Subgroup analyses of the safety and efficacy of ramucirumab in Japanese and Western patients in RAINBOW: a randomized clinical trial in second-line treatment of gastric cancer

Shitara, Kohei; Muro, Kei; Shimada, Yasuhiro; Hironaka, Shuichi; Sugimoto, Naotoshi; Komatsu, Yoshito; Nishina, Tomohiro; Yamaguchi, Kensei; Segawa, Yoshihiko; Omuro, Yasushi; Tamura, Takao; Doi, Toshihiko; Yukisawa, Seigo; Yasui, Hirofumi; Nagashima, Fumio; Gotoh, Masahiro; Esaki, Taito; Emig, Michael; Chandrawansa, Kumari; Liepa, Astra M.; Wilke, H.; Ichimiya, Yukako; Ohtsu, Atsushi

doi:10.1007/s10120-015-0559-z

Cited by 72 publications

(54 citation statements)

References 19 publications

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“…Multiple randomized trials have shown negative results for agents targeting EGFR, VEGF, MTOR, and hedgehog. To date, only two biologic therapies have been shown to improve overall survival in these patients: trastuzumab, a monoclonal antibody (mAb) targeting human epidermal growth factor 2 (HER2, ERBB2), and ramucirumab, a mAb targeting vascular endothelial growth factor receptor 2 (VEGFR2) (12)(13)(14)(15)(16)(17).…”

Section: Review Articlementioning

confidence: 99%

The promise of PD-1 inhibitors in gastro-esophageal cancers: microsatellite instability vs. PD-L1

Jin

Yoon

2016

J. Gastrointest. Oncol.

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Preliminary clinical studies of anti-programmed cell death-1 (anti-PD-1) therapy in gastroesophageal cancers have suggested promising single-agent activity. In patients who received prior treatment for advanced disease, pembrolizumab has been associated with a response rate of 20% in programmed cell death-1 ligand 1 (PD-L1)-positive tumors, and nivolumab with a response rate of 12% in unselected tumors.Both agents yielded a median duration of response lasting ~6-7 months. PD-L1 expression and microsatellite instability (MSI) have emerged as potential predictive markers for PD-1/PD-L1 blockade. PD-L1 expression in tumor cells and in immune cells within the tumor microenvironment has been detected in 14-24% and ~35% of patients with gastro-esophageal cancer, respectively. PD-L1 tumor cell expression appears to be more common in Epstein-Barr virus (EBV)-positive gastric cancers (GCs) and has been associated with an increased density of tumor-infiltrating lymphocytes (TIL). To date, data are too sparse to determine whether PD-L1 expression predicts efficacy of anti-PD-1 therapy in gastro-esophageal cancer, but data from other tumor types have not been consistent regarding its predictive value. MSI occurs in 10-20% of gastro-esophageal cancers and arises from deficient mismatch repair (MMR). MSI is highly correlated with non-synonymous mutation burden, as well as a dense accumulation of TILs. MSI has been associated with improved response to anti-PD-1 therapy in gastrointestinal cancers. Multiple studies are ongoing which examine therapeutic blockade of the PD-1/PD-L1 axis in unselected patients with gastro-esophageal cancer, as well as patients whose tumors express PD-L1 or exhibit MSI. These studies will clarify their activity in this disease and potentially can determine whether identify a strong predictive biomarker can be identified.Checkpoint inhibition is also being studied in combination with curative-intent chemo (radio) therapy and surgery.Keywords: Programmed cell death-1 (PD-1); programmed cell death-1 ligand 1 (PD-L1); gastro-esophageal cancer; microsatellite instability (MSI)

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Section: Review Articlementioning

confidence: 99%

The promise of PD-1 inhibitors in gastro-esophageal cancers: microsatellite instability vs. PD-L1

Jin

Yoon

2016

J. Gastrointest. Oncol.

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“…The incidence of gastric cancer in Japan was 131 893 in 2013, with 45 531 deaths from this disease in 2016 . Disparity in survival outcomes between patients from East Asia, including Japan, compared with those from the rest of the world has been observed in several clinical trials in advanced gastric cancer . For example, exploratory analyses from the AVAGAST study, a randomized phase III trial examining the addition of bevacizumab to capecitabine plus cisplatin in first‐line advanced gastric cancer, showed longer overall survival in patients from Asia (11.6‐14.1 months) compared with those from Eastern Europe/South America (7.3 months) or the USA/Western Europe (9.1 months) .…”

