Evolution of checkpoint inhibitors for the treatment of metastatic gastric cancers: Current status and future perspectives

Taı̈eb, Julien; Moehler, Markus; Boku, Narikazu; Ajani, Jaffer A.; Ruiz, Eduardo Yañez; Ryu, Min Hee; Guenther, Silke; Chand, Vikram K.; Bang, Yung Jue

doi:10.1016/j.ctrv.2018.04.004

Cited by 80 publications

(74 citation statements)

References 73 publications

(113 reference statements)

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“…With the increasing role of immunotherapies (such as immune checkpoint blockade with anti–PD‐L1 agents) in the treatment of a variety of advanced solid tumors, it is important to confirm the generalizability of findings in ethnically diverse patient groups. For example, in patients with gastric or gastroesophageal junction cancer, the anti–PD‐1 agent nivolumab increased OS compared with placebo in Asian patients confirming previous findings of nivolumab and leading to its regulatory approval in Japan …”

Section: Discussionsupporting

confidence: 70%

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Tolerability and efficacy of durvalumab in Japanese patients with advanced solid tumors

et al. 2019

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Blockade of programmed cell death ligand‐1 with durvalumab has shown efficacy and safety in large, international studies of patients with advanced solid tumors. A phase 1, non‐randomized, open‐label multicenter study was initiated to evaluate durvalumab in a Japanese population. The first part of this study used a standard 3 + 3 dose‐escalation design to determine the optimal dosing schedule of durvalumab. Primary objective was evaluation of safety and tolerability of durvalumab monotherapy. Secondary objectives were to evaluate maximum tolerated dose ( MTD ), immunogenicity, pharmacokinetics, and efficacy. Twenty‐two patients (median age, 61.5 years; range, 41‐76; 64% male) received durvalumab at doses of 1, 3, or 10 mg/kg every 2 weeks (q2w), 15 mg/kg q3w, or 20 mg/kg q4w. Twenty patients discontinued before completing 12 months of treatment as a result of progressive disease and two due to adverse events ( AE ). The most common treatment‐related AE (tr AE ) were rash (18%) and pruritus (14%); two patients had grade ≥3 tr AE including one patient each with hyponatremia and hypothyroidism. No patient experienced a dose‐limiting toxicity ( DLT ) during the DLT evaluation period and the MTD was not identified. There were no AE leading to a fatal outcome during study treatment. Durvalumab showed dose‐proportional pharmacokinetics across the 1‐20 mg/kg dose range; incidence of positive titers for antidrug antibodies was 9%. One patient with lung cancer had a partial response and disease control rate at 12 weeks was 36%. In conclusion, durvalumab at the doses and regimens evaluated was safe and well tolerated in Japanese patients with advanced solid tumors.

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Section: Discussionsupporting

confidence: 70%

“…For example, in patients with gastric or gastroesophageal junction cancer, the anti-PD-1 agent nivolumab increased OS compared with placebo in Asian patients confirming previous findings of nivolumab and leading to its regulatory approval in Japan. 27 In conclusion, durvalumab at the doses and regimens evalu-…”

Section: Efficacymentioning

confidence: 96%

Tolerability and efficacy of durvalumab in Japanese patients with advanced solid tumors

et al. 2019

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“…Regulation of the immune system through immune checkpoint inhibitors is an emerging therapeutic approach. Immunotherapies that target programmed cell death-ligand 1 (PD-L1) or programmed cell death-1 (PD-1) inhibitors have become cornerstones of treatments for malignant tumours such as gastrointestinal, pulmonary, renal cell carcinoma, and melanoma [2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Immune classification for the PD-L1 expression and tumour-infiltrating lymphocytes in colorectal adenocarcinoma

