1. Phase II study of pembrolizumab in refractory esophageal cancer with correlates of response and survival.
- Author
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de Klerk LK, Patel AK, Derks S, Pectasides E, Augustin J, Uduman M, Raman N, Akarca FG, McCleary NJ, Cleary JM, Rubinson DA, Clark JW, Fitzpatrick B, Brais LK, Cavanaugh ME, Rode AJ, Jean MG, Lizotte PH, Nazzaro MJ, Severgnini M, Zheng H, Fuchs CS, Enzinger PC, and Bass AJ
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized pharmacology, Antineoplastic Agents, Immunological pharmacology, Esophageal Neoplasms mortality, Female, Humans, Male, Middle Aged, Survival Analysis, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents, Immunological therapeutic use, Esophageal Neoplasms drug therapy
- Abstract
Background: Immune checkpoint inhibitors have revolutionized cancer treatment, but the benefits in refractory patients with esophageal cancer have been modest. Predictors of response as well as new targets for novel therapeutic combinations are needed. In this phase 2 clinical trial, we tested single-agent pembrolizumab in patients with advanced esophageal cancer, who received at least one prior line of therapy., Methods: Pembrolizumab 200 mg every 3 weeks was tested in 49 patients with refractory esophageal cancer: 39 with adenocarcinoma and 10 with esophageal squamous cell carcinoma. Major endpoints were radiological response by Immune-related Response Evaluation Criteria In Solid Tumors and survival. Tumor samples were evaluated for programmed cell death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), and immune contexture by both NanoString mRNA expression analysis and flow cytometry. Peripheral blood mononuclear cells and a panel of circulating chemokines were also analyzed., Results: The overall response rate (ORR) was 8% (4 of 49 patients; 95% CI 2.3% to 19.6%). Median overall survival (OS) was 5.8 months (95% CI 4.0 to 9.5). ORR and OS were not associated with histology. For PD-L1-positive patients, ORR was 13.3% (95% CI 1.7% to 40.5%) and median OS was 7.9 months (95% CI 4.7 to 15.5). A trend toward improved OS was observed in seven patients with a TMB ≥10 mut/Mb (p=0.086). Tumors with a PD-L1 Combined Positive Score ≥1 showed enrichment of LAG3 (p=0.005) and IDO1 (p=0.04) gene expression. Baseline levels of circulating CXCL10, interleukin 2 (IL2) receptor α (IL2RA) and IL6 were associated with survival: CXCL10 favorably, (HR 0.37, p=0.002 (progression-free survival); HR 0.55, p=0.018 (OS)); IL2RA and IL6 unfavorably (HR 1.57, p=0.020 for IL6 (OS); HR 2.36, p=0.025 for IL2RA (OS))., Conclusions: Pembrolizumab monotherapy was modestly effective in refractory esophageal cancer. Circulating CXCL10 at baseline appeared to be a robust predictor of response. Other T cell exhaustion markers are upregulated in PD-L1-positive patients, suggesting that immunotherapy combinations such as anti-LAG3/programmed cell death protein 1 (PD-1) or anti-IDO1/PD-1 may be of promise in refractory esophageal cancer., Competing Interests: Competing interests: AJB received funding support from Bayer, Merck and Novartis. JMC received research funding to his institution from Abbvie, Merus, Roche, and Bristol Myers Squibb, received research funding from Merck, Astrazeneca, Esperas Pharma, and Tesaro, received consulting fees from Bristol Myers Squibb, and received travel funding from Bristol Myers Squibb. PCE has consulted for and has received honoraria from ALX Oncology, Arcus Bioscience, Astellas, Astra-Zeneca, Blueprint Medicines, Bristol-Myers Squibb, Celgene, Daiichi-Sankyo, Five Prime, Ideaya, Istari, Legend, Lilly, Loxo, Merck, Ono, Taiho, Takeda, Turning Point Therapeutics, Xencor and Zymeworks., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2021
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