Nivolumab, Ipilimumab, and Cabozantinib Triplet Therapy Demonstrates Clinical Activity for Patients With Advanced Renal Cell Carcinoma

Results From a Discontinued Arm of the CheckMate 9ER Trial

Triplet combination therapy with nivolumab plus ipilimumab plus cabozantinib was found to have clinical activity in patients with previously untreated, advanced renal cell carcinoma, according to results of a phase 3 trial.

The phase 3, randomized, open-label CheckMate 9ER trial originally included 3 treatment arms comparing outcomes for nivolumab plus cabozantinib vs sunitinib and nivolumab plus ipilimumab plus cabozantinib vs sunitinib in patients with previously untreated clear-cell advanced renal cell carcinoma. Due to the protocol amendment in December 2017 establishing nivolumab plus ipilimumab as standard of care for this patient population, the nivolumab plus ipilimumab plus cabozantinib arm was discontinued early. However, as Andrea Apolo, MD, National Cancer Institute, Bethesda, Maryland, and coauthors wrote, the triplet regimen has “shown preliminary evidence of clinical activity in patients” with certain advanced genitourinary and hepatocellular cancers, adding that the triplet regimen is also “currently under investigations for various RCC populations in phase 2 and 3 clinical trial.”

There were 50 patients with clear cell advanced renal cell carcinoma who had not received any previous therapy randomized to this arm of the trial. Patients received nivolumab 3 mg/kp plus ipilimumab 1 mg/kg once every 3 weeks, plus cabozantinib 40 mg once every day, for 4 cycles. After, they received nivolumab 240 mg once every 2 weeks plus cabozantinib 40 mg once every day. The primary (progression-free survival [PFS] by blinded independent central review) and secondary (overall survival [OS], objective response rate [ORR] by blinded independent central review, and safety) from the original CheckMate 9ER trial were applied. Additional end points included investigator-assessed PFS and ORR.

After a median follow-up duration of 39.1 months, the median PFS was 9.9 (95% confidence interval [CI], 5.7 to 16.8) months by blinded independent central review, and 13.9 (95% CI, 7.3 to 24.7) months by investigator. The ORR was 44.0% (95% CI, 30.0 to 58.7) with 8% achieving a complete response by blinded independent central review and 48.0% (95% CI, 33.7 to 62.6) with  all partial responses by investigator. The median OS was 37.0 months (95% CI, 31.8 to not estimable).

Overall, grade 3/4 treatment-related adverse events were reported in 84.0% of patients. The most common treatment-related adverse events, in ≥16% of patients, were alanine aminotransferase increase (20%), aspartate aminotransferase increase (16%), and hepatotoxicity (16%). There were grade 3/4 hepatic immune-mediated adverse events reported in 40% of patients. There were no grade 5 treatment-emergent adverse events.

“These results suggest that the nivolumab plus ipilimumab plus cabozantinib triplet combination has clinical activity in patients with previously untreated aRCC, although monitoring of overlapping toxicities will be important in future studies of this regimen,” Dr Apolo et al concluded.

Source:

Apolo AB, Powles T, Escudier B, et al. Nivolumab plus ipilimumab plus cabozantinib triplet combination for patients with previously untreated advanced renal cell carcinoma: Results from a discontinued arm of the phase III CheckMate 9ER trial. Euro J Cancer. Published online October 31, 2022. doi: 10.1016/j.ejca.2022.09.020