On January 22, 2021, the U.S. Food and Drug Administration approved the combination of nivolumab and cabozantinib as first-line treatment for patients with advanced renal cell carcinoma.^1-3

Supporting Efficacy Data

Approval was based on the findings of the phase III, open-label CheckMate 9ER trial (ClinicalTrials.gov identifier NCT03141177).^2,3 In the trial, 651 patients with previously untreated advanced renal cell carcinoma were randomly assigned to receive nivolumab at 240 mg every 2 weeks in combination with cabozantinib at 40 mg once daily (n = 323) or sunitinib at 50 mg for the first 4 weeks of a 6-week cycle (n = 328). Treatment continued until disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or unacceptable toxicity; treatment beyond RECIST-defined disease progression was permitted if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. The primary outcome measure was progression-free survival on blinded independent central review.

Median patient age was 61 years (range = 28–90 years; 38% ≥ 65 years of age and 10% ≥ 75 years of age). Overall, 74% were male, 82% were White; 23% and 77% had a baseline Karnofsky performance status of 70% to 80% and 90% to 100%, respectively. International Metastatic RCC Database Consortium risk was favorable in 22%, intermediate in 58%, and poor in 20%.

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 < .0001). Median overall survival was not reached (95% CI = not reached to not reached) vs not reached (95% CI = 22.6 months to not reached) (HR = 0.60, 95% CI = 0.40–0.89, P = .0010). Confirmed objective response rate on blinded independent central review was 55.7% vs 27.1% (P < .0001), with a complete response in 8.0% vs 4.6%. The median duration of response was 20.2 months (95% CI = 17.3 months to not reached) vs 11.5 months (95% CI = 8.3–18.4 months).

How It Is Used

The recommended dose of the combination in advanced renal cell carcinoma is nivolumab at 240 mg every 2 weeks or at 480 mg every 4 weeks via 30-minute intravenous infusion in combination with oral cabozantinib at 40 mg once daily, with treatment continuing until disease progression or unacceptable toxicity or for up to 2 years for nivolumab.

No dose reductions for nivolumab are recommended. In general, nivolumab should be withheld for grade 3 immune-mediated adverse reactions and permanently discontinued for grade 4 immune-mediated adverse reactions, recurrent grade 3 immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce the corticosteroid dose to 10 mg or less of prednisone or its equivalent per day within 12 weeks of initiating steroids.

Specific instructions are provided in labeling for nivolumab alone or in combination with other agents for management and dose modification—including withholding or discontinuing treatment—for adverse reactions including the following immune-mediated adverse reactions: pneumonitis, colitis, hepatitis with and without tumor involvement of the liver, endocrinopathies, nephritis with renal dysfunction, exfoliative dermatologic conditions (including Stevens-Johnson syndrome and toxic epidermal necrolysis), myocarditis, neurologic toxicity, and infusion-related reactions. Specific guidance for nivolumab and cabozantinib when used in combination is provided for liver enzyme elevations in labeling for both agents.

Treatment with cabozantinib should be stopped at least 3 weeks prior to scheduled surgery, including dental surgery, and not resumed for at least 2 weeks following major surgery and adequate wound healing. The safety of resumption of treatment after resolution of wound-healing complications has not been established. Cabozantinib capsules should not be substituted for cabozantinib tablets.

Cabozantinib should be withheld for intolerable grade 2 adverse reactions, grade 3 or 4 adverse reactions, and osteonecrosis of the jaw. Upon return to baseline or resolution to grade 1, treatment when used in combination with nivolumab can be resumed at the sequentially reduced doses of 20 mg/d and 20 mg every other day; treatment should be discontinued if further dose reduction is required. Treatment should be permanently discontinued in the event of severe hemorrhage, development of gastrointestinal perforation or grade 4 fistula, and acute myocardial infarction or arterial or venous thromboembolic events that require medical intervention.

