NKT2152 Generates Responses in Heavily Pretreated Advanced ccRCC

Eric Jonasch, MD

Preliminary efficacy findings from a phase 1/2 trial (NCT05119335) evaluating NKT2152 in patients with pretreated advanced clear cell renal cell carcinoma (ccRCC) added to the building body of evidence of the role of HIF2α inhibition in the treatment of this patient population, according to Eric Jonasch, MD.

Findings from the study presented at the 2024 ESMO Congress showed that patients with pretreated advanced ccRCC (n = 100) achieved an overall response rate (ORR) of 20%. This group of patients received a median of 3 prior line of therapy (range, 1-9). Patients treated during the dose-escalation portion of the study (n = 57) had an ORR of 26.3%; the median number of prior lines of therapy for this group was 3 (range, 1-8).

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 the dose-escalation population. The respective 12-month PFS rates were 42% and 44%.

“It’s clear [NKT2152] is active, and the question now is: what would be an appropriate registrational strategy to move this agent forward as a potential treatment for patients with RCC?” Jonasch said in an interview with OncLive^®.

In the interview, Jonasch delved into the background of NKT2152, the role of HIF2α inhibition in the treatment of patients with ccRCC, key data from the study, and next steps for investigating this agent.

Jonasch is a physician and professor in the Department of Genitourinary Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

OncLive: What is the mechanism of action for NKT2152?

Jonasch: NKT2152 is a HIF2α inhibitor. It will bind to HIF2α [and] prevent heterodimerization with HIF1β. This is important when you lose VHL function—which happens in a lot of [patients with] ccRCC—because then you get an unbridled transcription of these HIF2α client genes, which are oncogenic.

What was the rationale for investigating NKT2152 in patients with previously treated advanced ccRCC?

This is a population where patients are likely to have VHL mutation–driven disease in their kidney tumors. Because [NKT2152] is an early-phase drug, we're looking at it in a subsequent-line setting to see whether [it has activity] in patients with refractory disease.

What were the key safety findings from this study presented at the 2024 ESMO Congress?

One of the things that we expect with HIF2α inhibition is a drop in hemoglobin because [this treatment] will block erythropoietin transcription. We did see that there was anemia [during the study]; this was an on-target, expected effect, and we did see [any-grade] anemia in approximately 71% of patients.

What were the preliminary efficacy findings presented?

We saw that in the entire group [n = 100] had an ORR of 20%. In the dose-escalation subgroup [n = 57], where we had longer follow-up, we saw an ORR of 26.3%. We saw a median PFS in the whole group of 7.392 months and 9.2 months in the dose-escalation group.

What are the potential clinical implications of this research?

[This study] shows that blocking HIF2α is a meaningful way of interacting with disease biology in ccRCC. Tt may be good to have more than 1 agent from the same class [as a treatment option for these patients]. We need to learn much more about which patients are most likely to respond, why resistance occurs, and what would be the best partners in terms of combination strategies for this agent.

Reference

Jonasch E, McGregor BA, Msaouel P, et al. NKT2152, a novel oral HIF-2a inhibitor, in participants with previously treated advanced clear cell renal cell carcinoma (accRCC): preliminary results of a phase 1/2 study. Ann Oncol. 2024;35(suppl 2):s1011-s1012. doi:10.1016/j.annonc.2024.08.1783