Chidamide Plus Nivolumab Shows Potential Frontline Role in Melanoma

Adding chidamide (HBI-8000; tucidinostat; Epidaza), an oral selective histone deacetylase (HDAC) inhibitor, to nivolumab (Opdivo) has demonstrated efficacy and safety vs nivolumab alone in patients with metastatic melanoma, according to results presented by Nikhil I. Khushalani, MD, of Moffitt Cancer Center, at the European Society for Medical Oncology (ESMO) Congress 2026.

In an interview, Khushalani discussed the primary analysis of the randomized, double-blind, placebo-controlled phase 3 HBI-8000-303 trial (NCT04674683) that he presented. The trial enrolled 404 patients with unresectable or metastatic melanoma who had not previously received PD-1/PD-L1 inhibitors. Patients received oral chidamide or placebo twice weekly plus nivolumab every 4 weeks.

At a median follow-up of 37 months, median progression-free survival (PFS) by blinded independent review was 11.7 months with chidamide plus nivolumab vs 7.4 months with placebo plus nivolumab (HR, 0.73; 96% CI, 0.56-0.95; P = .0141). The confirmed objective response rate was 41.4% vs 32.3%, respectively. Grade 3 or higher treatment-related adverse events occurred in 55% vs 18% of patients.

Khushalani explained that the rationale for the combination comes from preclinical work. In those studies, HDAC inhibitors enhanced cytotoxic T-lymphocyte and natural killer cell activity in the tumor microenvironment, whereas in mouse models, they converted nonresponsive tumors into responsive ones and improved tumor suppression when combined with anti–PD-1 therapy.

When asked how the combination would fit into the treatment landscape if approved, he said the data support its use as a frontline option. He identified patients with an ECOG performance status of 0 and normal lactate dehydrogenase (LDH) levels as the best candidates. He noted that this subgroup, which makes up about two-thirds of patients with metastatic disease, had a median PFS of 20 months. For patients with high-risk disease and very high LDH levels, he said ipilimumab (Yervoy) plus nivolumab remains an excellent frontline choice.

Khushalani added that having more treatment options benefits patients, as was seen after the introduction of nivolumab plus relatlimab (Opdualag) in the first-line setting. He said further clinical trial and real-world data will be needed to determine how best to sequence the available therapies.

REFERENCE

1. Khushalani NI, Pereira RP, Nakakogue TD, et al. Primary analysis of HBI-8000-303: A randomized phase 3 trial of nivolumab plus HBI-8000 or placebo in advanced melanoma. Presented at: European Society for Medical Oncology Congress 2026; October 23-27, 2026; Madrid, Spain. Abstract LBA54.