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HDAC inhibitor plus nivolumab cuts melanoma progression risk by 27% in Phase 3 trial

HDAC inhibitor plus nivolumab cuts melanoma progression risk by 27% in Phase 3 trial

New Capabilities

Oral HBI-8000 with nivolumab extends progression-free survival to 11.7 months in advanced melanoma, at a cost in serious side effects

October 26th, 2026: Full manuscript being submitted for peer review

Overview

Updated Oct 30

Adding an oral histone deacetylase (HDAC) inhibitor to nivolumab cut the risk of melanoma progression or death by 27% in a 404-patient Phase 3 trial. Median progression-free survival was 11.7 months with the combination and 7.4 months with nivolumab alone, according to results presented at the European Society for Medical Oncology congress in Madrid.

The trade-off is side effects: grade 3 or higher treatment-related events hit 55% of combination patients versus 18% on nivolumab alone, and 14% stopped treatment (5% on nivolumab alone). Investigators saw no rise in adrenal insufficiency or hypophysitis, immune side effects that are often permanent with dual checkpoint therapy. The companies said on October 26 that the full manuscript is being submitted for peer review.

Why it matters

An oral add-on that avoids dual checkpoint toxicity could widen frontline options for melanoma, if regulators accept a modest survival gain.

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Key Indicators

27%
Reduction in risk of disease progression or death
Hazard ratio 0.73 for HBI-8000 plus nivolumab vs nivolumab alone (p=0.014)
11.7 months
Median progression-free survival with combination
vs 7.4 months for nivolumab plus placebo
404
Patients enrolled in Phase 3 trial
Across 15 countries in the HBI-8000-303 study
41.4%
Objective response rate with combination
vs 32.3% for nivolumab alone
55%
Grade 3 or higher treatment-related side effects
vs 18% with nivolumab alone; 14% of combination patients discontinued for any-grade treatment-related events (5% on nivolumab alone)

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People Involved

NK
Nikhil Khushalani
Lead investigator; Vice-Chair, Department of Cutaneous Oncology, H Lee Moffitt Cancer Center
Presented the Phase 3 results at ESMO Congress 2026
PA
Paolo Ascierto
Professor, University of Naples Federico II; President, Melanoma Foundation
Key author of the Phase 3 study

Organizations Involved

HUYABIO International
HUYABIO International
Biopharmaceutical company
Presented Phase 3 data at ESMO on October 23; plans to share the data with the FDA, with no submission filed yet

San Diego-based biotech developing HBI-8000, an oral HDAC inhibitor already approved for lymphoma in China and Japan.
Bristol Myers Squibb
Bristol Myers Squibb
Pharmaceutical company
Manufacturer of nivolumab (Opdivo), the anti-PD-1 drug tested with and without HBI-8000 in the trial

Makes nivolumab, the anti-PD-1 checkpoint inhibitor used in the combination.

Timeline

August 2021 October 2026

5 events Latest: October 26th, 2026 · 2 weeks ago
Tap a bar to jump to that date

  1. Full manuscript being submitted for peer review

    Latest Publication

    HUYABIO and Chipscreen said the full HBI-8000-303 results are being submitted to a journal for peer review. Overall survival data remain immature.

  2. Full results presented at ESMO Congress 2026

    Conference Presentation

    Lead investigator Nikhil Khushalani presented the HBI-8000-303 data in a proffered paper session in Madrid: a 27% lower risk of progression or death and median PFS of 11.7 vs 7.4 months. Grade 3-4 treatment-related side effects were 54.8% with the combination versus 17.9% with nivolumab alone.

  3. Topline results released

    Clinical Trial

    HUYABIO announces the trial met its primary endpoint, showing improved progression-free survival for the combination.

  4. Japan grants orphan drug designation for tucidinostat in melanoma

    Regulatory

    Meiji Seika Pharma, which supported the Japanese portion of the HBI-8000-303 trial, said it received orphan drug designation for tucidinostat (HBI-8000) in malignant melanoma on November 27, 2025.

