Multicenter phase II study of trastuzumab with S-1 plus oxaliplatin for chemotherapy-naïve, HER2-positive advanced gastric cancer

Takahari, Daisuke; Chìn, Keisho; Ishizuka, Naoki; Takashima, Atsuo; Minashi, Keiko; Kadowaki, Shigenori; Nishina, Tomohiro; Nakajima, Takako Eguchi; Amagai, Kenji; Machida, Nozomu; Goto, Masahiro; Taku, Keisei; Wakatsuki, Takeru; Shoji, Hirokazu; Hironaka, Shuichi; Boku, Narikazu; Yamaguchi, Kensei

doi:10.1007/s10120-019-00973-5

Cited by 35 publications

(56 citation statements)

References 20 publications

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“…Three phase II studies that assessed the combination of trastuzumab with capecitabine plus oxaliplatin reported a median OS, a median PFS, and an ORR of 13.8 to 21.0 months, 7.1 to 9.8 months, and 46.7% to 67.3%, respectively [8][9][10]. Trastuzumab in combination with S-1 plus oxaliplatin was also shown to provide a similar treatment outcome in a phase II study, with a median OS, a median PFS, and an ORR of 18.1 months, 8.8 months, and 70.7%, respectively [11]. A meta-analysis of data from these trials revealed that S-1 or oxaliplatin can substitute effectively for capecitabine or 5-FU or for cisplatin, respectively [12].Immune checkpoint inhibitors such as antibodies to programmed cell death-1 (PD-1) have recently revolutionized treatment strategies for advanced cancer.…”

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confidence: 85%

Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

Mitani

Kawakami

2020

Cancers

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Trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), has improved survival in patients with HER2-positive advanced gastric or gastroesophageal junction cancer (AGC). The inevitable development of resistance to trastuzumab remains a problem, however, with several treatment strategies that have proven effective in breast cancer having failed to show clinical benefit in AGC. In this review, we summarize the mechanisms underlying resistance to HER2-targeted therapy and outline past and current challenges in the treatment of HER2-positive AGC refractory to trastuzumab. We further describe novel agents such as HER2 antibody-drug conjugates that are under development and have shown promising antitumor activity in early studies. basis of these results, trastuzumab was approved for AGC with a high HER2 expression level, and trastuzumab-containing regimens are now a standard option for the first-line treatment of such patients, who accounted for 7% to 17% of all individuals with gastric cancer [3-5]. Derivatives of the ToGA Regimen in the First-Line SettingThe ToGA trial adopted a regimen of cisplatin combined with either 5-fluorouracil (5-FU) or capecitabine, whereas subsequent prospective studies found similar treatment outcomes with regimens containing oxaliplatin or tegafur-gimeracil-oteracil (S-1). In a single-arm, nonrandomized phase II trial (HER2-based strategy in stomach cancer (HERBIS)-1) performed in Japan [6], trastuzumab in combination with S-1 plus cisplatin yielded a confirmed ORR of 68%, with a median OS and a median PFS of 16.0 and 7.8 months, respectively, in HER2-positive AGC patients with measurable lesions, with these results being similar to those of the ToGA trial [2]. Similar efficacy was also apparent in AGC patients without measurable lesions (HERBIS-1B study) [7]. Three phase II studies that assessed the combination of trastuzumab with capecitabine plus oxaliplatin reported a median OS, a median PFS, and an ORR of 13.8 to 21.0 months, 7.1 to 9.8 months, and 46.7% to 67.3%, respectively [8][9][10]. Trastuzumab in combination with S-1 plus oxaliplatin was also shown to provide a similar treatment outcome in a phase II study, with a median OS, a median PFS, and an ORR of 18.1 months, 8.8 months, and 70.7%, respectively [11]. A meta-analysis of data from these trials revealed that S-1 or oxaliplatin can substitute effectively for capecitabine or 5-FU or for cisplatin, respectively [12].Immune checkpoint inhibitors such as antibodies to programmed cell death-1 (PD-1) have recently revolutionized treatment strategies for advanced cancer. Given that trastuzumab was found to stimulate T cell responses [13], the combination of trastuzumab-containing regimens with antibodies to PD-1 is receiving attention. A phase II study including 37 patients with HER2-positive AGC treated in the first-line setting with capecitabine, oxaliplatin, and trastuzumab in combination with the anti-PD-1 antibody pembrolizumab reported an ORR of 83%, with a median PFS of 11.4 months and a median ...

