NKT2152 Data Reinforce the Importance of HIF2α Inhibition in Advanced Clear Cell RCC

The novel oral HIF2α inhibitor NKT2152 led to an objective response rate (ORR) of 20% in all-comers and 26.3% in the dose-escalation population of patients with previously treated advanced clear cell renal cell carcinoma (RCC), according to findings from a phase 1/2 study (NCT05119335) that were presented at the 2024 ESMO Congress.¹

Among evaluable patients within the all-comer population (n = 100) best overall responses included complete response (CR; n = 1), partial response (PR; n = 19), stable disease (SD; n = 52), and progressive disease (PD; n = 28). Within the dose-escalation phase (n = 57) best overall responses included CR (1.75%; n = 1), PR (24.6%; n = 14), SD (49.1%; n = 28), and PD (24.6%; n = 14).

Further divided, responses were also observed irrespective of International Metastatic RCC Database Consortium (IMDC) risk category (favorable, 33.3%; intermediate, 23.7%; poor, 11.4%), ECOG performance status (0, 30.2%; >0, 12.5%), prior lines of therapy (≤3, 20.9%; >3, 18.2%), and being naive to prior mTOR inhibition (35.6%).

“NKT2152 demonstrated robust antitumor activity in heavily pretreated patients with high-risk advanced clear cell RCC,” Eric Jonasch, MD, lead study author and professor in the Department of Genitourinary Medical Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, said in a presentation of the data. “We can see a trend towards better ORRs in favorable- vs intermediate- and poor-risk [disease], ECOG 0 vs 1, and in the mTOR-naive population.”

HIF2α has been shown to be a driver of clear cell RCC with somatic Von Hippel-Lindau (VHL) deficiency and VHL diseases with germline VHL mutations. With restricted expression in normal tissue, HIF2α represents an ideal target for anticancer treatment development. In December 2023, the FDA approved the first HIF2α-directed therapy belzutifan (Welireg) for patients with advanced RCC following a PD-(L)1 inhibitor and a VEGF TKI.²

NKT2152 is a potent, selective orally available HIF2α inhibitor optimized for enhanced pharmacokinetic exposure and sustained target inhibition, preventing transcription of HIF2α-regulated genes that are needed for angiogenesis, glycolysis, and tumorigenesis.¹

“[NKT2152] is another agent that will interact with HIF2α, prevent HIF2α and HIF1β heterodimerization, and will then prevent the downstream transcription of these various HIF dependent genes,” Jonasch said.

In part 1 dose escalation all 60 patients have been enrolled and in part 2 dose expansion 38 of 40 patients have been enrolled. Thirteen of the expected 17 patients have been enrolled in the clinical pharmacology cohorts and 2 of 10 have been enrolled in the post-belzutifan cohort in part 2.

Per the study design an initial 6 patients received NKT2152 at 200 mg daily, after which 3 patients each received the agent once daily at a dose of 50 mg, 100 mg, or 300 mg. A loading/maintenance regimen was added into the protocol, such that patients received either 200 mg of the agent once daily for 28 days followed by 50 mg once daily (n = 9); 200 mg once daily for 14 days followed by 50 mg once daily (n = 12); 200 mg once daily for 7 days followed by 200 mg weekly (n = 13); or 100 mg once daily for 7 days followed by 100 mg weekly (n = 11). In phase 2 expansion patients will be randomly assigned to 200 mg once daily for 14 days followed by 50 mg once daily or 100 mg once daily for 7 days followed by 100 mg weekly. 

“As it was apparent that there was significant accumulation of this agent due to long half-life loading and maintenance regimens were then investigated,” Jonasch said.

At the June 16, 2024, data cutoff, the median follow-up in part 1 was 20.8 months (range, 10.3-31.2) and was 13.5 months (range, 0.23-31.2) in the overall population.

Of the total 113 patients that have been enrolled to date 41% (n = 46) are ongoing treatment; the remainder have experienced disease or clinical progression (39%; n = 44), an adverse effect (AE; 12%; n = 14); withdrew consent (4%; n = 5), or gave another reason (4%; n = 4).