Section: Introductionmentioning

confidence: 99%

Efficacy of trastuzumab emtansine in Japanese patients with previously treated HER2‐positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma: A subgroup analysis of the GATSBY study

Shitara

Honma

Omuro

et al. 2019

Asia-Pac J Clncl Oncology

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Aim:The phase II/III GATSBY study (NCT01641939) showed that trastuzumab emtansine did not have an efficacy benefit over taxane in patients with previously treated, human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic gastric or gastroesophageal junction cancer. We evaluated patients from Japanese centers within GATSBY.Methods: In stage one, patients (randomized 2:2:1) received trastuzumab emtansine 3.6 mg/kg every 3 weeks, trastuzumab emtansine 2.4 mg/kg weekly, or physician's choice of taxane (docetaxel 75 mg/m 2 every 3 weeks or paclitaxel 80 mg/m 2 weekly). In stage two, patients (randomized 2:1) received trastuzumab emtansine 2.4 mg/kg weekly or taxane. Eligible patients had centrally assessed HER2-positive disease and progression during or after first-line therapy.Primary endpoint was overall survival. We present the 2.4 mg/kg weekly data.Results: Eighty-two patients were randomized (intention-to-treat: 48 to trastuzumab emtansine 2.4 mg/kg weekly, 23 to taxane; September 2012-August 2014) at 19 sites. Median overall survival was 11.8 months (95% confidence interval [CI],.3) with trastuzumab emtansine 2.4 mg/kg weekly and 10.0 months (95% CI, 7.1-18.2) with taxane (unstratified hazard ratio = 0.94, 95% CI, 0.52-1.72). Trastuzumab emtansine 2.4 mg/kg weekly, versus taxane, was associated with fewer grade ≥3 adverse events (AEs; 52.1% vs 68.2%) and serious AEs (14.6% vs 18.2%). There were no fatal AEs.Asia-Pac J Clin Oncol. 2020;16:5-13. c

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“…The Trastuzumab for Gastric Cancer (ToGA) trial revealed that trastuzumab, a recombinant monoclonal antibody against HER2 (also known as ERBB2), combined with fluoropyrimidine plus cisplatin provided a significant survival advantage compared with fluoropyrimidine plus cisplatin alone in patients with HER2-positive advanced GC [29,47,48] . The ramucirumab for patients with previously treated advanced gastric or gastro-esophageal junction [25,26,56,63] adenocarcinoma (RAINBOW) trial showed that the combination of ramucirumab and paclitaxel significantly improved overall survival compared with placebo plus paclitaxel and that this combination could be regarded as a new standard second-line chemotherapy for patients with advanced GC [49,50] .…”

Section: Current Treatment Of Gc and The Potential For Targeting Gcscsmentioning

confidence: 99%

Therapeutic targets against gastric cancer stem cells interacting with tumor microenvironment

Uchihara¹,

Ishimoto²,

Yonemura³

et al. 2018

JCMT

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Gastric cancer (GC) is a major cause of cancer-related deaths worldwide. The existence of cancer stem cells (CSCs) is known to be the main reason for resistance to anticancer agents as well as for the development of distant metastases. Although CSCs themselves harbor self-renewal and differentiation abilities, the tumor microenvironment that surrounds CSCs provides secreted factors and supports angiogenesis and is thus responsible for the maintenance of their CSC properties. The current review provides information regarding the impact of the tumor microenvironment on gastric CSCs, which will support the development of novel therapeutic strategies for targeting gastric CSCs.

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Subgroup analyses of the safety and efficacy of ramucirumab in Japanese and Western patients in RAINBOW: a randomized clinical trial in second-line treatment of gastric cancer

Cited by 72 publications

References 19 publications

The promise of PD-1 inhibitors in gastro-esophageal cancers: microsatellite instability vs. PD-L1

The promise of PD-1 inhibitors in gastro-esophageal cancers: microsatellite instability vs. PD-L1

Efficacy of trastuzumab emtansine in Japanese patients with previously treated HER2‐positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma: A subgroup analysis of the GATSBY study

Therapeutic targets against gastric cancer stem cells interacting with tumor microenvironment

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