New Renal Cancer Therapy Effective in Higher Risk Groups

At the 2019 American Society of Clinical Oncology (ASCO) annual meeting, Cleveland Clinic genitourinary oncologist Brian Rini, MD, presented an analysis of select findings from the phase 3 KEYNOTE-426 trial of a renal cell carcinoma (RCC) therapy.

KEYNOTE-426 builds on the tremendous progress made in treating RCC over the past decade, leading to the current standard of care, immunotherapy. Based on its results, the U.S. Food and Drug Administration recently approved pembrolizumab (an immunotherapy agent) in combination with axitinib (an inhibitor of the VEGF receptor which leads to angiogenesis) for first-line treatment of advanced clear cell RCC. This is the second immunotherapy regimen approved in the past year. In 2018, ipilimumab/nivolumab was approved as a first-line treatment for International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate- and poor-risk metastatic clear cell RCC patients.

The KEYNOTE-426 trial compared pembrolizumab plus axitinib with the previous standard of care, sunitinib (a tyrosine kinase inhibitor) in 861 patients with advanced clear cell RCC who had not received prior treatment for their metastatic kidney cancer. Patients were randomly assigned to receive either pembrolizumab (200 mg) intravenously every three weeks in combination with axitinib (5 mg) orally twice daily, or sunitinib (50 mg) orally once daily for four weeks followed by no treatment for two weeks.

The primary endpoints were overall survival (OS) and progression-free survival (PFS). A secondary endpoint was objective response rate (ORR). At a median of 12.8 months, KEYNOTE-426 found that:

• The 12-month OS rate was 89.9% in the pembrolizumab plus axitinib group and 78.3% in the sunitinib group, with a 47% reduction in the risk of death for patients receiving pembrolizumab plus axitinib.
• The median PFS was 15.1 months in the pembrolizumab plus axitinib group and 11.1 months in the sunitinib group.
• The ORR was 59.3% (95% CI, 54.5 to 63.9) in the pembrolizumab plus axitinib group and 35.7% (95% CI, 31.1 to 40.4) in the sunitinib group.

“These are the best results we’ve seen for RCC in any trial,” says Dr. Rini, the lead KEYNOTE-426 investigator.

Analyzing trial results in patient subgroups

Following the initial KEYNOTE-426 results, Dr. Rini and the trial investigators analyzed outcomes in two subgroups: intermediate/poor risk and sarcomatoid features.

Of the 861 trial participants, 592 (68.8%) were IMDC intermediate/poor risk: 294 in the pembrolizumab plus axitinib group and 298 in the sunitinib group. Of the 578 participants with known status, 105 (18.2%) had sarcomatoid features: 51 in the pembrolizumab plus axitinib group and 54 in the sunitinib group.

Outcomes in the intermediate/poor-risk group:

• The 12-month OS rate was 87.3% in the pembrolizumab plus axitinib group and 71.3% in the sunitinib group.
• The median PFS was 12.6 months in the pembrolizumab plus axitinib group and 8.2 months in the sunitinib group.
• The ORR was 55.8% (95% CI, 49.9-61.5) in the pembrolizumab plus axitinib group and 29.5% (95% CI, 24.4-35.1) in the sunitinib group.

Outcomes in the sarcomatoid features group:

• PFS wasn’t reached in the pembrolizumab plus axitinib group and was 8.4 months in the sunitinib group.
• The ORR was 58.8% (95% CI, 44.2-72.4) in the pembrolizumab plus axitinib group and 31.5% (95% CI, 19.5-45.6) in the sunitinib group, with a remarkable 98% of patients in the pembrolizumab plus axitinib group having tumor shrinkage on therapy.

More patients with tumor shrinkage

The analysis also looked at depth of response for the entire cohort. Pembrolizumab plus axitinib demonstrated consistently more patients with tumor shrinkage, including three times as many patients with deep responses and 9% of patients with complete disappearance of all target lesions.

“This new regimen shows a consistent effect across all subgroups and gives us another effective option for treating RCC,” says Dr. Rini. “This regimen is now the standard of care in advanced RCC, with particular activity in patients with sarcomatoid features.”