Dr Choueiri on Initial Efficacy Data With NKT2152 in Pretreated ccRCC

Toni K. Choueiri, MD, medical director, International Strategic Initiatives, director, Lank Center for Genitourinary Oncology, co-leader, Kidney Cancer Program, senior physician, Dana-Farber Cancer Institute; Jerome and Nancy Kohlberg Chair, professor of medicine, Harvard Medical School, discusses the unique mechanism of action of the novel oral HIF-2α inhibitor NKT2152 in patients with previously treated advanced clear cell renal cell carcinoma (ccRCC).

NKT2152 is a novel oral inhibitor of hypoxia-inducible factor-2 alpha (HIF-2α), currently in development for the treatment of advanced ccRCC, Choueiri begins. HIF-2α, a transcription factor previously considered undruggable, has become a promising target for new therapies, he says. NKT2152 is part of a growing class of agents aimed at inhibiting HIF-2α, following in the footsteps of belzutifan (Welireg), which was approved by the FDA in December 2023 for patients with RCC following treatment with a PD-L1 therapy and VEGF/TKI agent, he adds. Early data have shown a response rate of 20% with NTK2152, with on-target toxicities such as anemia and hypoxia—similar to those observed with other agents in this class, Choueiri notes.

The drug is being evaluated in heavily pretreated, high-risk patients with advanced ccRCC in a phase 1/2 trial (NCT05119335). Results presented at the 2024 ESMO Congress indicated that NKT2152 demonstrated robust anti-tumor activity in this difficult-to-treat patient population. The safety profile was consistent with other HIF-2α inhibitors, with adverse events (AEs) related to the drug occurring across all dose levels. The most common toxicities included anemia and hypoxia, which are typical for HIF-2α inhibitors.

Currently, 2 dosing regimens, including a loading and maintenance strategy, have been selected for further evaluation in the dose-expansion phase of the trial. While alternative dosing strategies are being explored due to the drug's relatively short half-life, these early results suggest that NKT2152 could offer an additional therapeutic option for patients with advanced ccRCC. The ongoing trials will provide further clarity on the drug's efficacy and optimal dosing strategy, Choueiri, concludes.