4534 Background: HC-7366 is a novel, selective, potent activator of general control nonderepressible 2 (GCN2) kinase, regulating metabolic stress via the integrated stress response. Our preclinical studies in RCC demonstrated that prolonged GCN2 activation by HC-7366 resulted in antitumor activity accompanied by inhibition of HIFs and cell cycle progression. Furthermore, combination with belzutifan (BEL) results in superior preclinical efficacy, accompanied by inhibition of HIF signaling and cell-cycle progression, supporting clinical evaluation of the combination in RCC. Methods: Patients with advanced ccRCC previously treated with ≥1 anti-PD/PD-L1 and ≥1 VEGF-TKI were enrolled into HC-7366 monotherapy (60 mg QD) or a dose-escalation/expansion cohort of HC-7366 (20, 40, 60 mg QD) with BEL (120 mg QD). Primary objectives were safety, tolerability, and investigator-assessed ORR per RECIST v1.1. Enrollment in escalation and expansion is complete; second expansion is ongoing. Results: As of the data cutoff 10 Dec 2025, 69 patients received study treatment: 16 monotherapy and 53 combination (7 at 20 mg, 22 at 40 mg, 24 at 60 mg). Median prior therapies were 3 (range 1-5) in monotherapy and 2 (range 1-4) in combination. Most TEAEs were Grade (Gr) 1-2. Gr 3 events were mainly hematological (anemia) and gastrointestinal (nausea and diarrhea), with one DLT (Gr 3 nausea, 40 mg combination). In efficacy-evaluable patients, the 40 mg combination demonstrated the best overall response rate (BORR) of 36.8%, including a confirmed ORR (cORR) of 26.3%, disease control rate (DCR) of 89.5%, and primary progressive disease (PD) rate of 10.5%. The 60 mg combination had a BORR of 31.6%, with a cORR of 31.6%, DCR of 84.2%, and primary PD rate of 15.8%. In monotherapy, BORR of 15.4% and DCR of 61.5% were observed. Early efficacy signals at 40–60 mg align with the preclinical projected maximal efficacious dose range. Conclusions: HC-7366, alone or in combination with BEL, was generally well tolerated. Preliminary efficacy analyses indicate favorable disease control, characterized by a high DCR and low primary PD. Clinical trial information: NCT06234605 . Efficacy and safety data by cohort. Monotherapy60 mgN=13 HC-7366 + BELZ20/120 mgN=7 HC-7366 + BELZ 40/120 mg N=19 HC-7366 + BELZ 60/120 mg N=19 Median follow-up (mo) 16.9 13.4 11.2 8.5 BORR /cORR (%) 2 (15.4) /0* 0 /0 7 (36.8) /5 (26.3) 6 (31.6) /6 (31.6) DCR (%) 8 (61.5) 5 (71.4) 17 (89.5) 16 (84.2) Primary PD (%) 5 (38.5) 2 (28.6) 2 (10.5) 3 (15.8) PFS 6 mo (%) 15.4 42.9 57.9 73.7 Any Gr /Gr 3 AEs 15 (93.8) /9 (56.3) 7 (100) /4 (57.1) 22 (100) /16 (72.7) 24 (100) /17 (70.8) Gr 3 Anemia /Hypoxia 0 /2 (12.5) 2 (28.6) /1 (14.3) 5 (22.7) /2 (9.1) 5 (20.8) /2 (8.3) Gr 3 Nausea /Diarrhea 2 (12.5) /3 (18.8) 0 /1 (14.3) 1 (4.5) /0 2 (8.3) /0 Dose Red /Discont. 6 (37.5) /2 (12.5) 1 (14.3) /0 11 (50.0) /2 (9.1) 7 (29.2) /3 (12.5) *PRs not confirmed due to emergence of brain metastases.
Shah et al. (2026) studied this question.