Treatment Options for Stage III Renal Cell Cancer

Radical nephrectomy.[1]

Preoperative embolization and radical nephrectomy.[2,3]

Radical nephrectomy followed by adjuvant systemic therapy with pembrolizumab or sunitinib.[4,5]

External-beam radiation therapy (EBRT) (palliative).[2]

Tumor embolization (palliative).[3]

Palliative nephrectomy.

Preoperative or postoperative EBRT and radical nephrectomy.[2]

Clinical trials involving adjuvant interferon alfa.

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 cancer 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 disease-free survival (DFS).[4]Questions have been raised about confounding issues that may have resulted in the significant improvement in DFS in the KEYNOTE-564 trial.[7] 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.[8,9] 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.[7,10]

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 cancer 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 disease-free survival (DFS).[4]Questions have been raised about confounding issues that may have resulted in the significant improvement in DFS in the KEYNOTE-564 trial.[7] 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.[8,9] 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.[7,10]

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).[4][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).[6]

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 cancer 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 disease-free survival (DFS).[4]Questions have been raised about confounding issues that may have resulted in the significant improvement in DFS in the KEYNOTE-564 trial.[7] 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.[8,9] 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.[7,10]

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 cancer 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 disease-free survival (DFS).[4]Questions have been raised about confounding issues that may have resulted in the significant improvement in DFS in the KEYNOTE-564 trial.[7] 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.[8,9] 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.[7,10]

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

A double-blind, placebo-controlled, randomized trial (NCT00375674) studied the impact of sunitinib after nephrectomy in patients with locoregional, high-risk, clear cell renal cell cancer (stage T3 or higher and/or regional lymph node metastases). The study randomly assigned 615 patients to receive either 1 year of sunitinib (50 mg) or placebo once daily for the first 4 weeks of a repeating 6-week cycle (i.e., a 4-week-on, 2-week-off schedule).[5]

A double-blind, placebo-controlled, randomized trial (NCT00375674) studied the impact of sunitinib after nephrectomy in patients with locoregional, high-risk, clear cell renal cell cancer (stage T3 or higher and/or regional lymph node metastases). The study randomly assigned 615 patients to receive either 1 year of sunitinib (50 mg) or placebo once daily for the first 4 weeks of a repeating 6-week cycle (i.e., a 4-week-on, 2-week-off schedule).[5]

The median DFS was 6.8 years for patients who received sunitinib and 5.6 years for patients who received placebo (HR, 0.76; 95% CI, 0.59–0.98; P = .03). No difference in OS was reported (HR, 1.01; 95% CI, 0.72–1.44; P = .94).

A double-blind, placebo-controlled, randomized trial (NCT00375674) studied the impact of sunitinib after nephrectomy in patients with locoregional, high-risk, clear cell renal cell cancer (stage T3 or higher and/or regional lymph node metastases). The study randomly assigned 615 patients to receive either 1 year of sunitinib (50 mg) or placebo once daily for the first 4 weeks of a repeating 6-week cycle (i.e., a 4-week-on, 2-week-off schedule).[5]

Dose reductions were reported in 34% of patients who received sunitinib. Dose interruptions were seen in 46% of patients, and 28% of patients assigned to sunitinib discontinued the medication.

A double-blind, placebo-controlled, randomized trial (NCT00375674) studied the impact of sunitinib after nephrectomy in patients with locoregional, high-risk, clear cell renal cell cancer (stage T3 or higher and/or regional lymph node metastases). The study randomly assigned 615 patients to receive either 1 year of sunitinib (50 mg) or placebo once daily for the first 4 weeks of a repeating 6-week cycle (i.e., a 4-week-on, 2-week-off schedule).[5]

Of patients who received sunitinib, 48% experienced grade 3 adverse events and 12% experienced grade 4 adverse events. The most common high-grade adverse events were palmar-plantar erythrodysesthesia, hypertension, fatigue, neutropenia, thrombocytopenia, and mucosal inflammation.