First-line nivolumab-cabozantinib superior to sunitinib for advanced renal cell carcinoma
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Nivolumab plus cabozantinib conferred superior PFS, OS and response rates compared with sunitinib as a first-line treatment for advanced renal cell carcinoma, according to results of a phase 3 study presented at ESMO Virtual Congress 2020.
“Nivolumab promotes antitumor responses by preventing cancer from evading immune detection, while cabozantinib has both antiangiogenic and immunomodulatory properties that may counteract tumor-induced immunosuppression,” Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and Jerome and Nancy Kohlberg chair and professor of medicine at Harvard Medical School, said during a press conference. “We have previously seen benefits with immune checkpoint inhibitor and tyrosine kinase inhibitor combinations in advanced renal cell carcinoma.”
Specifically, a previous phase 1 study showed the combination of the anti-PD-1 antibody nivolumab (Opdivo, Bristol Myers Squibb) and cabozantinib (Cabometyx, Exelixis), a multitargeted TKI, induced promising antitumor activity among patients with advanced genitourinary malignancies.
In the CheckMate -9ER trial, Choueiri and colleagues randomly assigned 651 patients with previously untreated advanced or metastatic renal cell carcinoma with a clear cell component to nivolumab in combination with cabozantinib (n = 323) or to standard-of-care sunitinib (Sutent, Pfizer; n = 328).
Researchers administered nivolumab via IV at a flat dose of 240 mg every 2 weeks and cabozantinib orally at a dose of 40 mg daily. Sunitinib was administered orally at a dose of 50 mg daily in 4-weeks-on, 2-weeks-off cycles. Treatment continued until disease progression or unacceptable toxicity.
PFS served as the primary endpoint. OS, objective response rate and safety served as secondary endpoints. Health-related quality of life served as an exploratory endpoint.
Median follow-up was 18.1 months (range, 10.6-30.6).
Results showed the combination therapy significantly improved PFS (median, 16.6 months vs. 8.3 months; HR = 0.51; 95% CI, 0.41-0.64) and OS (medians not reached; HR = 0.6; 98.89% CI, 0.4-0.89) compared with sunitinib, with results being consistent across prespecified International Metastatic RCC Database Consortium risk and PD-L1 subgroups.
The combination therapy also conferred an ORR twice as high as that of sunitinib (55.7% vs. 27.1%; P < .0001). Overall, 8% of patients in the combination group and 4.6% of patients treated with sunitinib achieved complete response.
Median duration of response was 20.2 months in the combination group and 11.5 months in the sunitinib group.
Treatment-related adverse events occurred among more than 90% of patients in each group, with 60.6% of patients in the combination group and 50.9% in the sunitinib group experiencing grade 3 or higher adverse events.
More than half of the patients assigned the combination required a dose reduction of cabozantinib due to adverse events. However, only 3% of patients assigned the combination had to discontinue treatment due to toxicity compared with 9% of the sunitinib group.
“In this study, the combination of nivolumab and cabozantinib demonstrated superiority over sunitinib by doubling the PFS time and significantly improving OS,” Choueiri said. “These results support [the combination] as a potential first-line option for patients with advanced renal cell carcinoma.”
Perspective
Back to TopDeirdre Cohen, MD, MS
I believe this study is practice changing. It’s one of the largest — if not the largest — studies in the front line for gastroesophageal cancer, and it has really moved the needle in terms of putting immunotherapy in the front line for treatment of our patients.
Chemotherapy alone leads to survival of less than 1 year, so we have been looking for ways to improve that for a long time. Immune checkpoint inhibitors, specifically nivolumab and pembrolizumab (Keytruda, Merck), are only approved for second- or third-line indications. This study showed survival of over a year in this disease, which hasn’t been done before.
There is a caveat that patients enrolled in the study had tumors with a PD-L1 combined positive score of greater than 5, meaning it’s an enriched population. This will be important going forward in determining for whom this regimen will be approved.
It’s unclear whether subsets of patients with lower PD-L1 combined positive scores will benefit from this regimen. But for those with a score of 5 or greater, this treatment will provide a huge advantage moving forward.
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Choueiri TK, et al. Abstract 696O_PR. Presented at: European Society for Medical Oncology Virtual Congress 2020; Sept. 19-21, 2020.
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