HiberCell's HC-7366 Shows Promise in Late-Line Renal Cell Carcinoma with 37% Response Rate in Phase 1b Trial
核心洞察
HiberCell (搜索)'s Phase 1b trial of HC-7366 combined with belzutifan demonstrated a 37% best overall response rate in patients with advanced clear cell renal cell carcinoma (搜索) who had failed prior checkpoint inhibitor and VEGF-TKI therapy.
The combination therapy showed a manageable safety profile with mostly Grade 1-2 adverse events and achieved an 84-89% disease control rate across dose levels in 69 enrolled patients.
Translational analyses confirmed HC-7366 pathway engagement and revealed favorable changes countering ccRCC (搜索) biology, including sustained HIF-2 target inhibition and modulation of angiogenic pathways.
HiberCell (搜索)'s first-in-class GCN2 (搜索) activator HC-7366 demonstrated encouraging preliminary efficacy when combined with Merck (搜索)'s HIF-2α (搜索) inhibitor belzutifan in patients with advanced clear cell renal cell carcinoma (搜索) (ccRCC (搜索)), according to Phase 1b trial results presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.
The ongoing Phase 1b study (NCT06234605) enrolled 69 patients with advanced ccRCC (搜索) whose disease had progressed after prior PD-1 (搜索)/PD-L1 (搜索) checkpoint inhibitor and VEGF-tyrosine kinase inhibitor (VEGF-TKI) therapy. As of the April 23, 2026 data cutoff, 53 patients received HC-7366 in combination with belzutifan across dose escalation and expansion cohorts.
Clinical Efficacy Results
In efficacy-evaluable patients, the 40 mg HC-7366 combination demonstrated a best overall response rate (BORR) of 37%, including a confirmed overall response rate (cORR) of 26%, with a median follow-up of 13.3 months. The disease control rate (DCR) reached 89%, while the primary progressive disease rate was only 11%.
The 60 mg combination cohort showed similar efficacy with a BORR and cORR of 37%, DCR of 84%, and primary progressive disease rate of 16% at a median follow-up of 10.9 months. In contrast, HC-7366 monotherapy achieved a BORR of 15% and DCR of 62%.
"In a patient population with limited treatment options following checkpoint inhibitor and VEGF-TKI therapy, the combination of HC-7366 and belzutifan demonstrated a manageable safety profile and early signals of disease control that warrant further investigation," said Robert Motzer, M.D., lead principal investigator for the study.
Safety Profile
The combination therapy was generally well tolerated, with most treatment-emergent adverse events (TEAEs) being Grade 1-2. Grade 3 events were primarily hematological (anemia) and gastrointestinal (nausea and diarrhea), with only one dose-limiting toxicity (Grade 3 nausea) observed in the 40 mg combination group.
The median number of prior therapies was 2 (range 1-4) in the combination cohorts and 3 (range 1-5) in the monotherapy group, highlighting the heavily pretreated nature of this patient population.
Mechanism of Action and Biomarker Evidence
HC-7366 is a first-in-class, selective, potent small molecule activator of the general control nonderepressible 2 (GCN2 (搜索)) kinase, part of the integrated stress response (ISR) family. Translational analyses from paired tumor biopsies and systemic biomarker assessments demonstrated clear evidence of HC-7366 pathway engagement and a differential pharmacodynamic profile distinguishing the combination from monotherapy.
The analyses revealed several favorable changes countering ccRCC (搜索) biology, including sustained inhibition of the HIF-2 target EPO, reduction of HIF-1α, cell cycle inhibition, and modulation of pro- and anti-tumor adipokines. These findings also showed modulation of angiogenic and immune-related pathways, supporting the scientific rationale for evaluating HC-7366/belzutifan in combination with immune checkpoint inhibitors and/or VEGF-TKIs.
Preclinical Combination Data
Supporting the clinical findings, HiberCell (搜索) also presented preclinical data at the 2026 American Association for Cancer Research (AACR) Annual Meeting demonstrating that HC-7366 enhanced the activity of multiple VEGFR (搜索)-TKIs, including lenvatinib, cabozantinib, and axitinib in preclinical metastatic ccRCC (搜索) models. The HC-7366 and VEGFR-TKI doublets outperformed the combination of HIF-2α (搜索) inhibitor and VEGFR-TKI in several preclinical patient-derived xenograft models.
"These findings build on the data presented at the 2024 AACR Annual Meeting demonstrating the combination potential of HC-7366 with HIF-2α (搜索) inhibitors and further support our ongoing clinical evaluation of HC-7366 in combination with all three major standard-of-care therapeutic classes in ccRCC (搜索): HIF-2α inhibitors, VEGFR (搜索)-TKIs, and immune checkpoint inhibitors," said Nandita Bose, Ph.D., Chief Development Officer of HiberCell (搜索).
Future Development
The second dose expansion cohort (Expansion 2) is fully enrolled with approximately 20 patients, and follow-up is ongoing. Updated results from both Expansion 1 and Expansion 2 are expected in the second half of 2026, with full results to be reported at a future date.
HiberCell (搜索) has also initiated a Phase 1b arm evaluating HC-7366 in combination with cabozantinib in metastatic ccRCC (搜索) as part of its ongoing clinical study, based on the supportive preclinical data showing enhanced antitumor activity with VEGFR (搜索)-TKI combinations.