First-line treatment with HDACis plus tislelizumab combined with chemotherapy in advanced NSCLC a single-arm phase II study

Wang L, Gao M, Wang T, et al. Oncologist. 2025;30(7):oyaf155. PMID: 40631772.

Introduction

This Phase II study evaluated chidamide (HDACi) plus tislelizumab with chemotherapy as first-line treatment in advanced NSCLC patients, aiming to improve on existing checkpoint inhibitor plus chemotherapy regimens.

Study Overview

Study Type: Single-arm, prospective Phase II clinical trial

Population: 20 treatment-naefve advanced NSCLC pts, driver-gene negative

Intervention: Chidamide + tislelizumab + platinum-based chemotherapy (4-6 cycles), then maintenance

Outcomes: ORR primary; secondary: DCR, PFS, OS, DoR, safety

Key Findings

• ORR was 80% (95% CI, 56.3 6.3 4.3)
• DCR reached 100%
• Median PFS 11.0 months (95% CI, 9.1 12.9)
• Median OS 17.5 months (95% CI, 9.2 25.8)
• Grade B33 TRAEs in 55%; leukopenia (25%) and neutropenia (20%) most common
• No treatment-related deaths reported

Context & Related Research

• Wang et al., 2025: Demonstrated promising efficacy of chidamide, tislelizumab, and chemo triplet in 20 NSCLC pts (PMID: 40631772), indicating enhanced response and PFS.
• Gray et al., 2019: Early phase pembrolizumab plus vorinostat combo showed feasibility and preliminary activity in ICI-naefve NSCLC (PMID: 31409616), supporting HDACi-ICI synergy.
• Johnson et al., 2023: Mocetinostat and durvalumab doublet in advanced NSCLC showed safety and preliminary efficacy (PMID: 36890020), underlying HDACi feasibility.
• Hellmann et al., 2021: Entinostat plus pembrolizumab showed activity in ICI-resistant metastatic NSCLC (PMID: 33203644), expanding clinical contexts.
• Zhang et al., 2024: Chidamide with envafolimab post anti-PD-1 failure NSCLC showed benefit and biomarker insights (PMID: 38597130).
• Shin et al., 2022: HDAC expression correlates with immunotherapy outcomes, lending mechanistic support for HDACi plus ICI (PMID: 34517693).

Clinical Implications

• Chidamide combined with tislelizumab and chemotherapy yields promising response rates and survival in advanced NSCLC, meriting further clinical exploration.
• Common Grade B33 adverse events are manageable hematologic toxicities linked to chemotherapy; regular monitoring is advised.
• Integration of HDAC inhibition with immunotherapy may enhance antitumor immunity; biomarker-guided patient selection is needed.

Future Directions

Randomized controlled trials evaluating HDACi + tislelizumab + chemotherapy versus standard ICI plus chemotherapy are urgently needed to confirm these promising results.

Biomarker-driven studies and translational research will be essential to identify optimal patient populations and elucidate mechanisms of synergy.

The combination of HDACi chidamide and tislelizumab with chemotherapy demonstrated promising antitumor activity and a manageable safety profile as first-line treatment in advanced NSCLC, highlighting the need for confirmatory randomized trials.

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