For patients with locoregional renal cell carcinoma (RCC), surgery (nephrectomy) is the standard of care and is potentially curative. However, nearly half of all patients experience disease recurrence, which is usually incurable. Risk factors for recurrence include tumor stage/size, nodal involvement, and nuclear grade. In addition, patients with resected oligometastatic disease are also at high risk of relapse. There is a considerable unmet need for effective adjuvant therapy to improve the outcomes of these patients. Based on proven efficacy of immune checkpoint inhibitors in metastatic RCC, the role of these agents is also being evaluated in the adjuvant setting.

During the recent ASCO 2021 plenary session, first results from the phase III KEYNOTE-564 study (LBA5) were presented by Dr Toni Choueiri, MD (Dana-Farber Cancer Institute, Boston, Massachusetts, US). This global, multicenter, double blind, placebo-controlled trial evaluated the PD-1 inhibitor pembrolizumab (200 mg every 3 weeks; n=496) versus placebo (every 3 weeks; n=498) as post-nephrectomy therapy (given for approximatelly 1 year) for patients with histologically confirmed clear cell RCC. Patients were stratified according to pre-specified risk categories for disease recurrence after surgery: intermediate–high risk, high risk, and M1 NED (no evidence of disease after resection of oligometastatic sites resected synchronous or within 1 year of the nephrectomy). At a median follow-up of 24.1 months, median disease-free survival (DFS) was not reached in either the pembrolizumab or placebo arms. However, adjuvant treatment with pembrolizumab demonstrated significant and clinically meaningful improvement in DFS compared with placebo, with a hazard ratio (HR) of 0.68 (P=0.001), a 32% reduction in the risk of recurrence or death with adjuvant pembrolizumab. At both 12- and 24-month timepoints, the difference between the estimated DFS rate for pembrolizumab versus placebo was around 10%. The DFS benefit was consistent across key subgroups, although some subgroups had small numbers of events, which limits interpretation. The overall survival (OS) data are immature, and an additional analysis is planned. Although the median OS was not reached in either arm, there is a favorable trend towards a benefit with pembrolizumab. The estimated 2-year OS rates were 96.6% for pembrolizumab and 93.5% for placebo. Pembrolizumab’s safety profile in the adjuvant setting was in line with expectations and previous experience in RCC. No new safety signals were observed. The most common treatment-related adverse events (AEs) were fatigue, pruritus, and thyroid abnormalities, which were all of low grade. Immune-related AEs were mainly hypo- and hyper-thyroidism and were manageable. In total, 18% of patients discontinued pembrolizumab due to treatment-related AEs, but there were no treatment-related deaths.

Dr Choueiri concluded that KEYNOTE-564 is the first positive phase III study of an adjuvant immunotherapy in RCC and highlighted that pembrolizumab is potentially a new standard of care for patients with clear cell RCC post-nephrectomy. Dr Rana McKay, MD (University of California San Diego, La Jolla, US), a discussant of the abstract, acknowledged the results as practice-changing and noted that future considerations are whether all patients, including those with non-clear cell RCC, may benefit from adjuvant pembrolizumab and how adjuvant pembrolizumab impacts the first-line treatment of patients who develop advanced disease.

Reference
Choueiri T, et al. ASCO 2021; Abstract LBA5