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Over a 42-month period, the combination of nivolumab and ipilimumab induced a longer treatment-free survival compared with sunitinib (Sutent) when used as frontline therapy in patients with advanced renal cell carcinoma.
Over a 42-month period, the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) induced a longer treatment-free survival (TFS) compared with sunitinib (Sutent) when used as frontline therapy in patients with advanced renal cell carcinoma (RCC), according to findings from a retrospective analysis of the phase 3 CheckMate 214 trial (NCT02231749) that were published in Clinical Cancer Research.1
Notably, the benefit with the combination vs the single agent was observed irrespective of International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group.
Moreover, at 42 months following randomization, 52% of patients with intermediate- and poor-risk disease who received nivolumab/ipilimumab were alive compared with 39% of those who received sunitinib. Of these patients, 18% vs 5% were surviving treatment-free, respectively.
Among favorable-risk patients, 70% of patients who received nivolumab/ipilimumab were alive compared with 73% of patients who received sunitinib. Of these patients, 20% vs 9% were surviving treatment-free, respectively.
The mean TFS at the data cutoff was 6.9 months with the doublet compared with 3.1 months with sunitinib in patients with intermediate-/poor-risk disease. In favorable-risk patients, the mean TFS was 11 months vs 3.7 months, respectively.
The mean TFS with grade 3 or higher treatment-related adverse effects (TRAEs) was low with both regimens at 0.6 months with nivolumab/ipilimumab vs 0.3 months with sunitinib in poor-/intermediate-risk patients and 0.9 months vs 0.3 months, respectively, in favorable-risk patients.
“This analysis is very patient-centered, and the implications of this work are that we have a new way to assess the value of new treatments to patients when we do clinical trials,” lead study author Meredith M. Regan, ScD, an associate professor of medicine and researcher at Dana-Farber Cancer Center, said in a news release.2
“We knew from the previous CheckMate-214 analysis that nivolumab [plus] ipilimumab improved survival compared with sunitinib; now, we are able to compare the way patients spent that overall survival time on these two different treatment approaches, and I think having this information is an important complement to the original trial results,” Regan added.
Patients with RCC who discontinue immunotherapy may experience periods of durable disease control without the need for additional therapy. However, toxicities from immunotherapy may be persistent beyond or emerge after checkpoint inhibitor discontinuation.
In this analysis of the CheckMate 214 trial, TFS represented a novel outcome measurement that characterized antitumor activity, as well as toxicity after patients discontinued immune checkpoint inhibitor therapy and before they started subsequent systemic therapy or died.
“One of the great challenges in conducting clinical trials is that some of the end points we’ve been using to measure the efficacy and value of a treatment are not optimal, especially when evaluating immuno-oncology-based therapy regimens,” Regan said. “As we continue to develop new treatments, we have an opportunity to think about new methods to better balance the efficacy and toxicity to the patients.”
“To do that, we needed a new end point to quantify those 2 aspects together—to continue to improve survival for patients while also focusing on how they are spending their time. That’s how TFS came to be,” Regan added.
TFS was defined as the time between 2 time-to-event end points: time to protocol therapy cessation and time to subsequent therapy initiation or death.
The patient population evaluated included all patients treated on the CheckMate 214 trial, which was comprised primarily of patients with advanced clear cell RCC.
The trial randomized 1096 patients 1:1 to 3 mg/kg of intravenous (IV) nivolumab plus 1 mg/kg of IV ipilimumab every 3 weeks for 4 doses followed by 3 mg/kg of nivolumab every 2 weeks (n = 550) or 50 mg of oral sunitinib daily for 4 weeks of each 6-week cycle (n = 546). Patients were treated until progression or unacceptable toxicity.
The amended protocol allowed patients to discontinue nivolumab/ipilimumab following 2 years of therapy without progression or unacceptable toxicity.
The majority of patients (77%) had IMDC intermediate-/poor-risk disease.
Further results demonstrated that the probability of being treatment-free at 42 months following randomization was 18% with nivolumab/ipilimumab compared with 4.9% with sunitinib.
The TFS difference without grade 2 or greater TRAEs was 2.4 months in favor of nivolumab/ipilimumab vs sunitinib (95% CI, 1.4-3.4). The 42-month mean TFS with grade 2 or greater TRAEs that persisted or were newly reported following treatment discontinuation was 3.0 months vs 1.6 months, respectively.
Patients with favorable-risk disease who received nivolumab/ipilimumab spent an average of 5.2 months with grade 2 or greater TRAEs and 8.8 months without grade 2 or greater TRAEs. Patients who received sunitinib spent an average of 13.7 months vs 6.5 months with and without grade 2 or higher TRAEs, respectively.
“This is a work in progress as we are continuing to refine this approach to better define how we evaluate toxicity. We counted the days when patients experienced adverse [affects (AE)] and registered their severity, but that didn’t take into account the type of AE or if more than one occurred on the same days,” Regan concluded.