Long-term data from CheckMate 9ER confirm superiority of first-line nivolumab plus cabozantinib versus sunitinib in advanced renal cell carcinoma

After three years of minimum follow-up in the CheckMate 9ER trial in patients with advanced renal cell carcinoma (aRCC), survival and response benefits were maintained with nivolumab and cabozantinib and remained consistent with previous follow-ups. Responses with nivolumab plus cabozantinib were durable, with higher complete response rates versus sunitinib, regardless of the IMDC risk group. These results continue to support nivolumab plus cabozantinib as a first-line treatment for patients with aRCC.

Previously, nivolumab plus cabozantinib (NIVO+CABO) has demonstrated superior efficacy outcomes with continued durability versus sunitinib (SUN) in the phase III CheckMate 9ER trial in patients with untreated clear cell, advanced or metastatic renal cell carcinoma (RCC). At ASCO GU 2023 updated efficacy and safety from CheckMate 9ER with a median follow-up for overall survival (OS) of 44.0 months (minimum follow-up, 36.5 months) were presented, including subgroup analyses by IMDC risk category and in patients who completed two years of nivolumab treatment.

Study design

In CheckMate 9ER, previously untreated advanced or metastatic RCC patients were randomised 1:1 (stratified by IMDC risk score, tumour PD-L1 expression, region) to nivolumab 240 mg flat dose IV once every two weeks plus cabozantinib 40 mg PO once daily vs. sunitinib 50 mg PO for 4 weeks (6-week cycles) until disease progression or unacceptable toxicity (maximum nivolumab treatment is two years). Any IMDC risk group was allowed. Primary endpoint is progression-free survival (PFS) by blinded independent central review (BICR). Secondary endpoints were OS, objective response rate (ORR) by BICR, and safety.

Results

In total, 323 patients were randomised to NIVO+CABO and 328 patients to SUN. After a median follow-up of 44.0 months, median PFS was 16.6 months for NIVO+CABO and 8.4 months for SUN (HR[95%CI]: 0.58[0.48-0.71], p< 0.0001). Median OS for NIVO+CABO and SUN were 49.5 months and 35.5 months, respectively, translating into a 30% reduction in the risk of death (HR[95%CI]: 0.70[0.56-0.87], p= 0.0014). Subgroup analysis of PFS and OS according to IMDC risk group showed that patients with intermediate or poor risk disease derived the most benefit from nivolumab plus cabozantinib versus sunitinib. The ORR was higher with NIVO+CABO vs. SUN (55.7% vs. 28.4%), and 12.4% vs. 5.2% of patients achieved complete response (CR), respectively. Median time to response was 2.8 months for NIVO+CABO and 4.2 months for SUN. Median duration of response was respectively 23.1 and 15.2 months.

Two additional patients discontinued treatment due to an any-grade treatment-related adverse event (AE) since the previous database lock (median follow-up 32.9 months). One patient discontinued either NIVO or CABO or both, and one patient discontinued SUN. Any-grade treatment-related adverse events (TRAEs) occurred in 97% vs. 93% of patients treated with NIVO+CABO vs. SUN (grade ≥3 TRAE, 67% vs. 55%). TRAEs led to discontinuation of CABO only in 9.7% of patients, NIVO only in 9.7% of patients, NIVO+CABO in 6.6% of patients and SUN in 11% of patients. No new deaths that investigators considered related to treatment occurred since the previous database lock. Overall, 22% of 320 patients treated with NIVO+CABO received corticosteroid treatment with ≥40 mg prednisone per day or equivalent to manage any-grade immune-mediated AEs, 13% and 5% of patients received corticosteroids continuously for ≥14 days and ≥30 days, respectively.

Finally, 115 patients in the NIVO+CABO arm, 36% of those originally assigned to the combination regimen, completed two years of nivolumab treatment. After that time, 88% continued to receive cabozantinib, and the median time to subsequent treatment (or death for those who did not receive subsequent treatment) was 20.6 months.

Conclusion

After 44.0 months of median follow-up, NIVO+CABO maintained clinically meaningful benefits in long-term survival and response vs. sunitinib. Median OS with NIVO+CABO improved by 11.8 months since the previous database lock. ORR with NIVO+CABO were durable, with higher complete response rates with NIVO+CABO vs. SUN, regardless of IMDC risk group. No new safety signals emerged with additional follow-up in either treatment arm. These results continue to support NIVO+CABO as a first-line treatment for patients with advanced or metastatic RCC.

Reference

Burotto M, et al. Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial. Presented at ASCO GU 2023; Abstract 603.