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confidence: 85%

Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

Mitani

Kawakami

2020

Cancers

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“…Similarly, trastuzumab's incorporation into chemotherapy as first-line therapy significantly improved the clinical outcome of HER2-positive GC patients. Several clinical studies have reported that the median progression-free survival and mOS lengths of patients with HER2-positive GC ranged from 7.1 to 9.2 months and 13.8 to 19.5 months with first-line treatment, respectively (6)(7)(8)(9). However, the role of trastuzumab as a second-line therapy remains unclear (10).…”

Section: Discussionmentioning

confidence: 99%

Effective treatment of apatinib for chemotherapy‑refractory advanced gastric carcinoma with AFP‑secretion and HER2‑positivity: A case report

Ding

2021

Mol Clin Oncol

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α-fetoprotein (AFP)-secreting gastric cancer (AFP-GC) is a relatively rare, aggressive malignancy among all GC types. However, no GC case with simultaneous expression of AFP and epidermal growth factor receptor 2 (HER2) has been reported to date. To the best of our knowledge, the present report was the first to describe the use of apatinib to treat a patient with advanced GC characterized by AFP-secretion and HER2-positivity. An 86-year-old man with advanced GC was diagnosed with AFP-secretive and HER2-positive GC with liver metastasis at The Affiliated Hospital of Jiujiang University (Jiujiang, China). The patient received first-line (i.e., S-1 plus oxaliplatin) and second-line (i.e., docetaxel) chemotherapy combined with trastuzumab for two cycles, respectively. However, the disease progressed rapidly. Subsequently, apatinib was administered as third-line therapy. After two cycles of apatinib therapy, the patient reported the disappearance of upper abdominal pain and an improvement in his appetite. Furthermore, the AFP level had sharply decreased to 620 ng/ml. Subsequently, upper abdominal computed tomography imaging revealed that the gastric lesion and liver metastatic lesion had reduced in size by 67% and 24%, respectively, suggesting partial remission. Currently, the patient has continued to receive apatinib therapy. It was speculated that AFP-secretion status could contribute to the chemoresistance of HER2-positive GC. Apatinib may be a promising anticancer agent in the case of advanced AFP-producing and HER2-positive GC.

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“…Two-Phase II and one retrospective study evaluating the results of Trastuzumab treatment in different chemotherapy regimens in HER2-positive advanced gastric cancer reported similar results to TOGA. [5,[32][33][34] It was thought that early diagnosis and treatment would be beneficial in patients with HER2 overexpression to improve the lower survival rates obtained in the case of increased HER2 expression.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of HER2 overexpression, clinicopathological characteristics, and factors affecting survival in gastric cancer

2021

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G astric cancer is one of the leading causes of cancer-related death worldwide. Around 1 million people are diagnosed with gastric cancer each year, making gastric cancer the seventh most common cancer worldwide. The cumulative risk of developing stomach cancer from birth to the age of 74 is estimated to be 1.87% in men and 0.79% in women. According to GLOBOCAN 2018 statistics, gastric cancer is the sixth most common cancer in Turkey with an incidence of 12.5/100.000 individuals (17.6 for men and 4.8 for women). [1] Objectives: The objective of the study was to evaluate the human epidermal growth factor receptor 2 (HER2) overexpression, clinicopathological features, and factors affecting survival in patients with gastric cancer. Methods:The study is a retrospective study conducted with 128 cases of gastric cancer who were admitted to Şişli Hamidiye Etfal Training and Research Hospital between 2005 and 2012. Patients' demographic characteristics, performance score, tumor localization, information about surgery, HER2 measurements, histopathological characteristics, stage, treatment features, metastasis sites, and overall survival time were obtained from medical records. Immunohistochemical analysis was performed for HER2 scoring. Results: There were 89 (69.5%) men and 39 (30.5%) women in the study group, and the median age of the patients was 64 years. The median survival time of the patients was 24.43 months. The survival rate of the patients was calculated as 35.4±5.9%. Overall survival time was found to be shorter in the group with higher HER2 levels and also those with advanced-stage cancer. The survival rate was found to be significantly lower in patients with perineural invasion and advanced stage. However, the survival rate was not associated with lymphovascular invasion, surgical margin involvement, and HER2 levels. In the multivariate Cox Regression analysis performed to assess the effects of gender, histological subtype, stage, and surgical margin on overall survival, disease stage was found to be the only factor effective on survival. Gender, histological subtype, and the surgical margin did not affect prognosis. Conclusion:The survival rate in gastric cancers was found to be lower in those with advanced-stage disease. Higher HER2 level and the disease stage were associated with shorter overall survival time.

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Multicenter phase II study of trastuzumab with S-1 plus oxaliplatin for chemotherapy-naïve, HER2-positive advanced gastric cancer

Cited by 35 publications

References 20 publications

Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

Effective treatment of apatinib for chemotherapy‑refractory advanced gastric carcinoma with AFP‑secretion and HER2‑positivity: A case report

Evaluation of HER2 overexpression, clinicopathological characteristics, and factors affecting survival in gastric cancer

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