(UPDATE) Nivolumab and Ipilimumab in Renal Cell Carcinoma
Updated: Wednesday, March 3, 2021
Nivolumab (Opdivo) plus ipilimumab (Yervoy) was the first combination treatment regimen (See Original Nivolumab/Ipilimumab Spotlight) to demonstrate superiority over sunitinib in the first-line setting for poor- or intermediate-risk advanced clear cell renal cell carcinoma,1 leading to its approval in the spring of 2018 by the U.S. Food and Drug Administration.2 Additionally, the regimen is included in the National Comprehensive Cancer Network Clinical Practice Guidelines in Kidney Cancer (NCCN Guidelines®) as a Category 1 Preferred recommendation for this indication.3 Ongoing research has indicated that the survival benefit observed with nivolumab plus ipilimumab in patients with poor- or intermediate-risk advanced disease has continued.4-6
Several other immunotherapy combinations, including axitinib plus pembrolizumab, axitinib plus avelumab, and cabozantinib plus nivolumab, were approved in the first-line treatment of advanced clear cell renal cell carcinoma, based on the results of the KEYNOTE-426, JAVELIN Renal 101, and CheckMate 9ER trials, respectively.7-12 To date, no head-to-head trials have compared the effectiveness of these combination therapies with nivolumab plus ipilimumab.
CheckMate 214 Updates
The results of extended follow-up of the phase III CheckMate 214 trial “continue to support the use of first-line nivolumab plus ipilimumab to achieve meaningful and durable clinical outcomes in patients with advanced renal cell carcinoma,” stated the study authors.6 After a median 32.4 months of follow-up, the combination of nivolumab plus ipilimumab increased overall survival, progression-free survival, and the proportion of patients achieving an objective response compared with sunitinib in patients with intermediate- or poor-risk disease.4
In the 42-month update, the authors noted a higher proportion of patients who achieved a complete response with nivolumab plus ipilimumab versus sunitinib (10.1% vs. 1.4%), regardless of risk category.5 Risk was assessed according to International Metastatic Renal Cell Carcinoma Database Consortium criteria. However, the benefits observed in the intermediate- and poor-risk groups did not appear to extend to all patients; in the favorable-risk subgroup, the hazard ratio for death was 1.19 (95% confidence interval = 0.77–1.85), and the objective response rate was 28.8% with nivolumab plus ipilimumab versus 54.0% with sunitinib.
At 4 years of follow-up, the nivolumab-plus-ipilimumab regimen maintained a significant overall survival benefit in patients with intermediate- and poor-risk disease compared with sunitinib (48.1 months vs. 26.6 months). The objective response rate was also higher in those with intermediate- and poor-risk disease, with more ongoing responses among those who received nivolumab plus ipilimumab versus sunitinib (65.2% vs. 49.6%). However, the difference in overall survival remained inconclusive in patients with favorable-risk clear cell renal cell carcinoma.6
At 4 years of follow-up, the nivolumab-plus-ipilimumab regimen maintained a significant overall survival benefit in patients with intermediate- and poor-risk disease compared with sunitinib.
Post Hoc Analyses
An exploratory post hoc analysis of the CheckMate 214 study found that in a subgroup of patients—those with target kidney lesion(s) but without prior nephrectomy—target kidney lesions shrunk with nivolumab plus ipilimumab compared with sunitinib; the size of target kidney lesion(s) was reduced by 30% in 35% versus 20% of patients, respectively. The overall survival hazard ratio of 0.63 was consistent between the intermediate- and poor-risk groups and the intention-to-treat group, although no complete responses were noted in either population without prior nephrectomy.13
Another post hoc analysis of CheckMate 214 identified patients with sarcomatoid renal cell carcinoma and intermediate- or poor-risk disease (n = 139) or favorable-risk disease (n = 6).14 According to the study authors, the nivolumab-plus-ipilimumab combination showed “unprecedented long-term survival, response, and complete response benefits versus sunitinib in previously untreated patients with sarcomatoid renal cell carcinoma and intermediate- or poor-risk disease, supporting the use of first-line [nivolumab plus ipilimumab] for this population.” With 42 months’ minimum follow-up, overall survival favored the nivolumab-plus-ipilimumab combination versus sunitinib (median not reached vs. 14.2 months, P = .0004). Progression-free survival was 26.5 versus 5.1 months in the nivolumab-plus-ipilimumab and sunitinib arms, with complete response rates of 18.9% versus 3.1%, respectively.
Finally, an analysis of treatment-free survival in CheckMate 214 revealed that patients who received the nivolumab-plus-ipilimumab regimen spent more survival time treatment-free without toxicity compared with those who received sunitinib, regardless of risk group.15 After 42 months of follow-up, 56% of those who received nivolumab plus ipilimumab and 47% of patients given sunitinib were still alive; 31% and 12% of patients, respectively, were surviving free of subsequent therapy. The mean treatment-free survival was more than twice as long after treatment with nivolumab plus ipilimumab compared with sunitinib in patients with intermediate- or poor-risk disease (6.9 vs. 3.1 months, respectively) and three times as long for favorable-risk patients (11.0 vs. 3.7 months, respectively).
The first-line treatment landscape for patients with advanced clear cell renal cell carcinoma will likely continue to evolve with extended study results and the development of additional immunotherapy combinations. Head-to-head comparisons of treatment combinations may elucidate ideal therapies for specific patient populations.
- Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378:1277–1290.
- FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-plus-ipilimumab-combination-intermediate-or-poor-risk-advanced-renal-cell. Accessed January 28, 2021.
- Motzer RJ, Jonasch E, Agarwal N, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Kidney Cancer. Version 1.2021—July 15, 2020. Accessed January 27, 2021. To view the most recent version of these guidelines, visit NCCN.org.
- Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol 2019;20:1370–1385.
- Motzer RJ, Escudier B, McDermott DF, et al. Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial. J Immunother Cancer 2020;8(2):e000891.
- Albiges L, Tannir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open 2020;5(6):e001079.
- Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1116–1127.
- FDA approves avelumab plus axitinib for renal cell carcinoma. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-avelumab-plus-axitinib-renal-cell-carcinoma. Accessed February 1, 2021.
- Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1103–1115.
- FDA approves pembrolizumab plus axitinib for advanced renal cell carcinoma. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-plus-axitinib-advanced-renal-cell-carcinoma. Accessed January 31, 2021.
- FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-cabozantinib-advanced-renal-cell-carcinoma. Accessed February 3, 2021.
- Choueiri TK, Powles T, Burotto M, et al. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase III CheckMate 9ER trial. Ann Oncol 2020;31:S1159.
- Albiges L, Tannir N, Burotto M, et al. Nivolumab + ipilimumab vs sunitinib for first-line treatment of advanced renal cell carcinoma in CheckMate 214: 4-year follow-up and subgroup analysis of patients without nephrectomy. Ann Oncol 2020;31:S559–S560.
- Tannir NM, Signoretti S, Choueiri TK, et al. Efficacy and safety of nivolumab plus ipilimumab versus sunitinib in first-line treatment of patients with advanced sarcomatoid renal cell carcinoma. Clin Cancer Res 2021;27:78–86.
- Regan M, Jegede OA, Mantia C, et al. Treatment-free survival, with and without toxicity, after immuno-oncology vs targeted therapy for advanced renal cell carcinoma: 42-month results of CheckMate 214. Ann Oncol 2020;31:S561.