SUMMARY: The American Cancer Society estimates that 81,610 new cases of kidney and renal pelvis cancers will be diagnosed in the United States in 2024 and about 14,390 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 (NED) 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 Primary endpoint of DFS was met at the first prespecified interim analysis, with a median follow up of 24.1 months. 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). Survival data were not mature at that time, and additional follow up was planned for OS. Based on this data, the FDA in November 2021 approved KEYTRUDA® for the adjuvant treatment of patients with RCC.
In this updated analysis, at a median follow up of approximately 57 months, there was a statistically significant improvement in OS with KEYTRUDA®, compared to placebo (medians not reached, HR=0.62, P=.0024). This represented a 38% reduction in the risk of death for patients receiving KEYTRUDA®, and at the 48-month mark, the estimated OS rate was 91.2% for the KEYTRUDA® group compared to 86.0% for the placebo group. The OS benefit was observed across key subgroups, including in patients with M0 disease, or M1 NED, patients with PD-L1 CPS less than 1 or CPS 1 or more, and with presence or absence of sarcomatoid features. The observed DFS benefit with KEYTRUDA® versus placebo was consistent with prior interim analyses. No new safety signals were observed.
It was concluded, that after a median of about 57 months of follow up, KEYTRUDA® demonstrated a statistically significant and clinically meaningful improvement in Overall Survival compared to placebo, in patients with Renal Cell Carcinoma, at a high risk of recurrence following surgery. The authors added that this is the first positive Phase III study with a checkpoint inhibitor to demonstrate survival benefit in adjuvant Renal Cell Carcinoma, and these practice changing results support KEYTRUDA® as a new standard of care for this patient group. Studies are underway exploring the potential of combining KEYTRUDA® with other agents, such as the Hypoxia-Inducible Factor-2 (HIF-2) inhibitor Belzutifan, to further optimize treatment outcomes for patients with clear cell Renal Cell Carcinoma.
Overall survival results from the phase 3 KEYNOTE-564 study of adjuvant pembrolizumab versus placebo for the treatment of clear cell renal cell carcinoma (ccRCC). Choueiri TK, Tomczak P, Park SH, et al.Journal of Clinical Oncology 42(4_suppl):LBA359. DOI:10.1200/JCO.2024.42.4_suppl.LBA359.
