Efficacy and Safety of Pembrolizumab for Heavily Pretreated Patients With Advanced, Metastatic Adenocarcinoma or Squamous Cell Carcinoma of the Esophagus

Shah, Manish A.; Kojima, Takashi; Hochhauser, Daniel; Enzinger, Peter C.; Raimbourg, Judith; Hollebecque, Antoine; Lordick, Florian; Kim, Sung‐Bae; Tajika, Masahiro; Kim, Heung Tae; Lockhart, A. Craig; Arkenau, Hendrik Tobias; El-Hajbi, Farid; Gupta, Mukul; Pfeiffer, Per; Liu, Qi; Lunceford, Jared; Kang, Soonmo Peter; Bhagia, Pooja; Kato, Ken

doi:10.1001/jamaoncol.2018.5441

Cited by 412 publications

(374 citation statements)

References 20 publications

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“…Two of the most recently published KEYNOTE trials (KEYNOTE-180 and KEYNOTE-181) examined the efficacy of pembrolizumab in treating PD-L1-positive esophageal or EGJ tumors defined as having a CPS $10. 37,151 This is in contrast to previous studies that have defined PD-L1positive tumors as having a CPS $1. In the phase II single-arm KEYNOTE-180 trial, which evaluated pembrolizumab monotherapy in 121 patients with progressive disease after $2 prior lines of therapy, the objective response rate was 9.9% (95% CI, 5.2%-16.7%) among all patients, 5.2% (95% CI, 1.1%-14.4%) among patients with adenocarcinoma (n558), and 13.8% (95% CI, 6.1%-25.4%) among patients with PD-L1-positive tumors (n558).…”

Section: Pembrolizumabmentioning

confidence: 61%

Esophageal and Esophagogastric Junction Cancers, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology

Ajani

D’Amico

Bentrem

et al. 2019

Journal of the National Comprehensive Cancer Network

830

724

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Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. Squamous cell carcinoma is the most common histology in Eastern Europe and Asia, and adenocarcinoma is most common in North America and Western Europe. Surgery is a major component of treatment of locally advanced resectable esophageal and esophagogastric junction (EGJ) cancer, and randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival. Targeted therapies including trastuzumab, ramucirumab, and pembrolizumab have produced encouraging results in the treatment of patients with advanced or metastatic disease. Multidisciplinary team management is essential for all patients with esophageal and EGJ cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on recommendations for the management of locally advanced and metastatic adenocarcinoma of the esophagus and EGJ.

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Section: Pembrolizumabmentioning

confidence: 61%

Esophageal and Esophagogastric Junction Cancers, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology

Ajani

D’Amico

Bentrem

et al. 2019

Journal of the National Comprehensive Cancer Network

830

724

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“…Tumoral PD-L1 expression has been shown to be a predictive marker for response to anti-PD-1 targeted therapies. However, some PD-L1positive patients of esophageal cancer did not benefit from such therapies, while some patients lack of PD-L1 still showed clinical response [10,12], implying that other molecular interacts with PD-1 such as PD-L2 may be important for immunotherapy efficacy in ESCC. In prostate cancer, PD-L2 was more highly expressed than PD-L1 and overwhelmingly correlated with immune- Fig.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, accumulating results suggest that the interaction between mutant cells and immune cells in tissue microenvironment directly influences and even determines the development of cancer [8,9]. Importantly, immunotherapies that target tumor microenvironment instead of tumor intrinsic cells have revealed remarkable efficacy in multiple cancer types, shedding light on the possible treatment of ESCC [10][11][12]. However, the sophisticated immune responses and their biological significance during ESCC carcinogenesis is still unclear.…”

Section: Introductionmentioning

confidence: 99%

CCL2-CCR2 axis recruits tumor associated macrophages to induce immune evasion through PD-1 signaling in esophageal carcinogenesis

