Renal surgery following HIF-2α antagonist therapy: Surgical indications, outcomes and growth kinetics

The development of HIF-2α antagonists marked an advancement in the treatment of localized VHL-deficient kidney cancer; however, their impact on subsequent surgical interventions remains unexplored. This study investigated the indications for and outcomes of patients undergoing renal surgery after exposure to HIF-2α antagonists and the growth rates (GR) of their index renal tumors.

We performed a retrospective analysis of patients who underwent renal surgery at a single institution following or during treatment with a HIF-2α antagonist. Data regarding the clinicopathologic characteristics, therapy management, and surgical outcomes were collected. Index tumor GRs before, during and after drug administration were calculated and compared.

Twenty-seven patients underwent 28 surgeries after exposure to a HIF-2α antagonist from 2015 to 2023, with a total of 82 tumors removed. About 24 patients were treated with Belzutifan, and 3 patients were treated with PT2385, with 26 patients having a diagnosis of VHL syndrome. The median time on therapy prior to surgery was 14.7 months, with a median washout time of drug to surgery of 10 days. Median preoperative hemoglobin prior to surgery was 11.6 g/dL. Two blood transfusions were administered, 1 intraoperatively and 1 postoperatively. Seven postoperative complications were noted, 2 of which were ≥ Grade 3. The median index tumor GR prior to treatment was 0.37 cm/y, 0.46 cm/y during treatment, and 0.54 cm/y post-treatment. There was no significant difference in GRs between the groups. Median time to restart HIF-2α antagonist after surgery was 43 days. Limitations of this study include retrospective nature, single center, and lack of control group.

Renal surgery after or during exposure to a HIF-2α antagonist is safe and feasible, with rates of both transfusions and complications commensurate with the reported literature from standard renal surgery. GRs of index renal tumors that eventually needed surgical intervention did not show a significant difference before, during, and after therapy. Tumors exhibiting a positive GR on drug may represent the indication that drives early surgical intervention prior to the tumor reaching the 3 cm threshold. A median washout time of 10 days from last dose of HIF-2α antagonist to surgery was safe and well tolerated.