Clinical trialPhase 3Kidney cancer

Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma

N Engl J Med · 2021651 patients (323 nivolumab + cabozantinib, 328 sunitinib)

Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, et al. N Engl J Med. 2021. 384:829-841

A newer report of this study has been published: Final analysis of nivolumab plus cabozantinib for advanced renal cell carcinoma from the randomized phase III CheckMate 9ER trial (2026)

Study type: Clinical trial
Study name: CheckMate 9ER
Phase: Phase 3
Design: Randomised, open-label trial
Sample size: 651 patients (323 nivolumab + cabozantinib, 328 sunitinib)
Source: N Engl J Med · 2021
Trial registration: NCT03141177

In plain words

This study compared a combination of the immunotherapy drug nivolumab and the tablet cabozantinib with the tablet sunitinib in advanced kidney cancer. With the combination, the time the disease was kept under control nearly doubled (about 16.6 months versus 8.3 months), more patients stayed alive and the tumour shrank in more than half of patients. Patients in the combination group also reported a better quality of life.

Key results

16.6 vs 8.3 months

Median progression-free survival

HR 0.51; 95% CI 0.41–0.64; P<0.001

85.7% vs 75.6%

12-month overall survival

HR for death 0.60; 98.89% CI 0.40–0.89; P=0.001

55.7% vs 27.1%

Objective response

P<0.001

75.3% vs 70.6%

Grade 3 or higher adverse events of any cause

19.7% stopped at least one of the drugs and 5.6% stopped both drugs because of adverse events

Drugs in this study:Nivolumab (Opdivo)

Dose and schedule cards

Nivolumab + cabozantinib (CheckMate 9ER)

Advanced RCC, first line, all IMDC risk groups; also an option in the papillary subtype (EAU)Each drug’s schedule in the tableOn the page “Kidney cancer” · First-line regimens for advanced RCC

Advanced RCC, first line, all IMDC risk groups; also an option in the papillary subtype (EAU)

Drug	Dose	Route	Schedule
Nivolumab	240 mg (or 480 mg)	IV, 30-minute infusion	Every 2 weeks (480 mg dose: every 4 weeks)
Cabozantinib	40 mg once daily	Oral, on an empty stomach (1 hour before or 2 hours after a meal)	Daily, continuously

Cycle schedule: Nivolumab every 2 weeks (or every 4 weeks with the 480 mg dose); cabozantinib daily and continuously
Duration: Nivolumab up to 2 years; cabozantinib until progression or unacceptable toxicity

Per the FDA labels and the trial. Cabozantinib dose reductions in this combination: 20 mg daily, then 20 mg every other day. ALT or AST >3 to 10 × ULN with bilirubin <2 × ULN: withhold both drugs until recovery to grade 0–1 (consider corticosteroids); >10 × ULN, or >3 × ULN with bilirubin ≥2 × ULN: permanently discontinue both. Liver enzymes should be monitored more frequently with this combination than with monotherapy. Stop cabozantinib 3 weeks before surgery (including dental surgery) and do not restart it for at least 2 weeks after major surgery; with strong CYP3A4 inhibitors, reduce the dose by 20 mg.

On the page “Kidney cancer” · First-line regimens for advanced RCC

Advanced RCC, with cabozantinib (CheckMate 9ER)

First lineCycle length: 14 or 28 daysOn the page “Nivolumab (Opdivo)” · Combination regimens with chemotherapy or cabozantinib (FDA label, revised 05/2026)

First line

Drug	Dose	Route	Schedule
Continuous
Nivolumab	240 mg every 2 weeks or 480 mg every 4 weeks	IV, 30-minute infusion	Day 1
Cabozantinib	40 mg	Oral, fasting	Once daily

Cycle length: 14 or 28 days
Duration: Nivolumab until progression, unacceptable toxicity or a maximum of 2 years; cabozantinib until progression or toxicity

ALT/AST above 3 to 10 times ULN with bilirubin below 2 times: withhold both drugs until grade 0 to 1; above 10 times, or above 3 times with bilirubin 2 times or more: discontinue both permanently.

On the page “Nivolumab (Opdivo)” · Combination regimens with chemotherapy or cabozantinib (FDA label, revised 05/2026)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Nivolumab + cabozantinib

Nivolumab 240 mg IV every 2 weeks (maximum 2 years) + cabozantinib 40 mg orally once daily, until disease progression or unacceptable toxicity. Dose reduction was not allowed for nivolumab but was allowed for cabozantinib; in case of toxicity related to one drug, the other drug could be continued.

2Sunitinib

Sunitinib 50 mg orally once daily for 4 weeks followed by 2 weeks off (6-week cycle), until progression or unacceptable toxicity; dose reduction was allowed.

Source of the regimen details: Full text of the paper (PMC8436591) and ClinicalTrials.gov NCT03141177

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with advanced (not amenable to curative surgery or radiotherapy) or metastatic (stage IV) renal cell carcinoma with a clear-cell component (including sarcomatoid features), without previous systemic therapy for advanced disease, in all IMDC risk groups, with a Karnofsky performance status of at least 70 and measurable disease per RECIST 1.1; patients with active brain metastases or active autoimmune disease were excluded.

Endpoints

Primary endpoint: progression-free survival by blinded independent central review. Secondary endpoints: overall survival, objective response (independent review) and safety. Health-related quality of life was an exploratory endpoint.

Safety and side effects

Grade 3 or higher adverse events of any cause occurred in 75.3% of patients in the combination group and 70.6% of the sunitinib group; grade 3 or higher treatment-related adverse events 60.6% versus 50.9%. Grade 3–4 ALT elevation was seen in 9.8% and AST elevation in 7.9% of patients in the combination group (versus 3.5% and 2.6%). In the combination group, 19.1% of patients received corticosteroids (prednisone 40 mg or more per day) for immune-mediated adverse events. In the combination group, 19.7% of patients stopped at least one of the drugs and 5.6% stopped both drugs because of adverse events. Patient-reported quality of life was better with the combination.

Clinical significance and place in guidelines

Based on this trial, the FDA approved cabozantinib with nivolumab in January 2021 for first-line treatment of advanced renal cell carcinoma. NCCN (version 3.2022) considers it a preferred option with category 1 evidence in all risk groups, and the EAU 2022 guideline lists it among the standard first-line treatments in all IMDC risk groups (level of evidence 1b).

Limitations

Open-label design; relatively short follow-up in the first report (median 18.1 months); comparison with sunitinib rather than with other immunotherapy combinations; the three-drug arm (with ipilimumab) was stopped by a protocol amendment.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.