NKT2152, a novel oral HIF2α inhibitor, has shown promising results in a phase 1/2 trial for patients with previously treated advanced clear cell renal cell carcinoma (RCC). The study, presented at the 2024 ESMO Congress, demonstrated an objective response rate (ORR) of 20% in the overall population and 26.3% in the dose-escalation population, offering a potential new treatment option for this challenging patient group.
The trial (NCT05119335) included heavily pretreated patients with high-risk advanced clear cell RCC. Eric Jonasch, MD, lead study author and professor at The University of Texas MD Anderson Cancer Center, highlighted the robust antitumor activity of NKT2152, particularly noting a trend towards better ORRs in favorable- vs intermediate- and poor-risk disease, ECOG 0 vs 1, and in the mTOR-naive population.
Objective Response and Disease Control
In the all-comer population (n = 100), the best overall responses included 1 complete response (CR), 19 partial responses (PR), 52 stable disease (SD), and 28 progressive disease (PD). The disease control rate was 60% (95% CI, 50%-70%). In the dose-escalation phase (n = 57), responses included 1 CR (1.75%), 14 PR (24.6%), 28 SD (49.1%), and 14 PD (24.6%). Responses were observed irrespective of International Metastatic RCC Database Consortium (IMDC) risk category, ECOG performance status, prior lines of therapy, and prior mTOR inhibition.
Progression-Free Survival
The median progression-free survival (PFS) was 7.392 months (95% CI, 3.745-12.58) in the overall efficacy-evaluable population, with a 12-month PFS rate of 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%. Notably, the median PFS varied across IMDC risk groups: 13.6 months for favorable-risk, 9.4 months for intermediate-risk, and 3.7 months for poor-risk populations. Patients with an ECOG PS of 0 had a median PFS of 12.7 months, compared to 5.5 months for those with an ECOG PS of 1. Patients who had not received prior mTOR inhibition experienced a median PFS of 12.7 months.
Dosing and Pharmacokinetics
The study investigated various dosing regimens, including loading and maintenance doses, to optimize pharmacokinetic exposure and sustained target inhibition. Initial dosing involved 200 mg daily, followed by explorations of 50 mg, 100 mg, and 300 mg once daily. Loading/maintenance regimens included 200 mg once daily for varying durations (7, 14, or 28 days) followed by lower maintenance doses. Pharmacokinetic and pharmacodynamic profiles supported loading and maintenance dosing, with an estimated median half-life of 38 days. Significant suppression of the HIF2α client gene EPO was observed at all dose levels, with a maximal fractional inhibition of EPO production of 72%.
Safety Profile
Any-grade adverse events (AEs) experienced by at least 10% of patients included anemia, fatigue, hypoxia, nausea, dizziness, peripheral edema, and dyspnea. Dose-limiting toxicities included fatigue and hypoxia. According to Dr. Jonasch, the safety profile was consistent with this class of agent.
Mechanism of Action and Rationale
HIF2α is a key driver of clear cell RCC, particularly in cases with somatic Von Hippel-Lindau (VHL) deficiency. NKT2152 is designed to inhibit HIF2α, preventing the transcription of HIF2α-regulated genes involved in angiogenesis, glycolysis, and tumorigenesis. The FDA approved belzutifan (Welireg), the first HIF2α-directed therapy, in December 2023 for advanced RCC following a PD-(L)1 inhibitor and a VEGF TKI, highlighting the clinical relevance of this target.
Ongoing Evaluation
Two dose regimens with loading/maintenance dosing have been selected and are under evaluation in the dose expansion phase of the study, with the aim of refining the optimal treatment strategy for patients with advanced clear cell RCC.
