The Evolving Role of Adjuvant Immunotherapy in Resected Renal Cell Carcinoma: Key Findings and Future Directions

Immunotherapy has been shown to improve survival outcomes in a variety of solid tumors. Renal cell carcinoma (RCC) has traditionally been managed by antiangiogenic agents, particularly in metastatic disease. Numerous clinical trials have reported the significant benefit of immunotherapy in advanced disease, and regimens incorporating immune checkpoint inhibitors (ICIs) are now the standard of care in unresectable RCC.¹ However, immunotherapy has only recently been evaluated in localized RCC, and large randomized clinical trials have now reported major findings. ICIs such as atezolizumab (Tecentriq; Genentech), nivolumab (Opdivo; Bristol Myers Squibb), pembrolizumab (Keytruda; Merck Sharp & Dohme LLC), and durvalumab (Imfinzi; AstraZeneca) have similar mechanisms of action but may have different levels of clinical activity depending on the disease state. Given the plethora of clinical trial data and practical impact on real-world practice, it is important to highlight the major findings of these studies evaluating adjuvant ICIs in patients with RCC who are at increased risk of recurrence following nephrectomy.

Adjuvant Atezolizumab

The randomized, double-blind, phase 3 IMmotion010 trial (NCT03024996) evaluated the clinical activity of adjuvant atezolizumab in patients with RCC at an increased risk of recurrence following nephrectomy. Within 12 weeks of trial enrollment, 778 patients who underwent nephrectomy were randomly assigned 1:1 to receive either adjuvant atezolizumab 1200 mg or placebo intravenously (IV) every 3 weeks for 16 cycles or 1 year. The median age was 60 years, and 36% of patients were 65 years or older. The predominant histology was clear cell RCC (93%), and the majority of patients had T2 or T3a disease (64%). Approximately 60% of patients had PD-L1 expression levels at 1% or greater.²

The primary end point of investigator-assessed disease-free survival (DFS) in the intent-to-treat (ITT) population was not met. The median DFS in the atezolizumab group was 57.2 months compared with 49.5 months in the placebo group (HR, 0.93; 95% CI, 0.75-1.15; P = .50). There was no significant difference in DFS between the subgroups of patients with low and high PD-L1 expression. Although the overall survival (OS) data are immature, there was no statistically significant difference in OS between atezolizumab and placebo (HR, 0.97; 95% CI, 0.67-1.42).²

There was a higher frequency of treatment-related adverse events (AEs) in the atezolizumab group compared with the placebo group (76% vs 53%). Similarly, there was a greater incidence of grade 3 or greater treatment-related AEs in patients who received atezolizumab (14% vs 5%). The most common grade 3 or greater AEs were hypertension (2% vs 4%), hyperglycemia (3% vs 2%), and diarrhea (1% vs 2%). Any-grade immune-mediated AEs occurred in 54% of patients receiving atezolizumab and 28% of patients receiving placebo. AEs that led to treatment discontinuation occurred in 12% of patients in the atezolizumab group compared with 3% in the placebo group.²

Adjuvant Nivolumab Plus Ipilimumab

The randomized, double-blind, phase 3 CheckMate 914 trial (NCT03138512) evaluated the efficacy of nivolumab plus ipilimumab (Yervoy; Bristol Myers Squibb) in resected localized RCC. During the trial, 816 patients were randomly assigned 1:1 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 matched placebo. Patients had localized RCC, clear cell histology, increased risk for disease relapse post nephrectomy, and no apparent metastatic or residual disease. The median age was 58 years, with approximately 73% of patients younger than 65 years. Patients mostly had undergone radical nephrectomy (93%) and had either high-risk (57%) or moderate-risk (43%) disease. Five percent of patients had sarcomatoid features present.³

At a median follow-up of 37 months, the primary end point of DFS assessed by blinded independent committee review was not met in the ITT population (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 (95% CI, 48.1-not estimable) in the placebo group. No significant differences were noted in the subgroups that assessed treatment effect based on age, race, gender, tumor stage, or disease risk. Among the small subset of patients who presented with sarcomatoid features, improved DFS was observed in those treated with nivolumab plus ipilimumab (HR, 0.29; 95% CI, 0.09-0.91). OS data were immature at time of data cutoff.³

