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

In this PACUPod update, Britany and Seth review Wang et al.'s phase II, single-arm trial of chidamide (an HDAC inhibitor) combined with tislelizumab (a PD-1 inhibitor) and platinum-based chemotherapy as first-line therapy for treatment-naïve, driver-gene-negative advanced NSCLC. They discuss the rationale for combining epigenetic therapy with immunotherapy and chemotherapy, the reported efficacy (ORR 80%, disease control rate 100%, median progression-free survival 11 months, median overall survival 17.5 months) and safety profile (55% of patients experienced grade 3 or higher treatment-related adverse events, primarily leukopenia and neutropenia), patient selection criteria, and pharmacologic considerations (CYP3A4 metabolism and potential drug interactions). The hosts place these findings in the context of prior HDAC inhibitor–immunotherapy studies and emphasize study limitations (small sample size, single-arm design) and the need for larger randomized trials and biomarker-driven patient selection to validate and refine this triplet therapy for NSCLC.

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Britany: Welcome back to PACULit, your source for the latest clinical literature updates. Today, we’re discussing a phase II study exploring a novel first-line treatment for advanced non-small cell lung cancer, or NSCLC. Seth, this study combines histone deacetylase inhibitors, or HDACis, with tislelizumab and chemotherapy. What’s your take?

Seth: Thanks, Britany. Advanced NSCLC remains a leading cause of cancer mortality. While immune checkpoint inhibitors plus chemotherapy have improved outcomes, better response rates and durability are needed. Adding HDAC inhibitors could modulate the tumor microenvironment and enhance immunotherapy via epigenetic reprogramming. This triple combination is innovative.

Britany: The study by Wang et al. enrolled treatment-naïve patients with advanced NSCLC who were driver-gene negative—no EGFR, ALK, or ROS1 mutations. These patients rely on chemo-immunotherapy but lack targeted options. HDACis may increase tumor antigen presentation and reverse immune evasion, while chemotherapy induces immunogenic cell death, potentially synergizing with the PD-1 inhibitor tislelizumab.

Seth: Right. Tislelizumab has shown favorable safety and efficacy in NSCLC. Combining it with chidamide, an oral HDAC inhibitor, plus platinum-based chemotherapy is logical. This prospective, single-arm phase II trial enrolled twenty patients with stage IIIB or IV NSCLC, excluding those with autoimmune diseases or prior immunotherapy or HDACi exposure to reduce confounding.

Britany: Patients received four to six cycles of chidamide, tislelizumab, and chemotherapy, followed by maintenance with chidamide plus tislelizumab. The primary endpoint was objective response rate (ORR) by RECIST. Secondary endpoints included disease control rate, progression-free survival (PFS), overall survival (OS), and safety.

Seth: Results were promising. ORR was 80%, disease control rate 100%. Median PFS was 11 months, and median OS 17.5 months—improvements over historical chemo-immunotherapy data.

Britany: However, grade 3 or higher treatment-related adverse events occurred in 55%, mainly leukopenia and neutropenia. No treatment-related deaths were reported. This underscores the need for proactive hematologic toxicity management.

Seth: Exactly. Close blood count monitoring and growth factor support may mitigate risks. Oral chidamide offers convenience but requires adherence monitoring. Also, chidamide is metabolized via cytochrome P450 enzymes, so drug interactions are a concern.

Britany: Clinicians should watch for concomitant medications that might increase toxicity or reduce efficacy. Seth, how does this study fit into the broader HDACi and immunotherapy landscape in NSCLC?

Seth: Prior studies combined HDAC inhibitors with immune checkpoint inhibitors without chemotherapy. For example, Gray et al. (2019) evaluated pembrolizumab plus vorinostat, showing feasibility and preliminary activity. Johnson et al. (2023) studied mocetinostat plus durvalumab with manageable safety and some efficacy. Hellmann (2021) focused on entinostat plus pembrolizumab in immunotherapy-resistant NSCLC, suggesting HDAC inhibition may overcome resistance. Zhang et al. (2024) reported chidamide plus envafolimab in anti-PD-1 resistant NSCLC, reinforcing HDACis’ role in later lines.

Britany: Wang et al.’s study is unique by adding chemotherapy to HDACi and PD-1 inhibitor as first-line therapy, leveraging chemotherapy-induced immunogenic cell death alongside epigenetic modulation and checkpoint blockade. Median follow-up was 23.4 months, strengthening survival data.

Seth: Limitations include the small sample size (20 patients) and single-arm design without a comparator, limiting generalizability and definitive conclusions about superiority over standard regimens. PD-L1 expression heterogeneity and other patient factors weren’t fully addressed. Findings are specific to chidamide and tislelizumab, so extrapolation to other agents should be cautious.

Britany: Clinically, this suggests a promising new option for treatment-naïve, driver-gene negative advanced NSCLC patients. The manageable safety and encouraging efficacy warrant larger randomized trials.

Seth: Future research should validate these results in phase III trials comparing the triplet to current standards. Identifying predictive biomarkers, like HDAC expression, could help select patients most likely to benefit.

Britany: Shin et al. (2022) showed histone deacetylase expression might predict immunotherapy response in NSCLC, supporting combining HDAC inhibitors with checkpoint blockade.

Seth: Integrating biomarkers could optimize patient selection and outcomes. Exploring other HDAC inhibitors with different selectivity might improve efficacy or reduce toxicity.

Britany: Regarding special populations, patients with autoimmune diseases were excluded due to immunotherapy risks. Managing such patients remains challenging, and safety of adding HDACis here is unknown.

Seth: Elderly or comorbid patients may be more susceptible to hematologic toxicities. Dose adjustments and close monitoring are essential. Oral chidamide may improve convenience but requires adherence support.

Britany: Another clinical pearl: chidamide is metabolized by CYP3A4, so co-administration with strong inhibitors or inducers could alter drug levels, affecting efficacy and safety—important in oncology patients with polypharmacy.

Seth: Clinicians should review medications carefully and consider therapeutic drug monitoring if available. HDAC inhibitors’ immunomodulatory effects might increase immune-related adverse events risk, though this study reported no unexpected toxicities.

Britany: That’s reassuring but highlights the need for vigilance and early management protocols for immune-mediated toxicities when combining immunomodulatory agents.

Seth: In summary, Wang et al.’s phase II study provides preliminary evidence that combining chidamide, tislelizumab, and chemotherapy as first-line treatment in advanced NSCLC achieves high response rates and durable disease control with manageable safety.

Britany: While promising, these findings require cautious interpretation due to study limitations. Larger randomized trials are needed to confirm efficacy, safety, and define optimal patient populations.

Seth: Until then, this triplet regimen remains investigational but offers hope for expanding options in a challenging population.

Britany: Thanks for the discussion, Seth. To our listeners, stay tuned for upcoming trials clarifying HDAC inhibitors’ role combined with immunotherapy and chemotherapy in NSCLC.

Seth: Thank you, Britany. Always a pleasure to review emerging literature with you. Looking forward to our next update.

Britany: Likewise. That wraps up today’s PACULit episode. Staying current with evolving evidence is key to optimizing patient care. See you next time!