2020

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Background: Colorectal adenocarcinoma is the third most common cancer worldwide and a leading cause of cancerrelated death. The recent emergence of diverse immunotherapeutic agents has made it crucial to interpret a complex tumour microenvironment intermingled with tumour-infiltrating immune cells to predict the immunotherapeutic response rate. However, in colorectal adenocarcinoma, studies are lacking that provide detailed analyses of programmed death-ligand 1 (PD-L1) and tumour-infiltrating lymphocytes (TIL) to elucidate their prognostic values and to identify immunotherapytargetable subgroups, preferably with multiple immune-related biomarkers. In the present study, we categorize colorectal adenocarcinomas into four types of tumour immune microenvironments according to PD-L1 expression and TIL, analyse their prognostic values, and propose an immunotherapy-targetable subgroup. Methods: Formalin-fixed, paraffin-embedded tissue samples of surgically resected primary colorectal adenocarcinomas (n = 489) were obtained and arrayed on tissue microarray blocks. Immunohistochemical stains for PD-L1, programmed cell death protein 1 (PD-1), cluster of differentiation 8 (CD8), and deficient mismatch repair (dMMR) were performed and evaluated. Results: Tumour microenvironment immune type (TMIT) I (PD-L1-positive tumour cells and CD8-high TIL) and type II (PD-L1negative tumour cells and CD8-low TIL) showed the best and worst prognoses, respectively. PD-L1 overexpression was significantly associated with dMMR status. PD-L1 immunoreactivity was positively correlated with TIL having CD8 or PD-1 overexpression. Conclusions: TMIT I subgroup showed stronger CD8/PD-L1/PD-1 signalling interaction compared to the other TMIT. Therefore, we propose that the TMIT I subgroup is a candidate TMIT to predict effective response rate for existing immune checkpoint inhibitors and determine targetable subgroups for emerging therapies.

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“…Patients with PC are highly symptomatic and can have an overall survival of <6 months. Only a small fraction of patients benefits, often only transiently, from immune checkpoint inhibitors 5,6 or HER2-directed therapy 7 . Molecular understanding of advanced GAC is limited.…”

Section: A Single-cell Transcriptome Map Of Pcmentioning

confidence: 99%

Cell-of-Origin Analysis of Metastatic Gastric Cancer Uncovers the Origin of Inherent Intratumor Heterogeneity and a Fundamental Prognostic Signature

Wang

Song

Harada

et al. 2019

Preprint

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Intra-tumoral heterogeneity (ITH) is the fundamental property of cancer, however, the origin of ITH remains poorly understood. Here we performed single-cell RNA sequencing of peritoneal carcinomatosis (PC) from 20 patients with advanced gastric adenocarcinoma (GAC), constructed a transcriptome map of 45,048 PC cells, determined the cell-of-origin of each tumor cell, and incisively explored ITH of PC tumor cells at single-cell resolution. The links between cell-of-origin and ITH was illustrated at transcriptomic, genotypic, molecular, and phenotypic levels. This study characterized the origins of PC tumor cells that populate and thrive in the peritoneal cavity, uncovered the diversity in tumor cell-of-origins and defined it as a key determinant of ITH. Furthermore, cell-of-origin-based analysis classified PC into two cellular subtypes that were prognostic independent of clinical variables, and a 12-gene prognostic signature was then derived and validated in multiple large-scale GAC cohorts. The prognostic signature appears fundamental to GAC carcinogenesis/progression and could be practical for patient stratification.

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Evolution of checkpoint inhibitors for the treatment of metastatic gastric cancers: Current status and future perspectives

Abstract: Anti-PD-1/PD-L1 antibodies have shown encouraging clinical activity in advanced GC/GEJC. Results from ongoing phase 3 trials are needed to further evaluate the potential roles of these agents within the continuum of care.

Cited by 80 publications

References 73 publications

Tolerability and efficacy of durvalumab in Japanese patients with advanced solid tumors

Tolerability and efficacy of durvalumab in Japanese patients with advanced solid tumors

Immune classification for the PD-L1 expression and tumour-infiltrating lymphocytes in colorectal adenocarcinoma

Cell-of-Origin Analysis of Metastatic Gastric Cancer Uncovers the Origin of Inherent Intratumor Heterogeneity and a Fundamental Prognostic Signature

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