Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer

Shitara, Kohei; Cutsem, Éric Van; Bang, Yung Jue; Fuchs, Charles S.; Wyrwicz, Lucjan; Lee, Moon Hyoung; Kudaba, Iveta; Garrido, Marcelo; Chung, Hyun Cheol; Lee, Jeeyun; Castro, Hugo R.; Mansoor, Wasat; Braghiroli, Maria Ignez; Karaseva, Nina; Caglevic, Christian; Villanueva, Luis; Goekkurt, Eray; Satake, Hironaga; Enzinger, Peter C.; Alsina, María; Benson, Al B.; Chao, Joseph; Ko, Andrew H.; Wainberg, Zev A.; Kher, Uma; Shah, Sukrut; Kang, Soonmo Peter; Tabernero, Josep

doi:10.1001/jamaoncol.2020.3370

Cited by 804 publications

(769 citation statements)

References 28 publications

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“…On the other hand, trials of anti-PD-1 agents have also shown comparably disappointing results, suggesting novel strategies are necessary to overcome primary or secondary resistance to therapy. For instance, the phase III KEYNOTE-062 trial failed to demonstrate the superiority of pembrolizumab compared to chemotherapy in the frontline setting with pembrolizumab failing to show superiority to chemotherapy even in the PD-L1 > 10% CPS group [ 26 ]. Furthermore, the phase II KEYNOTE-180 trial demonstrated a disappointing tumor response of pembrolizumab in the third line setting (ORR 5.2%) in GEJ cancer [ 27 ].…”

Section: Search Methodsologymentioning

confidence: 99%

The integration of immune checkpoint inhibitors with VEGF targeted agents in advanced gastric and gastroesophageal adenocarcinoma: a review on the rationale and results of early phase trials

2021

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Several targeted therapies have shown efficacy in patients with advanced gastric cancer (GC) and gastroesophageal junction adenocarcinoma (GEJC), including anti-angiogenic agents and immune checkpoint inhibitors. Ramucirumab, an anti-VEGFR2 antibody, has shown efficacy in GC, but the benefits are limited, in part due to MET-mediated resistance. Other VEGF targeted agents like VEGF tyrosine kinase inhibitors (TKIs) with broad multi-kinase inhibitory spectrum like regorafenib and cabozantinib have also shown modest single agent activity in early phase trials. For immune checkpoint inhibitors, pembrolizumab (anti-PD-1) monotherapy confers survival advantage as 3rd line therapy for the PD-L1 expressing GC and GEJC population and has been approved for use in this setting. Extensive tumor microenvironment immune modulatory effects from antiangiogenic agents have been demonstrated from preclinical data which support the clinical study rationale of dual blockade of VEGF and immune checkpoint. In addition, FDA has approved combinations of anti-VEGF/VEGFR with anti-PD-1/PD-L1 agents in hepatocellular carcinoma and renal cell carcinoma. Promising clinical activity has been demonstrated in patients with refractory GC/GEJC when treated with dual blockade combination with antiangiogenic agents and immune checkpoint inhibitors like PD-1/PD-L1 inhibitors in several phase I/II trials. This review highlights the trials investigating these novel combinations as well as their preclinical rationale.

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Section: Search Methodsologymentioning

confidence: 99%

The integration of immune checkpoint inhibitors with VEGF targeted agents in advanced gastric and gastroesophageal adenocarcinoma: a review on the rationale and results of early phase trials

2021

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“…Preoperative chemoradiotherapy has been indicated in the NCCN flow-chart as possible treatment for patients with resectable gastric cancer (based on level 2B evidence, meaning FIGURE 2 | Timeline of different randomized trials that have not led to change of clinical practice (yet) in the curative setting, but have investigated important research questions and/or form the rationale behind ongoing (possibly practice changing) studies (46,47,49,77,90,103). that this statement is based upon lower-level evidence, but with NCCN consensus that this intervention is appropriate) (9).…”