More patients experienced grade 3 or greater AEs in the nivolumab plus ipilimumab group compared with the placebo group (38% vs 10%). Most of the severe grade 3 or greater AEs that occurred in the nivolumab plus ipilimumab group were immune-mediated and included diarrhea or colitis (5%), adrenal insufficiency (3%), hypophysitis (3%), hepatitis (3%), and diabetes (2%). There were more patients who discontinued treatment due to AEs of any grade in the nivolumab plus ipilimumab group compared with placebo (32% vs 2%).³

Adjuvant Nivolumab With Priming Dose

The randomized, open-label, phase 3 PROSPER EA8143 trial (NCT03055013) studied the efficacy of a priming dose of neoadjuvant nivolumab before partial or full nephrectomy followed by adjuvant nivolumab. In the trial, 819 patients with clinical stage T2 or greater or TanyN+ RCC who planned to undergo partial or full nephrectomy were randomly assigned 1:1 to receive either nivolumab or surgery alone. In the investigational arm, nivolumab 480 mg was given IV every 4 weeks, with 1 dose prior to surgery and 9 subsequent doses after surgery.⁴

The primary end point of recurrence-free survival was similar between the nivolumab and observation arms (HR, 0.97; 95% CI, 0.74-1.28). OS, a key secondary end point, although not mature at the time of analysis, was not found to be statistically different between the treatment arms (HR, 1.48; 95% CI, 0.89-2.48). The trial was stopped early due to futility.⁴

The incidence of grade 3 or greater AEs was higher in the nivolumab group compared with the observation group (20% vs 6%). The most common grade 3 or greater AEs in the nivolumab and observation groups were kidney injury (1% vs 2%), rash (2% vs 0%), and elevated lipase level (4% vs < 1%).⁴

Adjuvant Pembrolizumab

The randomized, double-blind, phase 3 KEYNOTE-564 trial (NCT03142334) of 994 patients with clear cell RCC at an increased risk of recurrence assessed the efficacy and safety of adjuvant pembrolizumab. Patients were randomly assigned 1:1 to receive either pembrolizumab 200 mg or placebo IV every 3 weeks for up to 17 cycles. The median age was 60 years, with approximately 67% of patients younger than 65 years. Most patients had undergone radical nephrectomy (92%) and had intermediate- to high-risk disease (86%). Approximately 11% of patients had sarcomatoid features and 75% had PD-L1 expression levels of 1% or greater.⁵

At a median follow-up of 30.1 months, the primary end point of DFS was significantly improved with pembrolizumab compared with placebo (HR, 0.63; 95% CI, 0.50-0.80) in the ITT population. At 30 months, the estimated DFS rate in the pembrolizumab group was 75.2% (95% CI, 70.8%-79.1%) compared with 65.5% (95% CI, 60.9%-69.7%) in the placebo group. Patients with intermediate- to high-risk disease similarly had improved DFS with pembrolizumab vs placebo (HR, 0.68; 95% CI, 0.52-0.89). Likewise, in the subgroup of patients with PD-L1 expression levels of 1% or greater, there was a significant improvement in DFS with pembrolizumab vs placebo (HR, 0.63; 95% CI, 0.49-0.82).⁵

The secondary end point of OS in the ITT population was met at the time of analysis. Pembrolizumab demonstrated an improvement in OS compared with placebo (HR, 0.52; 95% CI, 0.31-0.86), although the median OS was not reached in either treatment arm. The 30-month OS rate was 95.7% (95% CI, 93.3%-97.2%) in the pembrolizumab group compared with 91.4% (95% CI, 88.3%-93.7%) in the placebo group.⁵

The incidence of grade 3 or greater AEs was higher in the pembrolizumab arm compared with the placebo arm. Specifically, 32% of patients experienced grade 3 or greater AE with pembrolizumab compared with 18% of patients receiving placebo. The most common grade 3 or greater AEs observed in the pembrolizumab arm were hypertension (3%) and increased alanine aminotransferase level (2%). Immune-mediated AEs occurred in 36% of patients receiving pembrolizumab and 7% of patients receiving placebo. AEs leading to treatment discontinuation occurred more frequently in the pembrolizumab arm compared with the placebo arm (21% vs 2%).⁵

