Exploratory subgroup analyses from the phase 3 CheckMate 9ER trial (NCT03141177) suggested that the frontline combination of nivolumab (Opdivo) and cabozantinib (Cabometyx) showed improvement in survival in patients with advanced renal cell carcinoma (RCC) and bone metastasis over sunitinib (Sutent).
Although both progression-free survival (PFS) and overall survival (OS) were improved with nivolumab/cabozantinib over sunitinib in patients without bone metastasis, the improvement was even greater in those with bone metastasis, according to results of a post hoc analysis presented in a poster during the 2021 International Kidney Cancer Symposium.
The overall safety profile of the combination was comparable in patients with and without bone metastasis and was consistent with that of all randomized patients in the trial, the study authors, led by Andrea B. Apolo, MD, of the National Cancer Institute, wrote in their poster. They added that there was a higher incidence of grade 3/4 adverse events (AEs) with nivolumab/cabozantinib over sunitinib in patients with bone metastasis.
The CheckMate 9ER trial enrolled 651 patients with advanced or metastatic RCC who were previously untreated and had clear cell histology. Seventy-nine patients treated with nivolumab/cabozantinib had bone metastasis at baseline.
These patients had a slightly higher median age compared with those treated with sunitinib (63 vs 61, respectively) and lower Karnofsky performance status compared with those without bone metastasis. More patients with bone metastasis had received radiotherapy compared with those without bone metastasis. Several patients with bone metastasis received prior or concomitant bone-targeted therapies to treat their metastasis, including denosumab and bisphosphonates.
In patients with bone metastasis, the median PFS among those treated with nivolumab/cabozantinib was 18.2 months (95% CI, 8.3-20.1) vs 4.4 months (95% CI, 3.7-7.0) with sunitinib monotherapy (HR, 0.38; 95% CI, 0.25-0.59). In those without bone metastasis, the median PFS was 17.0 months (95% CI, 12.5-20.0) with the combination and 9.5 months (95% CI, 7.9-11.0) with sunitinib (HR, 0.57; 95% CI, 0.45-0.72).
The median PFS among those treated with nivolumab/ cabozantinib was similar in those with or without bone metastasis (HR, 1.26; 95% CI, 0.90-1.76). With sunitinib, the median PFS was shorter in those with bone metastasis at baseline vs those without (HR, 1.85; 95% CI, 1.33-2.56).
Median OS among those with bone metastasis was not evaluable (NE) with nivolumab/cabozantinib (95% CI, 21.4- NE) compared with 29.5 months (95% CI, 12.5-NE) with sunitinib monotherapy (HR, 0.64; 95% CI, 0.39-1.06). The median OS was NE in both treatment arms among patients without bone metastasis (HR, 0.65; 95% CI, 0.46-0.91).
Median OS was shorter with combination therapy in those with bone metastasis at baseline compared with those without bone metastasis (HR, 1.72; 95% CI, 1.10-2.69). With sunitinib, the median OS was shorter in those with bone metastasis than in those without (HR, 1.69; 95% CI, 1.13-2.52).
Objective response rate (ORR) was higher among patients treated with nivolumab/cabozantinib with or without baseline bone metastasis. The ORR was 48% (95% CI, 37%-60%) in the nivolumab/cabozantinib arm among those with bone metastasis, which consisted of complete responses (CRs) in 6% and partial responses (PRs) in 42%; 34% had stable disease (SD). The median duration of response (DOR) was 18 months.
With sunitinib treatment in patients with baseline bone metastasis, the ORR was 11% (95% CI, 5%-21%), consisting of all PRs, and 40% had SD. The median DOR was 7 months.
Among those without bone metastasis, the ORR in the nivolumab/cabozantinib arm was 57% (95% CI, 51%-63%) and 33% (95% CI, 28%-39%) in the sunitinib arm. The median DOR was 22 months (95% CI, 17-NE) with nivolumab/cabozantinib and 13 months (95% CI, 10-21) with sunitinib.
Patients with bone metastasis treated with nivolumab/ cabozantinib had a higher degree of grade 3/4 treatment-related AEs than those treated with sunitinib (71% vs 42%, respectively) and those without bone metastasis treated with either regimen (59% vs 55%). In patients with bone metastasis treated with nivolumab/cabozantinib, the most common treatment-related AEs were lipase increase (11%), hyponatremia (10%), hypertension (9%), hypophosphatemia (8%), and asthenia (6%).
There were also more immune-mediated AEs with nivolumab/ cabozantinib treatment among patients with bone metastasis. The most common immune-mediated event of any grade was hypothyroidism in 29% of patients with bone metastasis and in 26% of those without bone metastasis.
Apolo A, Powles T, Bourlon MT, et al. Nivolumab plus cabozantinib vs sunitinib in patients with advanced renal cell carcinoma and bone metastasis: subgroup analysis of the phase 3 CheckMate 9ER trial. Presented at: 2021 International Kidney Cancer Symposium; November 5-6, 2021; Austin, TX. Abstract N22.