NKT-2152: A Promising HIF-2α Inhibitor in ccRCC

Eric Jonasch, MD, professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the mechanism of action of a novel, potent, selective orally available HIF-2α inhibitor called NKT-2152.

Currently, NKT-2152 is being investigated in an ongoing, multicenter, first-in-human, phase 1/2 trial (NCT05119335) for the potential treatment of patients with previously treated advanced clear cell renal cell carcinoma (ccRCC). Adult patients with advanced ccRCC who have an ECOG performance status of 0-2 and measurable disease per RECIST 1.1 are eligible for enrollment in the study. Patients treated previously with HIF2a inhibitors, require supplemental oxygen, and those with significant cardiac disease are excluded from the study.

Jonasch presented preliminary data from the phase 1/2 study during an oral presentation at the ESMO 2024 Congress.

Transcription:

0:09 | NKT-2152 is a HIF-2α inhibitor, so it will bind to HIF-2α to prevent heterodimerization with HIF-1 beta. And this is important when you lose VHL function, which happens in a lot of clear cell renal cell carcinomas, because then you get unbridled transcription of these HIF-2α client genes, which is oncogenic.

0:32 | So, it is similar to an approved agent called belzutifan [Welireg]. It is different from [tyrosine kinase inhibitors (TKIs)]. TKIs typically are VEGF receptor inhibitors, and so that would be a considerably downstream sort of effect of having HIF-2α upregulation. So, this is kind of getting upstream and closer to the source, if you will.

REFERENCE:

Jonasch E, Hauke R, Falchook G, et al. A Phase 1/2, open label dose-escalation and expansion trial of NKT2152, an orally administered HIF2α inhibitor, to investigate safety, PK, PD and clinical activity in patients with advanced ccRCC. Oncologist. 2023;28(Suppl 1):S12. Published 2023 Aug 23. doi:10.1093/oncolo/oyad216.019