Exploring the Role of Immunotherapy After Progression in Renal Cell Carcinoma

Immunotherapy's Potential in Advanced RCC

Treatment with a tyrosine kinase inhibitor (TKI) remains the standard of care for patients with metastatic renal cell carcinoma (RCC) who progress following immunotherapy in the frontline setting. However, ongoing clinical trials are investigating whether immunotherapy agents could still play a role after progression. The phase 3 CONTACT-03 trial is exploring the combination of cabozantinib plus atezolizumab versus cabozantinib monotherapy, and the phase 3 TiNivo-2 trial is investigating tivozanib plus nivolumab versus tivozanib monotherapy.

NeoAvAx Trial Insights

The phase 2 NeoAvAx trial investigated neoadjuvant avelumab and axitinib in patients with localized RCC at high risk for relapse following nephrectomy. The trial aimed to determine if this combination could downsize tumors, making surgery easier or allowing for additional nephron sparing. The study included patients at high risk of relapse, treating them with 6 doses of avelumab and axitinib before surgery. The primary endpoint was the objective response rate (ORR), with secondary endpoints including disease-free survival (DFS), overall survival (OS), safety, and tolerability.

Key Findings from NeoAvAx

A total of 40 patients were enrolled, with a median age of 63 years. The ORR was 30%, with 12 of the 40 patients achieving a partial response. Notably, 83% of the patients who had a response remained disease-free at the time of study follow-up. The median DFS and OS were not reached, but at a median follow-up of close to 2 years, recurrence occurred in approximately one-third of patients, meaning two-thirds remained disease-free.

Safety and Tolerability

The combination of avelumab and axitinib before surgery was well tolerated, with no unexpected toxicities or notable surgical complications. This establishes a standard where this combination can be done safely if needed in the right patient, although it is not yet a standard of care.

KEYNOTE-564 Trial Update

The phase 3 KEYNOTE-564 trial, which randomized patients with high-risk kidney cancer to receive either pembrolizumab or placebo for 1 year after surgery, showed a DFS improvement with pembrolizumab. The 24-month DFS rate was 78.3% in patients receiving pembrolizumab versus 67.3% in the placebo arm. The benefit was more significant in higher-risk groups and patients with sarcomatoid features.

Future Directions in RCC Research

Despite progress in treating metastatic RCC, challenges remain, especially in managing patients after progression on frontline therapy. Research is ongoing to find novel therapies that can produce a durable benefit in refractory RCC. Additionally, there is a need for more personalized treatment approaches based on prognostic and predictive biomarkers to improve response rates, cure rates, and long-term benefits for patients.