Product labeling provides dosage instructions for concomitant use of a strong CYP3A4 inhibitor (eg, ketoconazole, clarithromycin, indinavir) or a strong CYP3A4 inducer (eg, carbamazepine, phenobarbital, phenytoin, rifampin, St John’s wort) and in moderate and severe hepatic impairment.

Safety Profile

In CHECKMATE 9ER, 82% of patients in the nivolumab/cabozantinib group were exposed to treatment for at least 6 months and 60%, for more than 1 year.

The most common adverse events of any grade (≥ 20%) in patients receiving nivolumab/cabozantinib were diarrhea (64% vs 47% in sunitinib group), fatigue (51% vs 50%), hepatotoxicity (44% vs 26%), palmar-plantar erythrodysesthesia syndrome (40% vs 41%), stomatitis (37% vs 46%), rash (36% vs 14%), hypertension (36% vs 39%), hypothyroidism (34% vs 30%), musculoskeletal pain (33% vs 29%), decreased appetite (28% vs 20%), nausea (27%  vs 31%), dysgeusia (24% vs 22%), abdominal pain (22% vs 15%), cough (20% vs 17%), and upper respiratory tract infection (20% vs 8%). The most common grade 3 or 4 adverse events included hypertension (13% vs 14%), hepatotoxicity (11% vs 5%), fatigue (8% vs 8%), palmar-plantar erythrodysesthesia syndrome (8% vs 8%), and diarrhea (7% vs 4%). The most common grade 3 or 4 laboratory abnormalities were hypophosphatemia (28% vs 10%), increased alanine transaminase (ALT; 10% vs 4%), increased aspartate transaminase (AST; 8% vs 3%), and lymphopenia (7% vs 10%).

Serious adverse events occurred in 48% of the nivolumab/cabozantinib group, the most common (≥ 2%) being diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Adverse events led to dose interruption or reduction of either nivolumab or cabozantinib in 83% of patients (3% nivolumab alone, 46% cabozantinib alone, 21% both drugs at the same time due to the same adverse event, and 6% both drugs sequentially). Adverse reactions led to discontinuation of either drug in 20% of patients (7% nivolumab alone, 8% cabozantinib alone, and 6% both drugs at the same time due to the same adverse event). Fatal intestinal perforation occurred in three patients (0.9%).

Nivolumab has warnings/precautions for immune-mediated adverse reactions, which may be severe or fatal and can occur in any organ system or tissue, including pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, dermatologic adverse reactions, and nephritis and renal dysfunction; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation; and embryofetal toxicity.

Cabozantinib has warnings/precautions for hemorrhage, perforations and fistulas, thrombotic events, hypertension and hypertensive crisis, diarrhea, palmar-plantar erythrodysesthesia, hepatotoxicity, adrenal insufficiency, proteinuria, osteonecrosis of the jaw, impaired wound healing, reversible posterior leukoencephalopathy syndrome, and embryofetal toxicity. Cabozantinib should not be given to patients with a recent history of hemorrhage. Blood pressure and urine protein must be monitored. When used in combination with nivolumab, higher frequencies of grade 3 and 4 ALT and AST elevations may occur than with cabozantinib alone; liver enzymes should be monitored before the initiation of treatment and periodically thereafter. When used in combination with nivolumab, primary or secondary adrenal insufficiency may occur; for grade 2 or higher adrenal insufficiency, symptomatic treatment—including hormone replacement as clinically indicated—should be initiated. Patients should be advised not to breastfeed while receiving cabozantinib.

REFERENCES

1. U.S. Food and Drug Administration: FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-cabozantinib-advanced-renal-cell-carcinoma. Accessed February 23, 2021.

2. Opdivo (nivolumab) injection prescribing information, Bristol Myers Squibb Company, January 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125554s090lbl.pdf. Accessed February 23, 2021.

3. Cabometyx (cabozantinib) tablets prescribing information, Exelixis, Inc, January 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208692s010lbl.pdf. Accessed February 23, 2021.