Treatment Options for Stage II Renal Cell Cancer

Partial nephrectomy (selected patients).[1]

Radical nephrectomy.[1]

Radical nephrectomy followed by adjuvant pembrolizumab (high-risk patients).[2]

Nephrectomy before or after external-beam radiation therapy (EBRT) (selected patients).[1]

EBRT (palliative).[1]

Arterial embolization (palliative).

Clinical trials.

A double-blind, randomized, placebo-controlled trial (KEYNOTE-564 [NCT03142334]) studied the impact of 1 year of pembrolizumab after nephrectomy. The study enrolled 994 patients with clear cell renal cell carcinoma at high risk of recurrence after nephrectomy. Eligibility included patients with stage II disease with nuclear grade 4 or sarcomatoid differentiation, stage III disease or higher, regional lymph node metastases, or stage M1 status with no evidence of disease after resection. Patients were randomly assigned to receive up to 12 months of pembrolizumab (200 mg) or placebo administered intravenously every 21 days. The primary end point was DFS.[2]Questions have been raised about confounding issues that may have resulted in the significant improvement in DFS in the KEYNOTE-564 trial.[8] An uneven number of patients dropped out in the early follow-up period, which led to a lack of information about recurrence in the control group for the censored patients. Only 36% of the 166 patients in the control group received immunotherapy at relapse, despite conclusive evidence for an OS advantage when immunotherapy is given to patients with metastatic disease. Two other trials using atezolizumab or nivolumab plus ipilimumab failed to show a significant difference in DFS or OS.[9,10] These issues suggest that the U.S. Food and Drug Administration approval of pembrolizumab in the adjuvant setting, and the guidelines released by the National Comprehensive Cancer Network and the European Society for Medical Oncology may have been premature. Further follow-up for more mature DFS and especially OS results is needed.[8,11]

A double-blind, randomized, placebo-controlled trial (KEYNOTE-564 [NCT03142334]) studied the impact of 1 year of pembrolizumab after nephrectomy. The study enrolled 994 patients with clear cell renal cell carcinoma at high risk of recurrence after nephrectomy. Eligibility included patients with stage II disease with nuclear grade 4 or sarcomatoid differentiation, stage III disease or higher, regional lymph node metastases, or stage M1 status with no evidence of disease after resection. Patients were randomly assigned to receive up to 12 months of pembrolizumab (200 mg) or placebo administered intravenously every 21 days. The primary end point was DFS.[2]Questions have been raised about confounding issues that may have resulted in the significant improvement in DFS in the KEYNOTE-564 trial.[8] An uneven number of patients dropped out in the early follow-up period, which led to a lack of information about recurrence in the control group for the censored patients. Only 36% of the 166 patients in the control group received immunotherapy at relapse, despite conclusive evidence for an OS advantage when immunotherapy is given to patients with metastatic disease. Two other trials using atezolizumab or nivolumab plus ipilimumab failed to show a significant difference in DFS or OS.[9,10] These issues suggest that the U.S. Food and Drug Administration approval of pembrolizumab in the adjuvant setting, and the guidelines released by the National Comprehensive Cancer Network and the European Society for Medical Oncology may have been premature. Further follow-up for more mature DFS and especially OS results is needed.[8,11]

At a median follow-up of 24 months, pembrolizumab was associated with a higher 2-year DFS rate than placebo (77.3% for pembrolizumab vs. 68.1% for placebo; hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.53–0.87).[2][Level of evidence B1] A subsequent report with a median follow-up of 30 months showed a 75.2% DFS rate for patients who received pembrolizumab, compared with 65.5% for patients who received placebo (HR, 0.63; 95% CI, 0.50–0.80).[7]

A double-blind, randomized, placebo-controlled trial (KEYNOTE-564 [NCT03142334]) studied the impact of 1 year of pembrolizumab after nephrectomy. The study enrolled 994 patients with clear cell renal cell carcinoma at high risk of recurrence after nephrectomy. Eligibility included patients with stage II disease with nuclear grade 4 or sarcomatoid differentiation, stage III disease or higher, regional lymph node metastases, or stage M1 status with no evidence of disease after resection. Patients were randomly assigned to receive up to 12 months of pembrolizumab (200 mg) or placebo administered intravenously every 21 days. The primary end point was DFS.[2]Questions have been raised about confounding issues that may have resulted in the significant improvement in DFS in the KEYNOTE-564 trial.[8] An uneven number of patients dropped out in the early follow-up period, which led to a lack of information about recurrence in the control group for the censored patients. Only 36% of the 166 patients in the control group received immunotherapy at relapse, despite conclusive evidence for an OS advantage when immunotherapy is given to patients with metastatic disease. Two other trials using atezolizumab or nivolumab plus ipilimumab failed to show a significant difference in DFS or OS.[9,10] These issues suggest that the U.S. Food and Drug Administration approval of pembrolizumab in the adjuvant setting, and the guidelines released by the National Comprehensive Cancer Network and the European Society for Medical Oncology may have been premature. Further follow-up for more mature DFS and especially OS results is needed.[8,11]

Grade 3 or higher adverse events were reported for 32% of patients who received pembrolizumab, and 20% of the patients had serious adverse events. The most common high-grade adverse events were diarrhea and transaminitis, each occurring in 2% of patients who received pembrolizumab. The most common serious adverse events were adrenal insufficiency, colitis, and diabetic ketoacidosis, each occurring in 1% of patients who received pembrolizumab.

A double-blind, randomized, placebo-controlled trial (KEYNOTE-564 [NCT03142334]) studied the impact of 1 year of pembrolizumab after nephrectomy. The study enrolled 994 patients with clear cell renal cell carcinoma at high risk of recurrence after nephrectomy. Eligibility included patients with stage II disease with nuclear grade 4 or sarcomatoid differentiation, stage III disease or higher, regional lymph node metastases, or stage M1 status with no evidence of disease after resection. Patients were randomly assigned to receive up to 12 months of pembrolizumab (200 mg) or placebo administered intravenously every 21 days. The primary end point was DFS.[2]Questions have been raised about confounding issues that may have resulted in the significant improvement in DFS in the KEYNOTE-564 trial.[8] An uneven number of patients dropped out in the early follow-up period, which led to a lack of information about recurrence in the control group for the censored patients. Only 36% of the 166 patients in the control group received immunotherapy at relapse, despite conclusive evidence for an OS advantage when immunotherapy is given to patients with metastatic disease. Two other trials using atezolizumab or nivolumab plus ipilimumab failed to show a significant difference in DFS or OS.[9,10] These issues suggest that the U.S. Food and Drug Administration approval of pembrolizumab in the adjuvant setting, and the guidelines released by the National Comprehensive Cancer Network and the European Society for Medical Oncology may have been premature. Further follow-up for more mature DFS and especially OS results is needed.[8,11]

OS (the secondary end point) will be assessed when the study has longer follow-up.