As reported in The New England Journal of Medicine by Toni K. Choueiri, MD, of Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, 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 the first-line treatment of patients with advanced renal cell carcinoma.¹ 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. Randomization was stratified according to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk score (0 [favorable] vs 1 or 2 [intermediate] vs 3 to 6 [poor]), geographic region (United States and Europe vs the rest of the world), and tumor expression of PD-L1 (≥ 1% vs < 1% or indeterminate). Crossover between groups was not permitted. The primary endpoint was progression-free survival on blinded independent central review.

For the nivolumab/cabozantinib group vs the sunitinib group, median patient age was 62 years (range = 29–90 years, 40.9% ≥ 65 years) vs 61 years (range = 28–86 years, 36.0% ≥ 65 years), and 77% vs 71% of patients were male. Geographic region was the United States or Europe for 49% vs 49% and the rest of the world for 51% vs 51%. 

Karnofsky performance status score was 90 to 100 in 80% vs 74% and 70 to 80 in 20% vs 26%. IMDC prognostic risk score was favorable (0) in 23% vs 22%, intermediate (1–2) in 58% vs 57%, and poor (3–6) in 19% vs 21%. 

Tumor PD-L1 expression was ≥ 1% in 26% vs 25% and < 1% or indeterminate in 74% vs 75%. Among 313 vs 319 patients with available status, 11% vs 13% had sarcomatoid features, 14% vs 14% had prior radiotherapy, and 69% vs 71% had prior nephrectomy. The number of sites with target or nontarget lesions was at least two in 80% vs 78%, and the most common metastatic sites were the lungs (74% vs 76%), lymph nodes (40% vs 40%), bone (24% vs 22%), liver (23% vs 16%), and adrenal gland (11% vs 11%).

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), and 12-month rates were 57.6% vs 36.9%.

Hazard ratios for progression-free survival favored combination treatment in all subgroups examined. For stratification subgroups, hazard ratios were 0.62 (95% CI = 0.38–1.01), 0.54 (95% CI = 0.40–0.72), and 0.37 (95% CI = 0.23–0.58) for IMDC favorable, intermediate, and poor prognostic score; 0.46 (95% CI = 0.33–0.64) for the United States/Europe and 0.57 (95% CI = 0.42–0.76) for the rest of the world; and 0.49 (95% CI = 0.32–0.73) for PD-L1 ≥ 1% and 0.52 (95% CI = 0.40–0.67) for PD-L1 < 1% or indeterminate.

Subsequent anticancer treatment was received by 18.9% vs 32.9% of all patients.

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).

Hazard ratios for overall survival favored combination treatment in all subgroups examined. For stratification subgroups, hazard ratios were 0.84 (95% CI = 0.35–1.97), 0.70 (95% CI = 0.46–1.07), and 0.37 (95% CI = 0.21–0.66) for IMDC favorable, intermediate, and poor prognostic score; 0.48 (95% CI = 0.30–0.79) for the United States/Europe and 0.71 (95% CI = 0.48–1.07) for the rest of the world; and 0.80 (95% CI = 0.48–1.34) for PD-L1 ≥ 1% and 0.51 (95% CI = 0.34–0.75) for PD-L1 < 1% or indeterminate.

An objective response on independent review was observed in 55.7% vs 27.1% of patients (P < .001), with a complete response in 8.0% vs 4.6%. The median time to response was 2.8 months vs 4.2 months. The 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 events 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 levels 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 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) total score at baseline, week 7, and every 6 weeks thereafter, health-related quality of life was maintained in the nivolumab/cabozantinib group and steadily deteriorated from baseline in the sunitinib group through 91 weeks. Assessment of disease-related symptoms (DRS) on the FKSI-DRS subscale showed improvement from baseline in the nivolumab/cabozantinib group and a decline after week 7 in the sunitinib group through 91 weeks. In an analysis controlling for baseline score and other covariates, differences favoring the combination group were statistically significant at all time points except for week 7 for the FKSI-19 total score and week 79 for the FKSI-DRS score.

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. Dr. Choueiri has been employed by Dana-Farber Cancer Hospital; has served on committees for ASCO and NCCN; holds stock or other ownership interests in Pionyr and Tempest; has received honoraria from ASCO, AstraZeneca, Bayer, Bristol Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, EMD Serono, Exelixis, Foundation Medicine, Genentech/Roche, GlaxoSmithKline, Harborside Press, Ipsen, IQvia, Janssen Oncology, Kidney Cancer Journal, Lancet Oncology, Lilly, Lpath, Merck, Michael J. Hennessy Associates, Navinata Healthcare, NCCN, NEJM, Novartis, Peloton Therapeutics (now acquired by Merck), Pfizer, PlatformQ Health, Prometheus, Sanofi/Aventis, and UpToDate; has served in a consulting or advisory role for Alexion Pharmaceuticals, Allegiant, Analysis Group, ASCO, AstraZeneca, Bayer, Bristol Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, EMD Serono, ESMO, Exelixis, Foundation Medicine, GlaxoSmithKline, Harborside Press, HERON, Ipsen, Kidney Cancer Journal, Lancet Oncology, Lilly, Lpath, Merck, Michael J. Hennessy Associates, Navinata Healthcare, NCCN, NEJM, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus Laboratories, Roche/Genentech, Sanofi/Aventis, and UpTo-Date; has received institutional research funding from Agensys, Analysis Group, AstraZeneca, Bayer, Bristol Myers Squibb, Calithera Biosciences, Celldex, Cerulean Pharma, Congressionally Directed Medical Research Programs (DOD), Corvus Pharmaceuticals, Eisai, Exelixis, Foundation Medicine, Gateway for Cancer Research, GlaxoSmithKline, Ipsen, Merck, NCI, Novartis, Peloton Therapeutics, Pfizer, Prometheus, Roche, Roche/Genentech, Seattle Genetics/Astellas, Takeda, and Tracon Pharma; holds intellectual property for biomarkers in kidney cancer; has been reimbursed for travel, accommodations, or other expenses by Alexion Pharmaceuticals, Allegiant, Analysis Group, AstraZeneca, Bayer, Bristol Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, EMD Serono, ESMO, Exelixis, Foundation Medicine, GlaxoSmithKline, Harborside Press, Heron, Ipsen, Kidney Cancer Journal, Lancet Oncology, Lilly, Lpath, Merck, Michael J. Hennessy Associates, Navinata Healthcare, NCCN, NEJM, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus, Roche/Genentech, Sanofi/Aventis, and UpToDate; and has held other relationships with “communications companies funded by pharmaceutical companies such as Clinical Thinking, Health Interactions, Envision Pharma Group, Fishawack Group of Companies, Parexel.

REFERENCE

1. Choueiri TK, Powles T, Burotto M, et al: Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 384:829-841, 2021.