The combination of nivolumab plus cabozantinib was found to be superior to the former standard, sunitinib, in the first-line treatment of advanced or metastatic renal cell carcinoma, according to the results of the phase III CheckMate 9ER trial reported at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.¹ At a median follow-up of 18.1 months, nivolumab/cabozantinib led to superior rates of progression-free survival, overall survival, and overall response vs sunitinib, with a consistent benefit observed across all prespecified subgroups.

“In CheckMate 9ER, nivolumab plus cabozantinib demonstrated superiority over sunitinib by doubling progression-free survival, 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 Toni K. Choueiri, MD, Director of The Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, Boston.

“There was a statistical significance favoring the combination with both quality-of-life questionnaires we used.”

— Toni K. Choueiri, MD

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“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,” Dr. Choueiri stated.

Other checkpoint inhibitor combination regimens have also been shown to be superior to sunitinib in this setting, providing new first-line options for the treatment of advanced renal cell carcinoma. “The various combination treatments will not likely be compared head to head, but I think quality of life could differentiate nivolumab/cabozantinib. There was a statistical significance favoring the combination with both quality-of-life questionnaires we used. Also, clinicians are familiar with both of these drugs,” Dr. Choueiri continued.

Study Rationale

Both nivolumab (anti–PD-1 checkpoint inhibitor) and cabozantinib (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, whereas 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 phase III,” noted Dr. Choueiri.

CheckMate 9ER 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 nivolumab at 240 mg intravenously 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).

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 with sunitinib,” he stated.

The objective response rate (another secondary endpoint) was almost doubled 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 disappeared,” continued Dr. Choueiri.

Safety and Quality of Life

The incidence of the most common treatment-related adverse events of any grade or high grade was similar between the two treatment arms. The rate of treatment discontinuation due to treatment-related adverse events was 15.3% in the combination arm (3.1% for both agents, 5.6% for nivolumab alone, and 6.6% for cabozantinib alone) and 8.8% in the sunitinib arm.

The overall rate of serious adverse events was similar between the two arms. However, liver toxicity was more common with nivolumab/cabozantinib (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 with sunitinib. Between-arm differences were significant at most time points. Disease-related symptoms improved with the combination, whereas they worsened with sunitinib.

“In conclusion, these results support nivolumab/cabozantinib as a potential first-line option for patients with advanced renal cell carcinoma,” Dr. Choueiri stated.

Additional Commentary

At a press conference prior to the ESMO Virtual Congress, Dominik Berthold, MD, of Lausanne University Hospital, Switzerland, commended the study. “These results are obviously very good. The study met all primary and secondary endpoints, which is pretty impressive in this large, randomized phase III trial,” Dr. Berthold said.

Dominik Berthold, MD

“A drawback is that the medical community is divided about whether two immunotherapies or immunotherapy plus an antiangiogenic drug is the better choice, since the different combinations appear to have similar effectiveness. We have high response rates and long follow-up with two immunotherapies: ipilimumab/nivolumab,” he added.

Additionally, separate phase III studies have found the combination of immune checkpoint inhibitor plus antiangiogenic drug superior to sunitinib (pembrolizumab plus axitinib and avelumab plus axitinib, respectively) in advanced renal cell carcinoma.

“It will be interesting to see how to incorporate nivolumab/cabozantinib in the treatment algorithm,” suggested Dr. Berthold. “I think physicians and patients will have some choice. We need more data and longer follow-up to learn whether there are special populations who benefit more from each of these combinations. For example, the nivolumab/cabozantinib combination may target bone metastases.”

Dr. Berthold continued: “It would be useful to learn whether the combination of nivolumab plus cabozantinib is effective in non–clear cell carcinoma. This represents a minority of patients with advanced renal cell carcinoma who are not well studied and were excluded from CheckMate 9ER.”

An additional consideration is that the choice of first-line treatment may impact the selection of second-line therapy. “If you start with a combination of immune therapy alone, it becomes an automatic choice to use an antiangiogenic drug in the second line. However, if you begin with a combination with two separate mechanisms of action such as an immune therapy and an antiangiogenic drug, then the second-line choice becomes less clear. More data are needed on the most suitable order of therapy for the entire population [of advanced renal cell carcinoma], as well as specific groups, such as high tumor burden vs slow-growing disease,” Dr. Berthold explained. 

Publisher's Note: This article was originally published in the October 10, 2020 issue of The ASCO Post.

DISCLOSURE: CheckMate 9ER was supported by Bristol Myers Squibb. Dr. Choueiri holds stock or other ownership interests in Pionyr Immunotherapeutics and Tempest Therapeutics; has received honoraria from Alexion Pharmaceuticals, Alligent, Analysis Group, ASCO, AstraZeneca, Bayer, Bristol Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, EMD Serono, Exelixis, Foundation Medicine, Genentech/Roche, GlaxoSmithKline, Harborside Press, Heron, Ipsen, Kidney Cancer Journal, The Lancet Oncology, Lilly, Lpath, Merck, Michael J. Hennessy Associates, Navinata Healthcare, NCCN, The New England Journal of Medicine, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus, Sanofi/Aventis, and UpToDate; has served as a consultant or advisor to Alexion Pharmaceuticals, Alligent, 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, The Lancet Oncology, Lilly, Lpath, Merck, Michael J. Hennessy Associates, Navinata Healthcare, NCCN, The New England Journal of Medicine, Novartis, Peloton Therapeutics, Pfizer, Platform Q, Prometheus Laboratories, Roche/Genentech, Sanofi/Aventis, and UpToDate; has received institutional research funding from Agensys, Analysis Group, AstraZeneca, Bayer, Bristol Myers Squibb, Calithera Biosciences, Celldex, Cerulean Pharma, Congressionally Directed Medical Research Programs, Corvus Pharmaceuticals, Eisai, Exelixis, Foundation Medicine, Gateway for Cancer Research, GlaxoSmithKline, Ipsen, Merck, National Cancer Institute, Novartis, Peloton Therapeutics, Pfizer, Prometheus, Roche/Genentech, Seattle Genetics/Astellas, Takeda, and Tracon Pharma; holds international patents for biomarkers; has been reimbursed for travel, accommodations, or other expenses by Alexion Pharmaceuticals, Alligent, Analysis Group, AstraZeneca, Bayer, Bristol Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, EMD Serono, ESMO, Exelixis, Foundation Medicne, GlaxoSmithKline, Harborside Press, Heron, Ipsen, Kidney Cancer Journal, The Lancet Oncology, Lilly, Lpath, Merck, Michael J. Hennessy Associates, Navinata Healthcare, National Comprehensive Cancer Network, The New England Journal of Medicine, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus, Roche/Genentech, Sanofi/Aventis, and UpToDate; and has held other relationships with ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, and Parexel. Dr. Berthold reported no conflicts of interest.

REFERENCE

1. Choueiri TK, Powles T, Burotto M, et al: Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: First results from the randomized phase III CheckMate 9ER trial. ESMO Virtual Congress 2020. Abstract 696O_PR. Presented September 19. 2020.