Browsing by Author "Doi, Toshihiko"

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    Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study
    (Springer Nature, 2019-07) Bang, Yung-Jue; Kang, Yoon-Koo; Catenacci, Daniel V.; Muro, Kei; Fuchs, Charles S.; Geva, Ravit; Hara, Hiroki; Golan, Talia; Garrido, Marcelo; Jalal, Shadia I.; Borg, Christophe; Doi, Toshihiko; Yoon, Harry H.; Savage, Mary J.; Wang, Jiangdian; Dalal, Rita P.; Shah, Sukrut; Wainberg, Zev A.; Chung, Hyun Cheol; Medicine, School of Medicine
    BACKGROUND: The multicohort, phase II, nonrandomized KEYNOTE-059 study evaluated pembrolizumab ± chemotherapy in advanced gastric/gastroesophageal junction cancer. Results from cohorts 2 and 3, evaluating first-line therapy, are presented. METHODS: Patients ≥ 18 years old had previously untreated recurrent or metastatic gastric/gastroesophageal junction adenocarcinoma. Cohort 3 (monotherapy) had programmed death receptor 1 combined positive score ≥ 1. Cohort 2 (combination therapy) received pembrolizumab 200 mg on day 1, cisplatin 80 mg/m2 on day 1 (up to 6 cycles), and 5-fluorouracil 800 mg/m2 on days 1-5 of each 3-week cycle (or capecitabine 1000 mg/m2 twice daily in Japan). Primary end points were safety (combination therapy) and objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by central review, and safety (monotherapy). RESULTS: In the combination therapy and monotherapy cohorts, 25 and 31 patients were enrolled; median follow-up was 13.8 months (range 1.8-24.1) and 17.5 months (range 1.7-20.7), respectively. In the combination therapy cohort, grade 3/4 treatment-related adverse events occurred in 19 patients (76.0%); none were fatal. In the monotherapy cohort, grade 3-5 treatment-related adverse events occurred in seven patients (22.6%); one death was attributed to a treatment-related adverse event (pneumonitis). The objective response rate was 60.0% [95% confidence interval (CI), 38.7-78.9] (combination therapy) and 25.8% (95% CI 11.9-44.6) (monotherapy). CONCLUSIONS: Pembrolizumab demonstrated antitumor activity and was well tolerated as monotherapy and in combination with chemotherapy in patients with previously untreated advanced gastric/gastroesophageal junction adenocarcinoma.
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    Safety and Antitumor Activity of the Anti–Programmed Death-1 Antibody Pembrolizumab in Patients With Advanced Esophageal Carcinoma
    (ASCO, 2018-01) Doi, Toshihiko; Piha-Paul, Sarina A.; Jalal, Shadia I.; Saraf, Sanatan; Lunceford, Jared; Lunceford, Minori; Bennouna, Jaafar; Medicine, School of Medicine
    Purpose The anti–programmed death-1 antibody pembrolizumab was evaluated in KEYNOTE-028, a multicohort, phase IB study of patients with programmed death ligand-1 (PD-L1)–positive advanced solid tumors. Results from the esophageal carcinoma cohort are reported herein. Patients and Methods Eligible patients with squamous cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction in whom standard therapy failed and who had PD-L1–positive tumors received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed disease progression or intolerable toxicity. Response was assessed every 8 weeks up to 6 months and every 12 weeks thereafter. Primary end points were safety and overall response rate, determined by investigator review per Response Evaluation Criteria in Solid Tumors (version 1.1). Results Among 83 patients with esophageal carcinoma and samples evaluable for PD-L1 expression, 37 (45%) had PD-L1–positive tumors, and 23 were enrolled. Median age was 65 years; 78% had squamous histology; and 87% received ≥ two prior therapies for advanced/metastatic disease. As of the data cutoff (February 20, 2017), median follow-up was 7 months (range, 1 to 33 months). Nine patients (39%) experienced treatment-related adverse events, most commonly decreased appetite, decreased lymphocyte count, generalized rash, and rash (two patients [9%] each). No grade 4 adverse events or deaths were attributed to pembrolizumab. Overall response rate was 30% (95% CI, 13% to 53%); median duration of response was 15 months (range, 6 to 26 months). A six-gene interferon-γ gene expression signature analysis suggested that delayed progression and increased response occur among pembrolizumab-treated patients with higher interferon-γ composite scores. Conclusion Pembrolizumab demonstrated manageable toxicity and durable antitumor activity in patients with heavily pretreated, PD-L1–positive advanced esophageal carcinoma.