SUMMARY: The American Cancer Society estimates that 76,080 new cases of kidney cancers will be diagnosed in the United States in 2021 and about 13,780 people will die from the disease. Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer and is about twice as common in men as in women. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five year survival of patients with advanced RCC is less than 10% and there is a significant unmet need for improved therapies for this disease.
The prognosis for patients with Renal Cell Carcinoma (RCC) is dependent on the stage of disease and risk factors. Two validated models, the University of California Los Angeles Integrated Staging System (UISS) and the Stage, Size, Grade, and Necrosis (SSIGN) score were developed, to assess the risk for relapse. UISS is based on ECOG Performance Status, Fuhrman nuclear grading and TNM pathological stage, whereas the SSIGN score takes Stage, Size, Grade and Necrosis into consideration. Approximately 16% of patients with RCC present with Locoregional disease, and up to 40% of these patients relapse with metastatic disease, following nephrectomy. The 5-year survival for locoregional (stage III) disease is 53%, and 8% for metastatic disease. The standard management of high risk patients following nephrectomy has been surveillance, as there has been limited data demonstrating the benefit of adjuvant therapy in reducing the risk of relapse. Adjuvant therapy with immune check point inhibitors therapy is a potentially attractive treatment strategy for this patient group.
KEYNOTE-564 is a multicenter, double-blind, Phase III trial in which the benefit of adjuvant therapy with KEYTRUDA® was compared with placebo, following nephrectomy, in patients with clear cell RCC. In this study, 994 patients were randomized 1:1 to receive either KEYTRUDA® or placebo at least 12 weeks after surgery. Enrolled patients had histologically confirmed clear cell RCC, with Intermediate-High risk (pT2, Grade 4 or Sarcomatoid, N0 M0; or pT3, any Grade, N0 M0), High risk (pT4, any Grade, N0 M0; or pT any Stage, any Grade, N+ M0), or M1 with No Evidence of Disease after primary tumor and soft tissue metastases were completely resected, 1 year or less from nephrectomy. Treatment consisted of KEYTRUDA® 200 mg IV every 3 weeks (N=496) or placebo (N=498), every 3 weeks, for approximately 1 year. Both treatment groups were well balanced. The Primary end point of the trial was Disease Free Survival (DFS) assessment in all randomized patients and Secondary end points included Overall Survival (OS) and Safety. The median follow up at the time of data cut-off was 24.1 months.
At first prespecified interim analysis, the Primary endpoint of DFS was met. The median DFS was not reached for both treatment groups. KEYTRUDA® reduced the risk of recurrence or death by 32% compared with placebo, and this difference was statistically significant (HR=0.68; P=0.0010). The estimated DFS rate at 24 months was 77.3% with KEYTRUDA® versus 68.1% with placebo and this DFS benefit was consistent across subgroups. The estimated OS rate at 24 months was 96.6% with KEYTRUDA® versus 93.5% with placebo. Survival data are premature and additional follow up is planned for OS.
It was concluded that KEYTRUDA® demonstrated a statistically significant and clinically meaningful improvement in Disease Free Survival compared to placebo, in patients with Renal Cell Carcinoma, with a high risk of recurrence. The authors added that this is the first positive Phase III study with a checkpoint inhibitor, in adjuvant Renal Cell Carcinoma, and these practice changing results support KEYTRUDA® as a potential new standard of care for this patient group.
Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: Randomized, double-blind, phase III KEYNOTE-564 study. Choueiri TK, Tomczak P, Park SH, et al. J Clin Oncol 2021; 39: (suppl 15; abstr LBA5) DOI: 10.1200/JCO.2021.39.15_suppl.LBA5
