Adjuvant immunotherapies have shown promise in improving survival outcomes in various solid tumors, including renal cell carcinoma (RCC). While antiangiogenic agents have been the standard of care, especially in metastatic disease, recent clinical trials have explored the role of immune checkpoint inhibitors (ICIs) in localized RCC. Several large randomized clinical trials have reported findings that could change clinical practice.
Atezolizumab Fails to Show Benefit in IMmotion010 Trial
The phase 3 IMmotion010 trial evaluated adjuvant atezolizumab in patients with RCC at increased recurrence risk post-nephrectomy. The study randomized 778 patients to receive either atezolizumab 1200 mg or placebo intravenously every 3 weeks for 16 cycles. The primary endpoint of investigator-assessed disease-free survival (DFS) in the intent-to-treat (ITT) population was not met (HR, 0.93; 95% CI, 0.75-1.15; P = .50). Median DFS was 57.2 months in the atezolizumab group versus 49.5 months in the placebo group. Overall survival (OS) data were immature, with no statistically significant difference between the two groups (HR, 0.97; 95% CI, 0.67-1.42).
The atezolizumab group experienced a higher frequency of treatment-related adverse events (AEs) compared to placebo (76% vs 53%), including grade 3 or greater AEs (14% vs 5%).
Nivolumab Plus Ipilimumab Does Not Improve DFS in CheckMate 914 Trial
The phase 3 CheckMate 914 trial assessed nivolumab plus ipilimumab in resected localized RCC. 816 patients were randomized to receive either nivolumab (240 mg IV every 2 weeks for 12 doses) plus ipilimumab (1 mg/kg IV every 6 weeks for 4 doses) or placebo. The primary endpoint of DFS was not met (HR, 0.92; 95% CI, 0.71-1.19; P = .53). Median DFS was not reached in the nivolumab plus ipilimumab group and was 50.7 months in the placebo group. However, in a small subset of patients with sarcomatoid features, improved DFS was observed with nivolumab plus ipilimumab (HR, 0.29; 95% CI, 0.09-0.91).
Grade 3 or greater AEs were more frequent in the nivolumab plus ipilimumab group (38% vs 10%), leading to treatment discontinuation in 32% of patients compared to 2% in the placebo group.
PROSPER EA8143 Trial of Neoadjuvant and Adjuvant Nivolumab Stopped Early
The phase 3 PROSPER EA8143 trial studied neoadjuvant nivolumab before nephrectomy followed by adjuvant nivolumab. 819 patients with clinical stage T2 or greater or TanyN+ RCC were randomized to receive either nivolumab (480 mg IV every 4 weeks, 1 dose pre-surgery and 9 post-surgery) or surgery alone. Recurrence-free survival was similar between the two arms (HR, 0.97; 95% CI, 0.74-1.28). The trial was stopped early due to futility. OS, although not mature, was not statistically different (HR, 1.48; 95% CI, 0.89-2.48).
Grade 3 or greater AEs were higher in the nivolumab group (20% vs 6%).
KEYNOTE-564 Trial Shows Pembrolizumab Improves DFS and OS
The phase 3 KEYNOTE-564 trial evaluated adjuvant pembrolizumab in 994 patients with clear cell RCC at increased recurrence risk. Patients were randomized to receive either pembrolizumab 200 mg or placebo IV every 3 weeks for up to 17 cycles. DFS was significantly improved with pembrolizumab compared to placebo (HR, 0.63; 95% CI, 0.50-0.80). At 30 months, the estimated DFS rate was 75.2% in the pembrolizumab group versus 65.5% in the placebo group. Pembrolizumab also demonstrated an improvement in OS compared with placebo (HR, 0.52; 95% CI, 0.31-0.86). The 30-month OS rate was 95.7% in the pembrolizumab group versus 91.4% in the placebo group.
Grade 3 or greater AEs were higher in the pembrolizumab arm (32% vs 18%), leading to treatment discontinuation more frequently (21% vs 2%).
Ongoing Trials: Durvalumab and Belzutifan Plus Pembrolizumab
RAMPART is an ongoing phase 3 trial evaluating adjuvant durvalumab with or without tremelimumab in patients at intermediate and high risk of recurrence after surgical resection of locally advanced RCC. LITESPARK-022 is a phase 3 trial analyzing the efficacy of belzutifan plus pembrolizumab as adjuvant treatment in clear cell RCC.
Implications for Clinical Practice
While adjuvant atezolizumab and nivolumab-based regimens have not demonstrated significant improvements in DFS or OS, pembrolizumab is currently the only immunotherapy that has shown significant efficacy as an adjuvant therapy for resected RCC. Clinicians should be aware that other ICIs cannot be substituted for pembrolizumab despite their similar mechanisms of action. Further research into the use of immunotherapy as adjuvant therapy in RCC is warranted, and clinicians are encouraged to participate in ongoing clinical trials.
