Takeda Pharmaceutical. For full disclosures of the study authors, visit nejm.org.