Combination therapy with nivolumab and ipilimumab provides sustained survival benefit with durable responses compared with sunitinib for the first-line treatment of advanced renal cell carcinoma (aRCC), as shown by the phase III CheckMate 214 trial.
Moreover, grade 3/4 treatment-related adverse events (AEs) at 9 years are lower with the combination therapy than with sunitinib.
“Nivolumab plus ipilimumab remains a first-line standard of care in aRCC,” the investigators said.
A total of 1,096 patients with aRCC were randomly allocated to receive nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks x four doses, followed by nivolumab (3 mg/kg or 240 mg every 2 weeks or 480 mg every 4 weeks), or sunitinib 50 mg once daily (4 weeks on, 2 weeks off).
Over a median follow-up of 9.3 years, nivolumab plus ipilimumab vs sunitinib yielded a hazard ratio for overall survival (OS) of 0.71 (95 percent confidence interval [CI], 0.62‒0.82) in intention-to-treat patients, 0.69 (95 percent CI, 0.59‒0.81) in intermediate/poor-risk patients, and 0.80 (95 percent CI, 0.59‒1.09) in favourable-risk patients. [Ann Oncol 2026;37:960-973]
The respective 108-month OS probabilities were 31.4 percent vs 19.5 percent, 30.2 percent vs 18.7 percent, and 35.3 percent vs 21.8 percent. The 96-month progression-free survival probabilities were 22.7 percent vs 9.0 percent, 25.4 percent vs 8.5 percent, and 12.5 percent vs 11.3 percent, respectively.
Furthermore, the probabilities of remaining in response with nivolumab plus ipilimumab vs sunitinib at 96 months were 48.0 percent vs 19.0 percent in intention-to-treat patients, 50.0 percent vs 23.0 percent in intermediate/poor-risk patients, and 36.0 percent vs not estimable in favourable-risk patients.
Safety profile
The incidence of any-grade treatment-related AEs did not significantly differ between the two treatment groups (94.1 percent vs 97.6 percent). However, serious treatment-related AEs (grade 3/4) occurred less frequently with the combination therapy (48.6 percent vs 64.1 percent).
“These results not only reinforce the sustained clinical benefit of this immunotherapy combination but also offer valuable insights into the long-term outcomes and safety profile, confirming the durability of immunotherapy responses in this patient population,” the investigators said.
“This extended and final follow-up stands as a benchmark in the field, informing treatment decisions and setting new standards for long-term efficacy assessment in aRCC,” they added.
Longest follow-up
The CheckMate214 trial provides data from 9 years of follow-up, which is the longest follow-up period for a first-line immunotherapy combination in aRCC, according to the investigators.
“While initial trial results guide regulatory approvals and clinical practice, extended follow-up provides invaluable insights into the durability of responses, long-term survival outcomes, and potential latent toxicities,” the investigators said.
“This perspective is particularly crucial for immunotherapy-based regimens, as their mechanism of action can result in delayed responses and prolonged survival benefits that may not be fully captured in short-term analyses,” they added.
Moreover, these insights prove significant in improving patient care as treatment options expand in a therapeutic landscape that is becoming increasingly complex, according to the investigators.
Immune checkpoint inhibitor-based therapies modulate the regulatory pathways of the immune system by blocking inhibitory checkpoints such as programmed cell death-(ligand) protein or cytotoxic T-lymphocyte-associated protein 4. Doing so allows the immune system to recognize and target cancer cells. [Nat Rev Urol 2016;13:420-431; Cell 2023;186:1652-1669; J Immunother Cancer 2019;7:354]