A phase 2 clinical trial has evaluated the combination of the histone deacetylase (HDAC) inhibitor entinostat with the PD-1 inhibitor nivolumab in patients with advanced pancreatic ductal adenocarcinoma (PDA). The open-label, single-arm study was conducted at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland. Funding was provided by the Lustgarten Foundation, NIH, and other sources, with Bristol-Myers Squibb and Syndax supplying the study medications. The results were published on February 15, 2024 in Nature Communications.
The purpose of the study was to assess the safety and efficacy of combining epigenetic modulation via HDAC inhibition with immune checkpoint blockade in PDA, a cancer type that has historically been resistant to immunotherapy approaches. Preclinical research had suggested HDAC inhibition could reprogram the immunosuppressive tumor microenvironment in PDA to enhance responsiveness to checkpoint inhibition.
The trial enrolled 30 patients with unresectable or metastatic PDA who had progressed on 1-2 prior lines of therapy between November 2017 and November 2020. Key eligibility criteria included measurable disease, adequate organ function, and accessibility for tumor biopsies. Patients were heavily pretreated, with 63% having received 2 or more prior lines of systemic therapy. The median age was 63.5 years, 57% were male, and 93% were white.
Treatment consisted of a 2-week lead-in with entinostat 5 mg orally once weekly, followed by combination therapy with entinostat 5 mg weekly plus nivolumab 240 mg IV every 2 weeks. After 4 months, the nivolumab schedule was changed to 480 mg every 4 weeks. Treatment continued until disease progression or unacceptable toxicity.
The primary endpoint was objective response rate (ORR) by RECIST v1.1 criteria. In the 27 evaluable patients, the ORR was 11.1% (3 partial responses). The median duration of response in the 3 responders was 10.2 months. Median progression-free survival was 1.89 months and median overall survival was 2.73 months. The 6-month progression-free survival rate was 6.7%.
Treatment-related adverse events of any grade occurred in 90% of patients, with 63% experiencing grade 3-4 events. The most common grade 3-4 toxicities were decreased lymphocyte count (27%) and anemia (30%). Six patients (20%) required entinostat dose reduction. No grade 5 adverse events were observed.
Correlative studies were performed on serial tumor biopsies and blood samples to evaluate changes in the tumor microenvironment. Multiplexed immunohistochemistry showed trends toward decreased CD163+/CD68+ macrophages and increased mature dendritic cells after entinostat treatment. Mass cytometry analysis of peripheral blood revealed increased dendritic cell maturation markers and decreased myeloid-derived suppressor cell markers following entinostat exposure. RNA sequencing of tumor samples demonstrated upregulation of interferon-gamma signaling and antigen presentation pathways with combination therapy.
The authors concluded that while the primary efficacy endpoint was not met, the combination showed durable responses in a subset of patients and favorably modulated the tumor immune microenvironment. They noted the regimen was generally well-tolerated and demonstrated initial proof-of-concept for combining epigenetic and immune checkpoint therapies in PDA.
There were several important limitations to this study. As a single-arm trial, it is difficult to definitively attribute clinical activity to the combination versus potential single-agent effects. The sample size was small, particularly for the correlative analyses. The short lead-in period with entinostat monotherapy may have limited the ability to detect epigenetic reprogramming effects. Additionally, many patients progressed quickly, potentially before deriving full benefit from the combination approach.
Despite these limitations, this trial provides valuable insights into a novel therapeutic strategy for PDA. The correlative analyses offer mechanistic support for the ability of HDAC inhibition to enhance antitumor immunity and overcome resistance to checkpoint blockade. The durable responses observed in a subset of patients are encouraging in a disease with few effective treatment options after first-line therapy.
The potential clinical impact of this work is multifaceted. First, it establishes initial safety data for combining entinostat and nivolumab in PDA patients. Second, it provides rationale for further development of epigenetic-immunotherapy combinations in this disease. The biomarker data may help inform patient selection and optimal timing of biopsies in future trials. Additionally, the observed effects on dendritic cell maturation suggest potential synergy with cancer vaccine approaches.
Moving forward, key questions remain regarding how to expand the subset of patients who benefit from this strategy. Potential areas for investigation include alternative dosing schedules, combination with chemotherapy, and incorporation of additional immunomodulatory agents. Studies in earlier disease settings, such as the neoadjuvant or maintenance setting, may also be warranted. Ultimately, randomized studies will be needed to definitively establish the efficacy of this approach.
In conclusion, this phase 2 trial provides an important proof-of-concept for combining epigenetic modulation with checkpoint blockade in pancreatic cancer. While larger studies are needed, the durable responses and favorable immune modulation observed offer hope for improving outcomes in this challenging malignancy. As our understanding of the complex interplay between epigenetics and antitumor immunity grows, rational combinations such as this may help expand the reach of cancer immunotherapy to traditionally resistant tumor types.
References
Baretti M, Danilova L, Durham JN, et al. Entinostat in combination with nivolumab in metastatic pancreatic ductal adenocarcinoma: a phase 2 clinical trial. Nat Commun. 2024;15(1):9801. Published 2024 Nov 12. doi:10.1038/s41467-024-52528-7
