Background HBI–8000, an oral selective HDAC inhibitor has demonstrated extensive effects on immune cell function in the tumor microenvironment. HBI-8000-302 is a Phase 1b/2 trial evaluating the combination of HBI–8000 with nivolumab (an anti-PD1 immune checkpoint inhibitor) in advanced melanoma, kidney cancer and non-small cell lung cancer. The recommended Phase 2 dose of HBI-8000 was determined to be 30mg orally twice weekly (BIW) combined with intravenous nivolumab administered at the manufacturer’s approved dosing schedule.

Methods Patients with metastatic melanoma not previously treated with anti-PD(L)-1 inhibitor, with measurable disease, ECOG performance status 0–1, and adequate hematologic and biochemical parameters were enrolled. Previously treated stable brain metastases not requiring steroids were permitted. Disease status was assessed by standard imaging using RECIST v1.1 every 8 weeks. Treatment was continued until disease progression, unacceptable toxicity or completion of 24 months of therapy. Final analysis of data as of March 9, 2023 is presented here.

Results Thirty-nine (39) eligible patients were enrolled and received HBI-8000 (37 at 30 mg BIW in Phases 1b and 2, and 2 at 40mg BIW in Phase 1b) in combination with nivolumab. Median age was 63 years (range 28–83); 59% were male; 34/39 (87%) had normal LDH; 16/39 (41%) had M1c disease, none with CNS metastases. The most common treatment–related > grade 3 adverse events (AEs) included colitis (n=4), fatigue, decreased appetite, pancreatitis, and diarrhea (n=3 each), abdominal pain and weight loss (n=2, each). Most common treatment related laboratory grade ≥3 AEs included hypophosphatemia (n=9), neutropenia (n=8; no febrile neutropenia), lymphopenia (n=6), anemia (n=3), increased ALT and thrombocytopenia (n=2 each). Seventeen patients discontinued treatment due to AEs. Among 38 patients evaluable for efficacy, the overall response rate was 65.8% including 6 (15.8%) completes responses (CR) and 19 (50%) partial responses (PR). The clinical benefit rate (CR, PR or stable disease lasting at least 12 weeks) was 87%. The median follow-up was 37 months; median progression-free survival was 36.9 months (95% CI: 6.7, NE). Median duration of response was not reached at the time of this analysis.

Conclusions The combination of HBI-8000 and nivolumab demonstrated excellent efficacy and good tolerability in the treatment of anti-PD(L)-1-naïve advanced melanoma. Based on these encouraging results, a global Phase 3 trial evaluating HBI-8000 combined with nivolumab versus nivolumab alone as first-line treatment of unresectable or metastatic melanoma is currently ongoing.

Trial Registration NCT02718066.

Ethics Approval The study was approved by participating study sites’ Institutional Review Boards and the Sponsor has conducted the trial in full compliance with all GCP and FDA regulations.