Section: Preoperative Chemoradiotherapy-west (United States)mentioning

confidence: 99%

“…Since the observation that patients with advanced mismatch repair-deficient cancers resulting in microsatellite instability (MSI), had a good response on immune-checkpoint blockade regardless of tumor type (89), this feature has also been extensively studied within gastric cancer patients. In the metastatic setting, anti PDL-1 treatment with pembrolizumab resulted in increased OS (exploratory analysis among 33 patients with MSI-high tumors, 1-year OS 79% versus 47%, HR 0.29 (95% CI 0.11-0.81) for treatment with pembrolizumab versus chemotherapy) (phase III study) (90).…”

Section: Epstein-barr Virus (Ebv) and Mss/msi-highmentioning

confidence: 99%

Towards Personalization in the Curative Treatment of Gastric Cancer

et al. 2020

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Gastric cancer is the fifth most common cancer worldwide and has a high mortality rate. In the last decades, treatment strategy has shifted from an exclusive surgical approach to a multidisciplinary strategy. Treatment options for patients with resectable gastric cancer as recommended by different worldwide guidelines, include perioperative chemotherapy, pre- or postoperative chemoradiotherapy and postoperative chemotherapy. Although gastric cancer is a heterogeneous disease with respect to patient-, tumor-, and molecular characteristics, the current standard of care is still according to a one-size-fits-all approach. In this review, we discuss the background of the different treatment strategies in resectable gastric cancer including the current standard, the specific role of radiotherapy, and describe the current areas of research and potential strategies for personalization of therapy.

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“… 6 , 7 More recently, in a first-line setting, pembrolizumab, a programmed death-1 monoclonal antibody, was not superior in combination with chemotherapy compared with chemotherapy alone for OS in both PD-L1 combined positive score (CPS) ⩾1 and CPS ⩾10 in the KEYNOTE-062 study. 8 In contrast, nivolumab plus chemotherapy significantly improved OS and progression-free survival (PFS) compared with chemotherapy alone in HER2-negative or HER2-unknown patients with CPS ⩾5 in the CheckMate 649 study. 9 Moreover, OS was also prolonged in patients with CPS ⩾1 for all enrolled patients.…”

Section: Introductionmentioning

confidence: 99%

Trastuzumab deruxtecan for the treatment of patients with HER2-positive gastric cancer

Kotani

Shitara

2021

Ther Adv Med Oncol

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Trastuzumab deruxtecan (T-DXd) is a novel anti-human epidermal growth factor receptor 2 (HER2) antibody–drug conjugate composed of a monoclonal anti-HER2 antibody and a topoisomerase I inhibitor, DX-8951 derivative (an exatecan derivative). T-DXd showed potential anti-tumor activities in HER2-positive gastric cancer cell lines and xenograft models. In the randomized, phase II trial DESTINY-Gastric01, T-DXd demonstrated a significantly higher objective response rate as a primary endpoint and a longer overall survival as a secondary endpoint in patients with pretreated HER2-positive advanced gastric cancer (AGC). Although adverse events caused by T-DXd were generally manageable, approximately 10% of patients experienced treatment-related interstitial lung disease. Based on the results of the DESTINY-Gastric01 trial, T-DXd was approved for HER2-positive pretreated AGC in Japan. This study reviews the preclinical and clinical data of T-DXd for treating HER2-positive gastric cancer.

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Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer

Cited by 804 publications

References 28 publications

The integration of immune checkpoint inhibitors with VEGF targeted agents in advanced gastric and gastroesophageal adenocarcinoma: a review on the rationale and results of early phase trials

The integration of immune checkpoint inhibitors with VEGF targeted agents in advanced gastric and gastroesophageal adenocarcinoma: a review on the rationale and results of early phase trials

Towards Personalization in the Curative Treatment of Gastric Cancer

Trastuzumab deruxtecan for the treatment of patients with HER2-positive gastric cancer

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