Rationale Explained for Granting EMA Authorisation for Extended Use of Nivolumab Plus Ipilimumab as First-Line Treatment in Poor- and/or Intermediate-Risk Advanced RCC

On 15 November 2018 the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) extended the existing indication for the use of nivolumab (Opdivo) in combination with ipilimumab (Yervoy) for the first-line treatment of adult patients with intermediate/poor-risk advanced renal cell carcinoma (RCC). This extension was based upon efficacy, quality of life, clinical safety, and benefit/risk ratio data from the phase III pivotal CA209214 study. Support for the application was also provided by the phase I CA209016 open-label study that explored various dose regimens of nivolumab plus ipilimumab. Details were provided in an article published on 13 November 2020 in “ESMO Open-Cancer Horizons”.

According to the authors, the rationale behind the application for extension stemmed from the observation of synergistic anti-tumour activity following dual blockade of PD-1 and CTLA-4 in murine syngeneic tumour models. In addition, the nivolumab/ipilimumab combination had already been approved for the treatment of unresectable or metastatic melanoma. Taken separately, nivolumab was approved in adults as monotherapy for advanced RCC after prior therapy and ipilimumab was investigated as monotherapy for metastatic RCC in the phase II MDX010-11 study. Comparison of the combination was to sunitinib, a standard treatment option, which demonstrated a 42% response rate in a pooled analysis.

The overall survival estimates vary with poor-, intermediate-, and favourable-risk

The randomised, open-label, phase III CA209214 study evaluated nivolumab in combination with ipilimumab compared to sunitinib in patients aged ≥18 years with previously untreated advanced RCC who were not amenable for surgery or radiotherapy, and in patients with metastatic RCC and a clear-cell component.

Of the 1096 randomised patients in the study, 847 patients had intermediate/poor-risk RCC; of these, 425 patients were treated with nivolumab at 3 mg/kg combined with ipilimumab at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab monotherapy at 3 mg/kg every 2 weeks, and 422 patients received oral sunitinib at 50 mg once per day for 4 weeks followed by 2 weeks off, each cycle.

Using the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic score, median overall survival (OS) in patients at poor-risk is estimated to be approximately 7.8 months, compared to 22.5 months in patients with intermediate risk, and 43.2 months in patients with favourable risk.

A clinically meaningful improvement in the co-primary endpoint of OS in the intermediate/poor-risk cohort was seen with the combination

In the intermediate/poor-risk cohort, patients receiving nivolumab plus ipilimumab demonstrated a statistically significant difference in OS compared to patients on sunitinib; median OS was not reached (NR) with nivolumab/ipilimumab versus 25.95 months with sunitinib (hazard ratio [HR] 0.63; 99.8% confidence interval [CI] 0.44 to 0.89; stratified log-rank 2-sided p-value < 0.0001). In the combination and sunitinib arms, the 6-, 12-, and 24 month OS rates were 89.5% versus 86.2%, 80.1% versus 72.1%, and 66.5% versus 52.9%, respectively.

The Kaplan-Meier curves for OS separated after approximately 3 months, favouring the nivolumab/ipilimumab combination.

Regarding OS in subgroups stratified by age, the combination was favoured over sunitinib, especially in younger patients; patients aged <65 years (unstratified HR 0.53; 95% CI 0.40-0.71) compared to those aged ≥65 to <75 years (HR 0.86; 95% CI 0.58-1.27) and patients aged ≥75 years (HR 0.97; 95% CI 0.48-1.95).

Progression-free survival (PFS; co-primary endpoint) per RECIST v1.1, favoured nivolumab/ipilimumab versus sunitinib (HR 0.82; 99.1% CI 0.64-1.05), stratified 2-sided p = 0.0331), but did not meet the stringent pre-specified α = 0.009 for statistical significance.

With the combination versus sunitinib, respectively, the best overall response was complete response in 9.4% versus 1.2%, partial response in 32.2% versus 25.4% and stable disease in 31.3% versus 44.5%. With the respective treatments, 19.5% of patients versus 17.1% experienced progressive disease and the response was unable to determine in 7.3% versus 11.8% of patients.

Patients with RCC and favourable risk did not demonstrate improved survival with the combination over sunitinib

Patients having favourable risk showed no statistically significant difference with nivolumab/ipilimumab versus sunitinib (HR 1.45; 99.8% CI 0.51- 4.12; p = 0.2715).

Regarding the predictive value for OS of PD-L1 tumour expression, OS was longer in patients with PD-L1 tumour expression ≥1% compared with those having PD-L1 <1% (HR 0.93, 95% CI 0.62 to 1.39), but OS in the sunitinib group favoured patients with PD-L1 tumour expression <1 compared to ≥1% (HR 1.64, 95% CI 1.20 to 2.23). In the intermediate/poor-risk subjects, OS by baseline PD-L1 ≥1% expression clearly favoured nivolumab/ipilimumab over sunitinib (HR 0.45; 95% CI 0.29-0.71).


The authors stated that the CHMP considered that the benefit/risk of nivolumab in combination with ipilimumab for the first-line treatment of adult patients with intermediate/poor-risk advanced RCC was positive.

However, they noted that further investigation is still required to try to elucidate the contribution of ipilimumab to the efficacy and toxicity of the combination regimen. Due to this uncertainty, the CHMP imposed a post-authorisation efficacy measure and requested that the company submit the results of a randomised study comparing the efficacy and safety of the combination to nivolumab as monotherapy in adult patients with intermediate/poor-risk and previously untreated advanced RCC and an appropriate spectrum of PD-L1 expression.

No external funding for this article was disclosed.


Ali S, Camarero J, Hennik P, et al. European Medicines Agency extension of indication to include the combination immunotherapy cancer drug treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) for adults with intermediate/ poor-risk advanced renal cell carcinoma. ESMO Open 2020;5:e000798. doi:10.1136/ esmoopen-2020-000798.