Progression-free survival (PFS) in unresectable melanoma improved significantly with the addition of an investigational histone deacetylase (HDAC) inhibitor to immunotherapy, a randomized trial showed.
Median PFS increased from 7.36 months with nivolumab (Opdivo) and placebo to 11.66 months with nivolumab and HBI-8000. At 24 months, 41.3% of the combination arm remained alive and progression free compared with 28.7% of the control group. Patients with normal lactate dehydrogenase (LDH) levels at baseline, a majority of the study population, derived even more benefit from nivolumab-HBI-8000, with a median PFS of 20.04 months.
Grade 3/4 treatment-related adverse events (TRAEs) occurred three times as often with nivolumab and HBI-8000 but were manageable in most cases, reported Nikhil Khushalani, MD, of Moffitt Cancer Center in Tampa, Florida, at the European Society for Medical Oncology congress in Madrid.
“While GI [gastrointestinal] toxicities are certainly more common with this combination, these adverse events tend to be manageable with low rates of grade 3 and 4 nonhematologic adverse events,” said Khushalani. “‘The rate of endocrine toxicity appears similar to nivolumab alone. Combination HBI-8000 plus nivolumab can certainly be considered a standard-of-care option for advanced, unresectable melanoma, offering an advantage of oral dosing and potentially drug-specific dose attenuation for unique toxicities.”
The trial is clearly positive for the HDAC inhibitor-nivolumab arm, said ESMO invited discussant Olivier Michielin, MD, PhD, of Geneva University Hospital in Switzerland. The 2-year results compare favorably with 2-year results from two previous trials that established benchmarks for unresectable melanoma, CheckMate 067 (nivolumab with or without ipilimumab [Yervoy]) and RELATIVITY-047 (nivolumab alone or with relatlimab [Opdualag]). Two-year overall survival (OS) data for the earlier studies showed a nonsignificant trend favoring combination therapy, whereas 2-year OS data for the current study remain immature.
“HDAC inhibitors clearly have an impact on cancer cells, promoting antigen presentation, but also making the cells more susceptible to immune killing,” said Michielin. “There is also a wealth of impact on the tumor microenvironment, touching on all the cells, either directly or indirectly, and promoting generally a more immunostimulatory microenvironment, hence, a good rationale to combine these compounds with PD-1 blockade.”
“My personal take out of this abstract is that data could support HBI-8000 plus nivolumab as a first-line option, but the evolving dataset should be looked at carefully for OS but also toxicity in the coming months to really base our decision on the full package,” he added.
The phase III HBI-8000-303 trial followed a small phase Ib/II trial of the combination therapy in patients with anti-PD(L)1-naive advanced melanoma. The treatment led to an objective response rate of 65.8% with no unexpected toxicity.
Conducted at 123 sites in 15 countries, the phase III trial enrolled 404 patients with unresectable stage III/IV melanoma and no prior exposure to a PD(L)1 inhibitor or any other immune checkpoint inhibitor. They were randomized to nivolumab with HBI-8000 or placebo and followed until disease progression or unacceptable toxicity. PFS was the primary endpoint.
The patients had a median age of 67, and men accounted for 60-65% of the study population. Two-thirds of the patients had normal LDH levels at baseline, and about half had PD-L1-positive tumors. About 60% of the patients had clinical M0/M1a/M1b disease stage.
After a median follow-up of 37 months, the primary analysis showed a 4.3-month difference in PFS in favor of the HBI-8000 arm, representing a 27% reduction in the PFS hazard (95% CI 0.56-0.95, P=0.0141). The subgroup analysis favored HBI-8000 for almost all patient categories.
The PFS benefit with HBI-8000 in patients with normal LDH increased to 35% (CI 0.47-0.90, P=0.0082). PFS at 24 months showed a clear advantage for the HBI-8000 arm (41.3% vs 28.7% in all patients and 47.2% vs 32.6% in patients with normal LDH). Objective response rates were 41.4% versus 32.3%, a difference driven by a higher number of complete responses (14.3% vs 7.0%).
Grade 3/4 TRAEs occurred in 54.8% of the HBI-8000 group and 17.9% of the placebo group. TRAE-related discontinuation rates were 14.1% with HBI-8000 and 5.0% in the control group. Notable differences in grade 3/4 hematologic TRAEs included thrombocytopenia (7.5% vs 0%) and neutropenia (16.6% vs 0.5%). Rates of pneumonitis, hyperthyroidism, and adrenal insufficiency were similar, including all-grade and grade 3/4.