  5. Phase 3 trial HBI-8000-303 begins

    Clinical Trial

    Enrollment starts for 404 patients across 15 countries testing HBI-8000 plus nivolumab vs placebo plus nivolumab.

Scenarios

1

FDA approves HBI-8000 plus nivolumab for advanced melanoma

Possible Resolves by Q2 2028

Discussed by: HUYABIO says it will share the data with the FDA; no filing has been announced yet

HUYABIO plans to present the Phase 3 data to the US Food and Drug Administration. If the agency accepts a filing and the data hold up under review, the combination could become a new frontline option for advanced melanoma. Regulatory review typically takes months to a year or more after submission.

2

HUYABIO signs a global commercialization partnership

Likely Resolves by End of 2027

Discussed by: Company statement that it intends to engage with potential commercial partners

HUYABIO says it will seek commercial partners to bring the treatment to patients globally. A partnership would give the company resources to complete remaining trials and commercialize the drug outside China and Japan, where HBI-8000 is already approved for lymphoma.

3

Overall survival data confirm or weaken the benefit

Uncertain Resolves by End of 2028

Discussed by: Trial investigators; OS data remain immature with follow-up ongoing

The trial's overall survival data are not yet mature. If the final analysis shows a statistically significant survival benefit, it would strengthen the case for approval. If the benefit fades, regulators may ask for more data before clearing the combination.

4

LDH levels become the marker for choosing this combination

Uncertain Resolves by End of 2027

Discussed by: ESMO 2026 coverage by MedOncMD and reporting by Il Sole 24 Ore

Subgroup analyses presented at ESMO suggested patients with normal or low LDH did notably better on the combination, while PD-L1 and BRAF status did not predict benefit. If a follow-up analysis confirms that, a future label or trial could steer the combination toward patients with favorable LDH.

Historical Context

3 moments from history that rhyme with this story — and how they unfolded.

September 2015

Ipilimumab plus nivolumab approval (2015)

The FDA approved the combination of two checkpoint inhibitors, ipilimumab and nivolumab, for advanced melanoma. It was the first dual checkpoint regimen and became a standard of care, but it carries high rates of immune-related side effects.

Then

The combo improved survival, but roughly half of patients experienced serious immune-related adverse events.

Now

Dual checkpoint inhibition remains a standard for melanoma, but its toxicity has driven the search for alternatives.

Why this matters now

The HBI-8000 plus nivolumab combination aims to offer a frontline option that avoids the overlapping toxicities of dual checkpoint inhibition.

October 2006

Vorinostat approval (2006)

The FDA approved vorinostat, the first histone deacetylase (HDAC) inhibitor, for cutaneous T-cell lymphoma. Romidepsin followed in 2009.

Then

HDAC inhibitors became a treatment option for blood cancers.

Now

For two decades, HDAC inhibitors showed limited benefit in solid tumors. This trial is the first to show one improving anti-PD-1 therapy in melanoma.

Why this matters now

HBI-8000 is a newer, selective Class I HDAC inhibitor. The melanoma result is the first time this drug class has improved checkpoint inhibitor outcomes in a solid tumor.

September-December 2014

PD-1 inhibitor approvals (2014)

The FDA approved pembrolizumab and nivolumab for advanced melanoma, transforming treatment. These anti-PD-1 drugs became the backbone of melanoma immunotherapy.

Then

Response rates and survival improved dramatically compared with older chemotherapy.

Now

Anti-PD-1 monotherapy became standard, but many patients still don't respond, driving research into combinations.

Why this matters now

The HBI-8000 trial builds on nivolumab by adding an epigenetic modifier designed to turn non-responsive 'cold' tumors into responsive 'hot' ones.

Sources

(18)
+12
PR Newswire BioSpace HUYABIO International ClinicalTrials.gov Targeted Oncology Fierce Pharma University of Naples Federico II BioSpectrum Asia OncoDaily MedOncMD Il Sole 24 ORE 日経メディカル Meiji Seika Pharma investor release Business Wire (Chipscreen) Cancer Therapy Advisor Moffitt Cancer Center HUYABIO International BioSpace