HDAC Inhibitor Plus Cisplatin Stabilizes Advanced Adenoid Cystic Carcinoma

Adenoid cystic carcinoma (ACC) is a rare malignancy of the salivary glands that typically follows an indolent yet persistent clinical course, characterized by frequent perineural invasion, local recurrence, and late distant metastasis. While definitive surgery and radiotherapy remain the primary treatments for localized disease, recurrent or metastatic ACC presents a significant therapeutic challenge with no established standard of care for systemic therapy. Conventional cytotoxic chemotherapy, including platinum-based regimens, has historically produced modest and often non-durable responses, while targeted therapies such as multikinase inhibitors and immune checkpoint blockade have shown variable or limited activity. This clinical landscape underscores the urgent need for mechanism-based strategies that can improve durable disease control rather than relying solely on deep tumor regression, a gap that recent epigenetic research aims to address.

Epigenetic dysregulation has emerged as a potential therapeutic vulnerability in ACC, with histone deacetylase (HDAC) inhibitors showing promise in modulating chromatin accessibility and promoting cell-cycle arrest. Chidamide, also known as tucidinostat, is an oral benzamide HDAC inhibitor with established clinical use in other malignancies and preliminary activity in ACC. Preclinical models suggest that HDAC inhibition may sensitize tumor cells to cisplatin-induced DNA damage and promote senescence, providing a biological rationale for combining chidamide with platinum chemotherapy. To evaluate this combination, researchers conducted a prospective, single-arm, phase 2 study in patients with recurrent or metastatic ACC, focusing on confirmed objective response rate as the primary endpoint alongside disease control rate, progression-free survival, and safety.

The study enrolled 24 patients between June 2018 and February 2020, of whom 22 were efficacy-evaluable after at least one post-baseline tumor assessment. The patient population was predominantly female, with a mean age of 48.5 years, and most patients had distant metastases, with lung metastases present in 83.3% of the cohort. A significant proportion of patients, 62.5%, had a disease-free interval of less than 30 months, a recognized adverse prognostic feature in recurrent or metastatic ACC. Half of the patients had received no prior systemic therapy, while the other half had undergone at least one prior regimen, reflecting the heterogeneous treatment histories typical of this rare cancer population.

Safety assessments in all 24 treated patients revealed that hematologic adverse events were the most common, with neutropenia occurring in 54.2% of patients, including grade 3 or 4 events in 16.7%. Leukopenia and thrombocytopenia were also frequent, while nonhematologic events such as nausea and vomiting were generally manageable. Dose reductions occurred in 12.5% of patients, and two patients discontinued treatment due to adverse events, but no treatment-related deaths were reported. This manageable safety profile supports the feasibility of the combination regimen in a clinical setting, although the small sample size limits the generalizability of these safety findings.

In terms of efficacy, the prespecified objective response rate endpoint was not met, with a confirmed objective response rate of 13.6% and no complete responses observed. However, the disease control rate was high at 86.4%, with most patients achieving stable disease. The Kaplan-Meier estimated 6-month progression-free survival rate was 71.0%, and the median progression-free survival was 17.9 months, while the median overall survival was 40.3 months. These results suggest that while objective tumor regression was limited, the combination provided a disease-control signal in a subset of patients, which may be clinically meaningful given the indolent nature of ACC.

The apparent discordance between the modest objective response rate and the prolonged progression-free survival should be interpreted in the context of ACC’s clinical behavior, where durable disease stabilization may represent a meaningful therapeutic goal. However, stable disease in a nonrandomized study without a contemporaneous control group can also reflect underlying tumor biology, and the observed progression-free survival should be viewed as supportive evidence requiring prospective validation. Historical data from conventional cytotoxic regimens and multikinase inhibitors show median progression-free survival estimates ranging from 6 to 18 months, placing the current study’s results within the range of active systemic approaches, though cross-study comparisons are limited by differences in eligibility criteria and endpoint definitions.

Individual-level efficacy displays, including waterfall and swimmer plots, further support a pattern of limited tumor regression with disease stabilization, where only a minority of patients experienced confirmed shrinkage, while several maintained stable target lesion burden over prolonged intervals. Exploratory analyses indicated that early tumor shrinkage after cycle 2 was associated with longer progression-free and overall survival, although this post-baseline association was limited by the small sample size and should be interpreted descriptively. These findings help characterize treatment kinetics but do not alter the primary conclusion that the prespecified objective response rate endpoint was not met, highlighting the need for further investigation into the mechanisms underlying disease control.

The biological rationale for combining chidamide with cisplatin remains plausible but unproven, as the study did not include paired tumor biopsies, pharmacodynamic assays, or molecular stratification to establish target engagement or a mechanistic link between HDAC inhibition and disease control. Future studies should integrate pharmacodynamic and molecular endpoints to identify tumors most likely to benefit from HDAC inhibitor-platinum therapy, potentially focusing on specific genomic or epigenetic states such as MYB/MYBL1 programs or NOTCH1 status. Patient-reported outcomes, summarized descriptively using the EORTC QLQ-C30 questionnaire, showed higher global health status scores during treatment, but questionnaire completion declined over time, introducing potential informative missingness that limits the interpretation of these data as definitive evidence of population-level quality of life improvement.

Limitations of the study include its single-center design, small sample size, lack of a randomized control group, and absence of central radiologic review, which result in wide confidence intervals around key survival estimates and limited precision. The absence of formal pre-enrollment tumor growth-rate assessment limits the ability to separate treatment-associated disease control from the natural history of ACC, and subgroup analyses were exploratory and underpowered. These limitations underscore the need for subsequent multicenter, biomarker-enriched trials with independent response verification and prespecified success thresholds to better capture durable disease control in ACC, ultimately guiding the development of more effective therapeutic strategies for this challenging malignancy.

Subject of Research: A single arm phase II trial of chidamide plus cisplatin in advanced adenoid cystic carcinoma

Article Title: A single arm phase II trial of chidamide plus cisplatin in advanced adenoid cystic carcinoma

Article References: Liu, Y., Chen, G.-L., Xue, K., Zhang, Q., Xia, Z., Ji, D., Jin, J., Lv, F., Liu, X., Wang, Y., Hong, X., & Cao, J. (2026). A single arm phase II trial of chidamide plus cisplatin in advanced adenoid cystic carcinoma. iScience, 29(11), Article 117925. https://doi.org/10.1016/j.isci.2026.117925

Image Credits: AI Generated

DOI: 10.1016/j.isci.2026.117925

Keywords: single, phase, trial, chidamide, plus, cisplatin, advanced, adenoid, cystic, carcinoma, scientific research