NKT2152 Ushers in a New Era of HIF-2α Inhibition in Pretreated Advanced ccRCC

The novel HIF-2α inhibitor NKT2152 has demonstrated promising antitumor activity and a tolerable safety profile in patients with advanced clear cell renal cell carcinoma (ccRCC) that may prompt changes to the treatment paradigm in the future, according to Toni Choueiri, MD.

A phase 1/2 trial (NCT05119335) investigated NKT2152 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).1 Among 57 evaluable patients enrolled in the part 1 dose-escalation portion of the study (n = 60), the ORR was 26.3%, including 1 CR and 14 PRs. In the overall and part 1 populations, respectively, the median progression-free survival was 7.4 months and 9.2 months.

“It’s refreshing to see another drug [elicit] a response that is [part of a] novel class of agents,” Choueiri said in an interview with OncLive® during the 2024 ESMO Congress.

In the interview, Choueiri discussed the unique features of NKT2152, the agent’s safety profile in patients with ccRCC, and future treatment and research directions across the spectrum of genitourinary (GU) oncology.

Choueiri is the director of the Lank Center for GU Oncology at Dana-Farber Cancer Institute; co-leader of the Kidney Cancer Program at Dana-Farber/Harvard Cancer Center; and the Jerome and Nancy Kohlberg Chair and a professor of medicine at Harvard Medical School in Boston, Massachusetts.

OncLive: What is the mechanism of action of NKT2152?

Choueiri: NKT2152 is a HIF-2α inhibitor. This is a somewhat novel class of agent, with a target of a transcription factor that was thought to be undruggable. However, this is not the first [HIF-2α

inhibitor for RCC]. As of [2023], belzutifan [(Welireg) is FDA approved for the treatment of patients with advanced RCC who have received prior treatment with a PD-1/PD-L1 inhibitor and a VEGF TKI].2

Now, NKT2152 is another drug that is showing activity [in patients with advanced RCC]. [In the phase 1/2 trial assessing NKT2152 in this population], the ORR was 20%, [and the drug was associated with] the same on-target toxicities [we see with belzutifan], including anemia and hypoxia.1 At the same time, NKT2152 showed a long half-life, so we’re still exploring alternative dosing [schedules].

What is the significance of targeting HIF-2αin RCC?

HIF-2α is a transcription factor at the center of all this machinery for the degradation of VHL at the center of RCC. 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. Finally, regarding anticancer activity, we have drugs [directed against] target that are successful [and that have] a toxicity-benefit ratio in favor of responses and activity over toxicity.

What are some of the adverse effects (AEs) associated with NKT2152?

On-target [toxicities include] hypoxia, anemia, and fatigue. Anemia [occurs] because of erythropoietin level decreases, so this was not a surprise. The distinction [between NKT2152 and] other [HIF-2α inhibitors], mainly belzutifan, is the long half-life [of NKT2152]. In this [phase 1/2] study, preliminary results show the [median] half-life [with the agent] is prolonged, at 38 days.

What other GU oncology research have you been excited to see recently?

Some of the [2024 ESMO Congress] plenary [session data] could be practice changing relevant to my field, GU. The phase 3 PEACE-3 trial [(NCT02194842) led by] Silke Gillessen, MD, [of the Università della Svizzera Italiana in Lugano, Switzerland] showed an overall survival benefit combining radium plus enzalutamide [(Xtandi) vs enzalutamide alone] in metastatic prostate cancer. Another study presented by Thomas Powles, MBBS, MRCP, MD, [of the Barts Cancer Institute in London, United Kingdom] is the phase 3 NIAGARA study [NCT03732677], which integrated the PD-L1 inhibitor durvalumab [Imfinzi] with chemotherapy in the neoadjuvant setting [in patients with muscle-invasive bladder cancer]. That will be practice changing.

There were a lot of studies about drug development. There is an antibody-drug conjugate, [BL-B01D1], that targets HER3 EGFR that was presented by investigators from China. It’s in preliminary studies, but the drug seemed to have an interesting AE profile with less skin toxicity and more hematologic toxicity, and responses were seen. The authors are working on a pivotal study, but [the presented] results [from a phase 1b/2 trial (NCT05785039) in patients with locally advanced or metastatic urothelial cancer] were intriguing.

References

1. Jonasch E, McGregor BA, Msaouel P, et al. NKT2152, a novel oral HIF-2α inhibitor, in participants (pts) with previously treated advanced clear cell renal carcinoma (accRCC): preliminary results of a phase I/II study. Ann Oncol. 2024;35(2):S1012-S1030. doi:10.1016/j.annonc.2024.08.1783
2. FDA approves belzutifan for advanced renal cell carcinoma. FDA. December 14, 2023. Accessed January 27, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-advanced-renal-cell-carcinoma?utm_medium=email&utm_source=govdelivery