First-Line Nivolumab/Ipilimumab Demonstrates Treatment-Free Survival in Advanced RCC

Patients with advanced renal cell carcinoma treated with first-line nivolumab (Opdivo) plus ipilimumab (Yervoy) had longer treatment-free survival without toxicity regardless of risk group, compared with those treated with sunitinib (Sutent), according to results from the CheckMate 214 trial (NCT02231749).¹

At 42 months following randomization, 52% of patients in the combination group and 39% in the sunitinib group with intermediate- or poor-risk disease were, and 18% and 5% of whom were treatment-free, respectively. A total of 70% of patients with favorable-risk disease in the combination group and 73% in the sunitinib group were alive at the same time point. Within this group 20% and 9% of patients from either group were treatment-free, respectively. Treatment-free survival (TFS) over the 42-months was twice as long in the intermediate- to poor-risk patients, with the combination regimen yielding a median TFS of 6.9 months vs 3.1 months in the sunitinib group, and 3 times as long in favorable-risk patients (11.0 months vs 3.7 months).

“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 endpoint to quantify those two 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,” Meredith Regan, ScD, an associate professor at Harvard Medical School and Dana-Farber Cancer Institute, said in a press release.²

A total of 1096 patients were randomized 1:1 to receive either unblinded nivolumab at a dose of 3 mg/kg and 1 mg/kg of ipilimumab every 3 weeks followed by 3 mg/kg of nivolumab every 2 weeks or 50 mg of oral sunitinib once daily for 4 weeks of every 6-week cycle.

In total, 77% of patients had International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) poor- to intermediate-disease.

At a follow-up of 42 months since randomization, among patients with poor- to intermediate-risk disease, 31% of patients in the combination group and 9% in the sunitinib group were not receiving subsequent therapy, and 14% and 4.1% of patients remained on protocol therapy, respectively. A total of 18% of those in the combination group and 4.9% in the sunitinib group had a probability of being treatment-free at 42 months.

The difference in the mean overall survival (OS) and TFS was 3.7 months (95% CI, 2.5-5.0), as a result of a 7.1 months longer mean time from randomization to subsequent therapy initiation or death (21.0 months vs 13.9 months). The 42-month mean TFS was 6.9 months in the combination arm compared with 3.7 months in the single-agent arm. In the combination group, the mean TFS at 42 months was 3.4 months (95% CI, 2.2-4.6) without grade 3 or higher treatment-related adverse effects (TRAEs), and 2.4 months (95% CI, 1.4-3.4) without any grade 2 or higher TRAEs. Grade 2 or high TRAEs that continued or were newly reported following discontinuation of protocol therapy resulted in a 42-month mean TFS of 3.0 months in the combination group vs 1.6 months in the sunitinib group.

Within the population of patients with IMDC favorable-risk disease (n = 249), 29% and 24% free from subsequent therapy initiation in the combination and sunitinib groups, respectively. Additionally, 9.6% and 15% remained on therapy in each respective group. Additionally, 19.5% of patients in the combination group and 8.8% in the sunitinib group were treatment-free at 42-months. 

A shorter mean protocol therapy was identified for the favorable risk patients, including 14.0 months in the combination group and 20.2 months in the sunitinib group, with a similar mean time from randomization to subsequent therapy initiation or death. 

Despite patients experiencing a mean TFS with grade 2 or higher toxicity of 4.1 months in the combination group vs 1.4 months in the sunitinib group, the mean toxicity was longer in the combination group at 6.9 months compared with 2.3 months in the sunitinib group.

On average, the favorable-risk patients in the combination group spent 5.2 months with and 8.8 months without grade 2 or higher TRAEs compared with 13.7 months and 6.5 months in the sunitinib group. The mean time on protocol therapy with grade 3 or higher TRAEs was 0.9 month in the combination group and 2.8 months in the sunitinib group.

“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. We knew from the previous CheckMate-214 analysis that nivolumab + 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 concluded.

References

1. Regan MM, Jegede OA, Mantia CM, et al. Treatment-free survival after immune checkpoint Inhibitor Therapy versus Targeted Therapy for Advanced Renal Cell Carcinoma: 42-Month Results of the CheckMate 214 Trial. Clin Cancer Res. 2021;10.1158/1078-0432.CCR-21-2283. doi:10.1158/1078-0432.CCR-21-2283

2. Immunotherapy may yield longer treatment-free survival than targeted therapy in advanced renal cell carcinoma patients. News Release. American Association for Cancer Research. November 10. 2021. Accessed December 14, 2021. https://bit.ly/3pXURud