Tucidinostat Plus Nivo Improves PFS vs Nivo Alone in Advanced Melanoma

Tucidinostat (HBI-8000) in combination with nivolumab (Opdivo) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with nivolumab plus placebo in patients with immunotherapy-naive advanced melanoma, according to topline results announced in a news release from Huyabio International.¹

In the global phase 3 HBI-8000-303 trial (NCT04674683), patients who received tucidinostat plus nivolumab achieved a median PFS of 11.7 months, compared with 7.4 months among those who received nivolumab plus placebo, representing a 58% improvement in PFS. According to the company, further statistical analyses are underway to more fully characterize the efficacy advantage observed with tucidinostat.

Trial Design

The randomized, double-blind, placebo-controlled trial (NCT04674683) enrolled 404 patients with unresectable or metastatic melanoma across 15 countries. Eligible patients had histopathologically confirmed, nonuveal stage III or IV melanoma and had not previously received anti–PD-1, anti–PD-L1, or other systemic therapy for unresectable or metastatic disease.² Patients were randomly assigned on a 1:1 basis, stratified by PD-L1 expression status and lactate dehydrogenase level, to receive either oral tucidinostat at 30 mg twice weekly plus intravenous nivolumab at 480 mg every 4 weeks or placebo plus nivolumab, dosed according to a 28-day cycle.³

A separate, nonrandomized, open-label cohort was also enrolled for approximately 30 adults with new, progressive brain metastases and for adolescents with or without progressive brain metastases, who received the combination regimen.

The primary end point is PFS; secondary end points include overall response rate, overall survival, and safety.

Therapeutic Background

Tucidinostat is an oral histone deacetylase inhibitor that modulates gene expression through epigenetic mechanisms without altering the underlying DNA sequence. The agent is already approved for the treatment of lymphoma in China and Japan with an established safety profile.¹

The phase 3 program builds on earlier findings from the phase 1b/2 study of tucidinostat plus nivolumab (NCT02718066), whose results were presented at the 2024 Society for Immunotherapy of Cancer Annual Meeting.⁴ In that trial, 39 patients with anti–PD-1/PD-L1–naive advanced melanoma received tucidinostat at 30 mg or 40 mg twice weekly plus nivolumab. Among 38 patients evaluable for efficacy, the overall response rate was 65.8%, including complete responses in 15.8% of patients and partial responses in 50%, with a clinical benefit rate of 87%. At a median follow-up of 37 months, median PFS was 36.9 months, and median duration of response had not been reached.

The most common treatment-related grade 3 or higher adverse events in the phase 2 study included colitis, fatigue, decreased appetite, pancreatitis, and diarrhea; common laboratory abnormalities included hypophosphatemia, neutropenia, and lymphopenia. No febrile neutropenia was reported, and 17 patients discontinued treatment because of adverse events.

Next Steps

According to Huyabio, full data from the phase 3 trial will be presented at future medical meetings.¹ If confirmed with additional follow-up and regulatory review, the combination could offer clinicians an oral, chemotherapy-free addition to frontline immunotherapy for patients with advanced, treatment-naive melanoma.

“These results represent an exciting milestone for patients and the future of melanoma treatment,” Mireille Gillings, PhD, chief executive officer and executive chair of Huyabio, said in the release. Gillings added that the company believes tucidinostat will become an important addition to the melanoma treatment armamentarium as physicians look to build on the improvements already made with immunotherapy.

REFERENCES

1. HUYABIO International Delivers Significant Landmark Phase 3 Results in Advanced Melanoma. News release. Huyabio. July 14, 2026. Accessed July 14, 2026. https://tinyurl.com/2xc3demn

2. Study Comparing Investigational Drug HBI-8000 + Nivolumab vs. Placebo + Nivolumab in Patients With Advanced Melanoma. ClinicalTrials.gov. Updated September 24, 2025. Accessed July 14, 2026. clinicaltrials.gov/study/NCT04674683

3. Khushalani NI, Shue H, Gedye C, et al. A multicenter, randomized, double-blind phase III study of HBI-8000 combined with nivolumab versus placebo with nivolumab in patients with unresectable or metastatic melanoma not previously treated with PD-1 or PD-L1 inhibitors. Ann Oncol. 2022;33(suppl 9):S1444. doi:10.1016/j.annonc.2022.10.052 External Link

4. Khushalani NI, Brohl A, Markowitz J, et al. HBI-8000, a class I histone deacetylase (HDAC) inhibitor, in combination with nivolumab for treatment of anti-PD(L)1-naive advanced melanoma: final analysis of Study HBI-8000-302. Presented at: 2024 SITC Annual Meeting; November 6-10, 2024; Houston, TX. Abstract 620.