The combination of nivolumab plus cabozantinib was superior to the former standard, sunitinib, as first-line treatment for advanced/metastatic renal cell carcinoma, according to results of the phase III CheckMate 9ER trial reported by Toni K. Choueiri, MD, and colleagues at the ESMO Virtual Congress 2020 (Abstract 696O_PR). At a median follow-up of 18.1 months, nivolumab/cabozantinib led to better progression-free survival, overall survival, and response rates vs sunitinib, with a consistent benefit observed across subgroups.
“In CheckMate 9ER, nivolumab plus cabozantinib demonstrated superiority over sunitinib by doubling the progression-free survival time, doubling the overall response rate, and significantly improving overall survival. The combination was generally well tolerated, with a low rate of treatment-related discontinuations. Patients had significantly better quality of life on the combination vs sunitinib,” stated lead author Dr. Choueiri, Director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and and the Jerome and Nancy Kohlberg Chair and Professor of Medicine at Harvard Medical School.
Toni K. Choueiri, MD
“With expanded options for the treatment of patients with advanced renal cell carcinoma, the overall efficacy, safety, and quality of life benefits as well as individual patient characteristics are important considerations when selecting appropriate therapy. These results support nivolumab/cabozantinib as a potential first-line option for patients with advanced renal cell carcinoma,” stated Dr. Choueiri.
Both nivolumab, an anti–PD-1 checkpoint inhibitor, and cabozantinib, a small-molecule tyrosine kinase inhibitor, are approved for the second-line treatment of renal cell carcinoma. The combination of nivolumab/ipilimumab is also approved as first-line treatment for intermediate- and poor-risk advanced renal cell carcinoma.
The rationale for combing the two agents is that nivolumab promotes antitumor responses by preventing cancer from evading immune detection, while cabozantinib has both antiangiogenic and immunogenic properties that may counteract tumor-induced immunosuppression.
“Clinical benefits have been observed with multiple immune checkpoint inhibitor/tyrosine kinase inhibitor combinations in advanced renal cell carcinoma. Preliminary study of nivolumab/cabozantinib supported further study of this combination in [a] phase III [setting],” said Dr. Choueiri.
Study Details
The multinational phase III CheckMate 9ER study included 651 patients with previously untreated advanced or metastatic renal cell carcinoma with a clear cell component in any risk group. Patients were randomly assigned in a 1:1 ratio to first-line treatment with intravenous nivolumab at 240 mg every 2 weeks plus oral cabozantinib at 40 mg/d vs standard oral sunitinib at 50 mg/d in 4-week-on, 2-week-off cycles.
Treatment was continued until disease progression or unacceptable toxicity. The first results of the study presented by Dr. Choueiri were based on a median follow-up of 18.1 months (range = 10.6–30.6 months).
Results
“In CheckMate 9ER, nivolumab plus cabozantinib demonstrated superiority over sunitinib by doubling the progression-free survival time, doubling the overall response rate, and significantly improving overall survival. The combination was generally well tolerated, with a low rate of treatment-related discontinuations.”— Toni K. Choueiri, MD
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The study met the primary endpoint, with a doubling of progression-free survival for the experimental arm: a median of 16.6 months for the combination vs 8.3 months for sunitinib, which was highly statistically significant (P < .0001).
“Nivolumab/cabozantinib reduced the risk of death or disease progression by almost 50%,” Dr. Choueiri told listeners.
Median overall survival, a secondary endpoint, was not reached in either arm, but at this first analysis, the risk of death was reduced by 40% (P = .0010). “Patients on the combination are more likely to live longer compared to sunitinib,” he stated.
Objective response rate, another secondary endpoint, was almost double with the combination: 55.7% vs 27.1%, respectively (P < .0001). Complete response rates were doubled: 8% vs 4.6%, respectively.
“This means that twice as many patients responded to treatment with nivolumab/cabozantinib vs sunitinib, and more of the responses were complete—that is, cancer lesions have disappeared,” Dr. Choueiri continued.
Safety and Quality of Life
The incidence of the most common treatment-related adverse events of any grade or higher grade was similar between the two treatment arms. The rate of treatment discontinuations due to treatment-related adverse events was 15.3% in the combination arm (3.1% for both drugs, 5.6% for nivolumab, and 6.6% for cabozantinib) and 8.8% in the sunitinib arm.
The overall rate of serious adverse events was similar between the two arms, but liver toxicity was more common with nivolumab/cabozatinib. Increased liver enzymes were reported in about 25% of patients vs 6% with sunitinib.
Health-related quality of life, an exploratory endpoint, was measured by two instruments: the Functional Assessment for Cancer Therapy Kidney Symptom Index (FKSI) and the revised FKSI scale (FKSI-19). On the FKSI-19, health-related quality of life was maintained over time with nivolumab/cabozantinib vs a consistent deterioration in the sunitinib arm. Between-arm differences were significant at most time points. Disease-related symptoms improved on the combination, whereas they worsened with sunitinib.
In a statement released by ESMO, Dr. Choueiri concluded, “This will become an important treatment option to choose from. The various combination treatments 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.”
Disclosure: CheckMate 9ER was supported by Bristol Myers Squibb. For full disclosures of the study authors, visit oncologypro.esmo.org.