Adjuvant Durvalumab

RAMPART (NCT03288532) is an ongoing, international, unblinded, randomized, phase 3 trial that will evaluate adjuvant durvalumab with or without tremelimumab (Imjudo; AstraZeneca) in patients at intermediate and high risk of recurrence after surgical resection of locally advanced RCC. In the trial, 1750 patients will be randomly assigned in a 3:2:2 ratio to either undergo active monitoring for 1 year, receive durvalumab 1500 mg IV every 4 weeks for up to 13 cycles, or receive durvalumab 1500 mg IV every 4 weeks for up to 13 cycles plus tremelimumab 75 mg IV at day 1 and week 4 (2 total tremelimumab doses).⁶

The primary end point will assess DFS, which is defined as the interval from random assignment to the first evidence of local recurrence, new metastases, new primary RCC, or death from any cause. OS will be evaluated for patients with high-risk disease only (Leibovich score of 6-11) and is contingent on seeing improvements in DFS. Key secondary outcomes include safety, RCC-specific survival time (defined as time from random assignment to death from RCC), metastasis-free survival (defined as the interval from random assignment to first evidence of metastases or death from RCC), and patient-reported outcomes.⁶

Adjuvant Belzutifan Plus Pembrolizumab

Belzutifan (Welireg; Merck Sharp & Dohme LLC) is an inhibitor of hypoxia-inducible factor 2α that is FDA approved in advanced RCC following previous ICI and antiangiogenic therapy.⁷ LITESPARK-022 (NCT05239728) is an ongoing, global, double-blind, randomized, phase 3 trial analyzing the efficacy of belzutifan plus pembrolizumab as adjuvant treatment in clear cell RCC. The study is anticipated to enroll approximately 1800 systemic therapy–naive patients with intermediate- to high-risk clear cell RCC.

Patients must have an ECOG performance status score of 0 to 1 and nephrectomy within 12 weeks prior to random assignment. Patients will be randomly assigned 1:1 to receive either belzutifan 120 mg orally once daily plus pembrolizumab 400 mg IV every 6 weeks or pembrolizumab 400 mg IV alone every 6 weeks. Belzutifan may be continued for a maximum of 54 weeks and pembrolizumab for up to 9 doses.⁸

During years 1 to 2, disease recurrence will be radiologically monitored every 12 weeks; during years 3 to 5, every 16 weeks; and during years 6 and beyond, every 24 weeks. The primary end point is investigator-assessed DFS (defined as time from random assignment to the first of 3 outcomes: documented local recurrence, distant kidney cancer metastasis, or all-cause death). Key secondary end points include OS, safety, disease recurrence–specific survival (defined as time from randomization to first documented local recurrence of RCC), and patient-reported outcomes.⁸

Conclusion

Adjuvant atezolizumab did not demonstrate significant improvement in DFS or OS in patients with RCC at an increased risk of recurrence following nephrectomy.² Adjuvant nivolumab similarly did not improve efficacy outcomes, and the addition of a neoadjuvant priming dose of nivolumab may be suggestive of worse OS outcomes (HR, 1.48; 95% CI, 0.89-2.48).^3,4 Pembrolizumab is the only immunotherapy that demonstrated significant improvement in efficacy outcomes as an adjuvant therapy and is now an appropriate treatment option for patients with resected RCC at an increased risk of recurrence.^1,5 Ongoing trials of adjuvant durvalumab and the combination of belzutifan plus pembrolizumab will evaluate whether different immunotherapy strategies will further improve survival outcomes for this patient population.^6,8

Although there have been mixed data regarding the use of immunotherapy as adjuvant therapy in resected RCC, clinicians should be aware that pembrolizumab is currently the only agent that demonstrated improved outcomes and that other ICIs cannot be substituted for pembrolizumab despite the similar mechanism 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 that may further transform the treatment landscape of resectable RCC.

REFERENCES

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6. Oza B, Frangou E, Smith B, et al. RAMPART: a phase III multi-arm multi-stage trial of adjuvant checkpoint inhibitors in patients with resected primary renal cell carcinoma (RCC) at high or intermediate risk of relapse. Contemp Clin Trials. 2021;108:106482. doi:10.1016/j.cct.2021.106482
7. Welireg. Package insert. Merck Sharp & Dohme LLC; 2023. Accessed July 19, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215383s006lbl.pdf
8. Choueiri TK, Bedke J, Karam JA, et al. LITESPARK-022: a phase 3 study of pembrolizumab + belzutifan as adjuvant treatment of clear cell renal cell carcinoma (ccRCC). J Clin Oncol. 2022;40(suppl 16):TPS4602. doi:10.1200/JCO.2022.40.16_suppl.TPS4602