Nivolumab plus cabozantinib extends treatment-free survival vs sunitinib in aRCC

Findings from an analysis of the phase 3 CheckMate 9ER trial (NCT03141177) presented during the 2024 ASCO Annual Meeting showed that patients with advanced renal cell carcinoma (RCC) who received frontline nivolumab (Opdivo) plus cabozantinib (Cabometyx) achieved a 1.5-times longer mean time surviving treatment-free before the initiation of second-line therapy vs those who received sunitinib (Sutent).¹

CheckMate 9ER was an open-label study that enrolled patients with histologically confirmed untreated advanced or metastatic clear cell RCC.

Over the 48-month period following random assignment, patients in the intention-to-treat (ITT) population who received the combination (n = 323) experienced a mean treatment-free survival (TFS) of 7.0 months compared with 4.6 months in the sunitinib arm (n = 328), for a difference of 2.4 months (95% CI, 0.8-3.9). Patients without a grade 2 or higher treatment-related adverse effect (TRAE) experienced a mean TFS of 3.0 months vs 2.3 months, respectively. Those who experienced a grade 2 or higher TRAE experienced a mean TFS of 3.9 months vs 2.3 months. The 48-month mean overall survival (OS) was 35.1 months in the doublet arm vs 30.7 months in the sunitinib arm. The mean times on protocol treatment were 22.6 months compared with 14.1 months, respectively.

Additionally, the 48-month OS rates were 49.2% in the nivolumab plus cabozantinib arm vs 40.2% in the sunitinib arm, and the 48-month TFS rates were 33.3% compared with 12.9%, respectively.

“There are multiple immunotherapy-based combination treatments with similar efficacies approved for first-line treatment of advanced RCC. Therefore, it’s important to characterize patient survival time after treatment initiation,” Charlene Mantia, MD, a medical oncologist at Dana-Farber Cancer Institute and instructor in medicine at Harvard Medical School in Boston, Massachusetts, said during a presentation of the findings. “Over the 4-year period since first-line protocol therapy initiation, [patients treated with] nivolumab plus cabozantinib achieved a 1.5-times longer mean TFS vs sunitinib.”

CheckMate 9ER was an open-label study that enrolled patients with histologically confirmed untreated advanced or metastatic clear cell RCC who did not receive prior systemic therapy for RCC. However, treatment with 1 prior adjuvant or neoadjuvant therapy was permitted for patients with completely resectable disease if the agent was not VEGF-targeted and if recurrence occurred at least 6 months following treatment.^2,3

Patients were randomly assigned 1:1 to receive intravenous nivolumab 240 mg every 2 weeks in combination with oral cabozantinib 40 mg daily or sunitinib 50 mg daily for 4 weeks in 6-week cycles. Treatment in both arms continued until disease progression or unacceptable toxicity, and the maximum duration of nivolumab therapy was 2 years.

The primary end point was progression-free survival by blinded independent central review per RECIST 1.1 criteria. Secondary end points included OS, objective response rate, and safety.

In the ITT population, the baseline characteristics were well balanced between the combination and sunitinib arms; the median age was 62 years (range, 29-90) vs 61 years (range, 28-86), respectively. Most patients in both arms were not from North America or Europe (51.1% vs 50.9%), had a Karnofsky performance status (KPS) of 90 or 100 (79.6% vs 73.5%), underwent prior nephrectomy (68.7.% vs 71.0%), and had tumors without sarcomatoid features (89.1% vs 87.1%).²

Additional findings from the TFS analysis showed that patients with IMDC favorable-risk disease in the combination (n = 74) and control (n = 72) arms achieved a 48-month mean TFS of 6.1 months vs 4.3 months, respectively, for a difference of 1.8 months (95% CI, –1.1 to 4.6). The mean OS during this time frame was 38.2 months in the nivolumab plus cabozantinib arm vs 38.6 months in the sunitinib arm. Patients spent a mean time of 25.2 months vs 19.9 months on protocol treatment, respectively.¹

Further, patients with IMDC intermediate- or poor-risk disease in the combination (n = 249) and sunitinib (n = 256) arms achieved a 48-month mean TFS of 7.2 months vs 4.7 months, respectively, for a difference of 2.5 months (95% CI, 0.8-4.3). The 48-month mean OS was 34.2 months vs 28.5 months, respectively, and patients spent a mean time of 21.8 months in the combination arm vs 12.5 months in the sunitinib arm on protocol treatment.

Results from a TFS subgroup analysis showed that the benefit with nivolumab plus cabozantinib vs sunitinib was observed across prespecified subgroups. The largest differences in 48-month mean TFS in favor of the combination were reported among patients with a KPS of 80 or less (5.3 months [95% CI, 2.1-8.5]), IMDC poor-risk disease (4.0 months [95% CI, 0.5-7.5]), and a PD-L1 expression of at least 1% (3.5 months [95% CI, 0.8-6.1]).

“Mean TFS differences were similarly longer for nivolumab plus cabozantinib vs sunitinib across most baseline subgroups analyzed,” Mantia said in conclusion. “TFS was more frequently observed after patients stopped therapy due to adverse effects, study drug toxicity, or prespecified other reasons with nivolumab plus cabozantinib vs sunitinib. We believe that future studies should continue to investigate the impact of having a defined treatment duration for patients. This partitioned OS analysis highlights important aspects of patient survival time that can be considered in making decisions when choosing a first-line treatment for patients.”

References

1. Mantia C, Jegede O, Viray H, et al. Partitioned overall survival: Comprehensive analysis of survival states over 4 years in CheckMate 9ER comparing first-line nivolumab plus cabozantinib versus sunitinib in advanced renal cell carcinoma (aRCC). J Clin Oncol 2024;42(suppl 16):4507. doi:10.1200/JCO.2024.42.16_suppl.4507

2. Powles T, Burotto M, Escudier B, et al. Nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended follow-up from the phase III randomised CheckMate 9ER trial. ESMO Open. 2024;9(5):102994. doi:10.1016/j.esmoop.2024.102994

3. A study of nivolumab combined with cabozantinib compared to sunitinib in previously untreated advanced or metastatic renal cell carcinoma (CheckMate 9ER). ClinicalTrials.gov. Updated January 17, 2024. Accessed June 4, 2024. https://clinicaltrials.gov/study/NCT03141177