KEY TAKEAWAYS
- The phase 1 trial aimed to investigate the synergistic antitumor effects of HC-7366 and belzutifan in pts with advanced RCC.
- Researchers concluded that the combination of HC-7366 and belzutifan demonstrates promising antitumor activity in relapsed RCC.
HC-7366 is a novel, orally administered, highly selective, and potent activator of general control nonderepressible 2 (GCN2) kinase, pivotal in metabolic stress regulation via the integrated stress response (ISR). GCN2 activation promotes cell survival but can induce apoptosis with prolonged activation, halting cell growth in nutrient-deprived conditions.
Moreover, HC-7366 diminishes HIF expression, inhibits glycolysis, oxidative phosphorylation, and the TCA cycle, and suppresses HIF in immunosuppressive myeloid cells like macrophages. These effects suggest therapeutic potential in clear cell renal cell carcinoma (ccRCC), particularly in combination with HIF2a antagonists and immune checkpoint inhibitors.
HC-7366 (0.5-1 mg/kg) combined with belzutifan (1 mg/kg) demonstrated synergistic efficacy in HIF-2 dependent A-498 and 786-O RCC xenografts, achieving substantial tumor growth inhibition (90%) and tripling complete response rates. HC-7366 also exhibited significant monotherapy antitumor activity in patient-derived xenograft (PDX) models resistant to belzutifan. Mechanistic studies identified pathway engagements and potential efficacy biomarkers (Stokes, et al., 2024).
Rana R. McKay and the team aimed to assess the synergistic antitumor effects of HC-7366 and belzutifan in advanced RCC, focusing on safety and dose evaluation to inform clinical translation.
About 80 patients with advanced or metastatic RCC, regardless of VHL gene mutation status, participated in a multicenter, open-label phase 1b study. The study aimed to determine the Maximum Tolerated Dose (MTD) and Recommended phase 2 Dose (RP2D) of HC-7366 in combination with a fixed dose of belzutifan (120 mg orally once daily). Monotherapy with HC-7366 (60 mg orally once daily) was evaluated alongside the combination therapy. Patients in the monotherapy arm had experienced relapse after 1 to 4 prior lines of standard care, potentially including belzutifan or another HIF-2α inhibitor.
The combination arm enrolled patients who had received 1 to 3 prior lines of standard care and were belzutifan or HIF-2α inhibitor-naïve. HC-7366 dose escalation in the combination arm involved fixed-dose belzutifan (120 mg orally once daily) paired with HC-7366 at doses of 20, 40, or 60 mg orally once daily.
Enrollment began with the HC-7366 monotherapy arm, followed by initiation of the combination therapy HC-7366 dose escalation arm, with ongoing enrollment in the monotherapy arm. Expansion cohorts evaluated the combination of fixed-dose belzutifan with 2 selected doses of HC-7366 from the escalation phase. Assessments included safety, pharmacokinetics (PK), and anti-tumor activity across US study sites.
The study concluded that the combination of HC-7366 and belzutifan, supported by preclinical evidence, effectively assessed antitumor activity in patients with relapsed RCC. Establishing safety and determining optimal dosing were fundamental aspects of the study design.
The trial was sponsored by HiberCell, Inc.
Source: https://kcrs.kidneycan.org/wp-content/uploads/2024/06/KCRS24-Abstract-Book-6.27.24.pdf
Clinical Trial: https://clinicaltrials.gov/study/NCT06234605
McKay R R, Garmezy B, Barata P, et al. (2024). “A Phase 1b, Open-Label, Safety, Tolerability, and Efficacy Study of HC7366 in Combination with Belzutifan (WELIREGTM) in Patients with Advanced or Metastatic Renal Cell Carcinoma, NCT06234605.” Presented at KCRS 2024 (Abstract 5).