At baseline, most patients in the overall population had an ECOG performance status of 1 (55.4%; n = 62), IMDC intermediate risk (58.4%; n = 66), and had received either 2 (27.4%; n = 31) or 4 or more (33.6%; n = 38) prior lines of therapy. The median number of prior lines of therapy was 3 (range, 1-9), and most patients had received a prior VEGF TKI (93.8%; n = 106) and immuno-oncology agent (97.3%; n = 110), whereas only 28.3% (n = 32) had received a prior mTOR inhibitor.

Additional results indicated that the median time to response was 3.7 months (range, 1.6-9.1) and the median duration of response was not evaluable (NE; 95% CI, 8.31-NE). The disease control rate was 60% (95% CI, 50%-70%).

“The waterfall plot shows that in all the risk subcategories we see response and the majority of individuals had some degree of tumor shrinkage. The spider plot shows that there is a subset of individuals that had durable and fairly deep response,” Jonasch said.

The median progression-free survival (PFS) was 7.392 months (95% CI, 3.745-12.58) in the overall efficacy-evaluable population and the 12-month PFS rate was 41.8% (95% CI, 30.5%-52.6%). In the dose-escalation population the median PFS was 9.2 months and the 12-month PFS rate was 44%. The median PFS was 13.6 months, 9.4 months, and 3.7 months in the IMDC favorable-, intermediate-, and poor-risk populations, respectively. The median PFS in patients with an ECOG PS of 0 or 1 was 12.7 months and 5.5 months, respectively. Patients who had received 3 or fewer prior lines of therapy had a median PFS of 9.1 months vs 7.4 months in those who had received more than 3. Patients who had not received prior mTOR inhibition experienced a median PFS of 12.7 months.

“Once again we see that there’s a trend that is hypothesis generating of improved PFS with better [risk] status, ECOG performance status, as well as mTOR-naive status,” Jonasch said.

Jonasch stated that the pharmacokinetic and pharmacodynamic profiles support loading and maintenance dosing with NKT2152, evidenced by dose linear and time independent concentrations with an estimated median half-life of 38 days based on a 2-compartment population pharmacokinetic model. Additionally, significant and sustained suppression of the HIF2α client gene EPO was seen at all dose levels with a maximal fractional inhibition of EPO production of 72% and plasma NKT5152 concentration for 50% maximal inhibition of 16.4 ng/mL, which Jonasch stated was significantly exceeded with all doses.

Regarding safety, any-grade AEs experienced by at least 10% of patients occurred in approximately 92.0% of patients and included anemia, fatigue, hypoxia, nausea, dizziness, peripheral edema, and dyspnea. Dose-limiting toxicities included fatigue and hypoxia in 1 of 12 patients who received 200 mg of NKT2152 daily for 14 days followed by 50 mg once daily, and fatigue and hypoxia in 1 of 9 patients who received 200 mg of NKT2152 daily for 28 days followed by 50 mg once daily.

“The safety profile was consistent with this class of agent,” Jonasch said. “Two dose regimens with loading/maintenance dosing have been selected and are under evaluation in the dose expansion of this study,” Jonasch concluded.

Disclosures: Dr Jonasch reported research support from AbbVie, Arrowhead, Aveo, BMS, Vorvus, Merck, NiKang, ProFoundBio, and Telix; honoraria from Aveo, Clinical Care Options, DAVA, EBSCO, Eisai, Exelixis, GSK, IDEO Oncology, i3 Health, Ipsen, Kaplan, Merck, Novartis, NiKang, Petra Drugstore, and Plexus; and leadership positions in NCCN Guidelines (vice chair, Kidney Cancer Panel), member of the NCI RCC Steering Committee, and board member on the International Kidney Cancer Coalition.

References

1. 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. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Presentation 1690O.
2. FDA approves belzutifan for advanced renal cell carcinoma. FDA. December 14, 2023. Accessed September 19, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-advanced-renal-cell-carcinoma