et al. 2020

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Background: The poor prognosis of esophageal squamous cell carcinoma (ESCC) highlights the need for novel strategies against this disease. Our previous study suggested the involvement of CCL2 and tumor associated macrophages (TAMs) in esophageal carcinogenesis. Despite the recognition of TAMs as a promising target for cancer treatment, mechanisms underlying its infiltration, activation and tumor-promotive function in ESCC remain unknown. Methods: Human esophageal tissue array and TCGA database were used to evaluate the clinical relevance of CCL2 and TAMs in ESCC. F344 rats and C57BL/6 mice were treated with N-nitrosomethylbenzylamine (NMBA) to establish orthotopic models of esophageal carcinogenesis. CCL2/CCR2 gene knockout mice and macrophage-specific PPARG gene knockout mice were respectively used to investigate the role of infiltration and polarization of TAMs in ESCC. CCL2-mediated monocyte chemotaxis was estimated in malignantly transformed Het-1A cells. THP-1 cells were used to simulate TAMs polarization in vitro. RNA-sequencing was performed to uncover the mechanism. Results: Increasing expression of CCL2 correlated with TAMs accumulation in esophageal carcinogenesis, and they both predicts poor prognosis in ESCC cohort. Animal studies show blockade of CCL2-CCR2 axis strongly reduces tumor incidence by hindering TAMs recruitment and thereby potentiates the antitumor efficacy of CD8 + T cells in the tumor microenvironment. More importantly, M2 polarization increases PD-L2 expression in TAMs, resulting in immune evasion and tumor promotion through PD-1 signaling pathway. Conclusion: This study highlights the role of CCL2-CCR2 axis in esophageal carcinogenesis. Our findings provide new insight into the mechanism of immune evasion mediated by TAMs in ESCC, suggesting the potential of TAMstargeted strategies for ESCC prevention and immunotherapy.

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“…Tumors with a higher density of infiltrating immune cells, called hot tumors, are more responsive to ICI than cold tumors with a lower density of infiltrating immune cells 20,21 . In ESCC, the usability of PD‐L1 expression as a biomarker of ICI sensitivity remains controversial 9,33 . However, in other cancers, several studies have reported the predictive value of ICI sensitivity markers, such as tumoral PD‐L1 expression, 34 hot tumor phenotype, 20,21 tumor mutation burden 35 and IFN‐γ gene signature 36,37 .…”

Section: Discussionmentioning

confidence: 99%

Uptake of positron emission tomography tracers reflects the tumor immune status in esophageal squamous cell carcinoma

et al. 2020

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The relationship between the local immune status and cancer metabolism regarding 18F‐FDG and 18F‐FAMT uptake in esophageal squamous cell carcinoma (ESCC) remains unknown. The present study examined the correlations between tumor immune status, clinicopathological factors, and positron emission tomography (PET) tracer uptake in ESCC. Forty‐one ESCC patients who underwent 18F‐FDG PET and 18F‐FAMT PET before surgery were enrolled in the study. Immunohistochemistry was conducted for programmed death 1 (PD‐1), CD8, Ki‐67, CD34, GLUT1 (18F‐FDG transporter) and LAT1 (18F‐FAMT transporter). ESCC specimens with high tumoral PD‐L1 and high CD8‐positive lymphocytes were considered to have “hot tumor immune status.” High PD‐L1 expression (53.7%) was significantly associated with tumor/lymphatic/venous invasion (P = 0.028, 0.032 and 0.018), stage (P = 0.041), CD8‐positive lymphocytes (P < 0.001), GLUT1 (P < 0.001), LAT1 expression (P = 0.006), Ki‐67 labelling index (P = 0.009) and CD34‐positive vessel counts (P < 0.001). SUVmax of 18F‐FDG was significantly higher in high PD‐L1 cases than in low PD‐L1 cases (P = 0.009). SUVmax of 18F‐FAMT was significantly higher in high PD‐L1 (P < 0.001), high CD8 (P = 0.012) and hot tumor groups (P = 0.028) than in other groups. High SUVmax of 18F‐FAMT (≥4.15) was identified as the only predictor of hot tumor immune status. High PET tracer uptake was significantly associated with cancer aggressiveness and hot tumor immune status in ESCC. PET imaging may be an effective tool to predict tumor immune status in ESCC with respect to immune checkpoint inhibitor sensitivity.

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Efficacy and Safety of Pembrolizumab for Heavily Pretreated Patients With Advanced, Metastatic Adenocarcinoma or Squamous Cell Carcinoma of the Esophagus

Cited by 412 publications

References 20 publications

Esophageal and Esophagogastric Junction Cancers, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology

Esophageal and Esophagogastric Junction Cancers, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology

CCL2-CCR2 axis recruits tumor associated macrophages to induce immune evasion through PD-1 signaling in esophageal carcinogenesis

Uptake of positron emission tomography tracers reflects the tumor immune status in esophageal squamous cell carcinoma

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