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Cited by 133Cancer Immunotherapy and BiomarkersLung Cancer Treatments and MutationsHistone Deacetylase Inhibitors Research

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Entinostat plus Pembrolizumab in Patients with Metastatic NSCLC Previously Treated with Anti–PD-(L)1 Therapy

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Hellmann, Matthew D., Jänne, Pasi A., Opyrchal, Mateusz, Hafez, Navid, Raez, Luis E., Gabrilovich, Dmitry I., Wang, Fang, Trepel, Jane B., Lee, Min-Jung, Yuno, Akira, Lee, Sunmin, Brouwer, Susan, Sankoh, Serap, Wang, Lei, Tamang, David, Schmidt, Emmett V., Meyers, Michael L., Ramalingam, Suresh S., Shum, Elaine, Ordentlich, Peter·2021·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-20-3305PMC PMC7887114
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Abstract

Purpose: New therapies are needed to treat immune checkpoint inhibitor–resistant non–small cell lung cancer (NSCLC) and identify biomarkers to personalize treatment. Epigenetic therapies, including histone deacetylase inhibitors, may synergize with programmed cell death-1 (PD-1) blockade to overcome resistance. We report outcomes in patients with anti-programmed cell death ligand-1 [PD-(L)1]–resistant/refractory NSCLC treated with pembrolizumab plus entinostat in ENCORE 601. Patients and Methods: The expansion cohort of ENCORE 601 included patients with NSCLC who previously experienced disease progression with immune checkpoint inhibitors. The primary endpoint for the phase II expansion cohort is overall response rate (ORR); safety, tolerability, and exploratory endpoints are described. Results: Of 76 treated patients, 71 were evaluable for efficacy. immune-regulated RECIST–assessed ORR was 9.2% [95% confidence interval (CI): 3.8–18.1], which did not meet the prespecified threshold for positivity. Median duration of response was 10.1 months (95% CI: 3.9–not estimable), progression-free survival (PFS) at 6 months was 22%, median PFS was 2.8 months (95% CI: 1.5–4.1), and median overall survival was 11.7 months (95% CI: 7.6–13.4). Benefit was enriched among patients with high levels of circulating classical monocytes at baseline. Baseline tumor PD-L1 expression and IFNγ gene expression were not associated with benefit. Treatment-related grade ≥3 adverse events occurred in 41% of patients. Conclusions: In anti–PD-(L)1–experienced patients with NSCLC, entinostat plus pembrolizumab did not achieve the primary response rate endpoint but provided a clinically meaningful benefit, with objective response in 9% of patients. No new toxicities, including immune-related adverse events, were seen for either drug. Future studies will continue to evaluate the association of monocyte levels and response.

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Research works printed but not linked: 30

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Metadata

Authors
Hellmann, M. D., Jänne, P. A., Opyrchal, M., Hafez, N., Raez, L. E., Gabrilovich, D. I., Wang, F., Trepel, J. B., Lee, M.-J., Yuno, A., Lee, S., Brouwer, S., Sankoh, S., Wang, L., Tamang, D., Schmidt, E. V., Meyers, M. L., Ramalingam, S. S., Shum, E., & Ordentlich, P.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • 2Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Roswell Park Comprehensive Cancer Center (US)
  • Yale Cancer Center (US)
  • Florida International University (US)
  • The Wistar Institute (US)
  • National Institutes of Health (US)
  • Syndax Pharmaceuticals (United States) (US)
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
  • Winship Cancer Institute (US)
  • NYU Langone Health (US)
Corresponding author
Hellmann, Matthew D.
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2021-02-15
Volume
27
Issue
4
Pages
1019-1028
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-20-3305
PMC
PMC7887114
OpenAlex
W3100080748
Cited by
133
References
10
Citations by year
2026: 21 · 2025: 30 · 2024: 24 · 2023: 28 · 2022: 18 · 2021: 11
FWCI
5.15
Type
journal article
Language
en
Open access
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion)
Funders
  • Syndax Pharmaceuticals, Inc
  • Memorial Sloan Kettering Cancer Center Support Grant (CI-98-18, P30-CA008748)
  • NIH (P30-CA010815)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
Keywords
entinostat, pembrolizumab, non-small cell lung cancer, metastatic non-small cell lung cancer, PD-L1 blockade, immune checkpoint inhibitor resistance, histone deacetylase inhibitors, epigenetic therapy, classical monocytes, PD-L1 expression, overall response rate, progression-free survival, immune-related adverse events
MeSH terms
Progression-Free Survival, Immune Checkpoint Inhibitors, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Benzamides, Carcinoma, Non-Small-Cell Lung, Female, Follow-Up Studies, Humans, Lung Neoplasms, Male, Middle Aged, Neoplasm Recurrence, Local, Pyridines, Drug Resistance, Neoplasm, B7-H1 Antigen, Antibodies, Monoclonal, Humanized

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