Dr Choueiri on the Significance of Targeting HIF-2α With NKT2152 in ccRCC

“HIF-2α governs the activity of multiple genes downstream involved in RCC carcinogenesis and the proliferation of VEGF and other [disease factors]. There has been a lot of work on targeting [HIF-2α via] another mechanism that could be central, more active, and more beneficial [than available therapies].”

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, medicine, Harvard Medical School, discusses the significance of targeting HIF-2α using NKT2152 in patients with previously treated advanced clear cell renal cell carcinoma (ccRCC), as well as key adverse effects (AEs) associated with the agent.

HIF-2α is a key transcription factor involved in RCC pathogenesis, particularly in the context of von Hippel-Lindau protein degradation, Choueiri begins. HIF-2α regulates genes critical to RCC carcinogenesis and promotes the activity of VEGF and other factors contributing to disease progression, he explains. Targeting HIF-2α offers a promising therapeutic approach, with efforts focused on optimizing efficacy and minimizing toxicity, Choueiri states.

A phase 1/2 trial (NCT05119335) evaluated NKT2152, a novel HIF-2α inhibitor, as monotherapy in 113 patients with advanced ccRCC. Among 100 evaluable patients, the overall response rate (ORR) was 20%, including 1 complete response (CR) and 19 partial responses (PRs). In the dose-escalation cohort (n = 57 evaluable patients), the ORR was higher, at 26.3%, consisting of 1 CR and 14 PRs. The median progression-free survival (PFS) was 7.392 months (95% CI, 3.745-12.58) in the overall population and 9.2 months in part 1, the dose-escalation portion of the study.

On-target toxicities associated with NKT2152 include hypoxia, anemia, and fatigue, Choueiri notes. Anemia arises due to decreased erythropoietin levels, a known effect of HIF-2α inhibition, he adds. A distinguishing feature of NKT2152 is its extended half-life, measured at a median of 38 days in this trial, which sets this agent apart from other HIF-2α inhibitors, such as belzutifan (Welireg), Choueiri says. These preliminary findings support the further investigation of NKT2152 in advanced ccRCC, he concludes.