Kohei Shitara1, Hiroji Iwata2, Shunji Takahashi3, Kenji Tamura4, Haeseong Park5, Shanu Modi6, Junji Tsurutani7, Shigenori Kadowaki2, Kensei Yamaguchi3, Satoru Iwasa4, Kaku Saito8, Yoshihiko Fujisaki8, Masahiro Sugihara9, Javad Shahidi10, Toshihiko Doi11. 1. Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. Electronic address: kshitara@east.ncc.go.jp. 2. Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan. 3. Department of Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan. 4. Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan. 5. Department of Medicine, Washington University School of Medicine, St Louis, MO, USA. 6. Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 7. Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan; Department of Medical Oncology, Advanced Cancer Translational Research Institute, Showa University, Tokyo, Japan. 8. Research and Development, Daiichi Sankyo Co, Ltd, Tokyo, Japan. 9. Biostatistics and Data Management, Daiichi Sankyo Co, Ltd, Tokyo, Japan. 10. Research and Development, Daiichi Sankyo, Inc, Basking Ridge, NJ, USA. 11. Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
Abstract
BACKGROUND: Trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanised anti-HER2 antibody, cleavable peptide-based linker, and topoisomerase I inhibitor payload. A phase 1, non-randomised, open-label, multiple-dose study was done to assess the safety, tolerability, and activity of trastuzumab deruxtecan in HER2-expressing advanced solid tumours. The dose escalation (part 1) has previously been reported and the recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg were established. In this Article, we report the safety and preliminary activity results from this phase 1 trial in all patients with HER2-positive gastric or gastro-oesophageal junction cancer who received trastuzumab deruxtecan at the recommended doses for expansion. METHODS: This was an open-label, dose-escalation and dose-expansion phase 1 trial done at eight hospitals and clinics in the USA and six in Japan. Eligible patients were at least 18 years old in the USA and at least 20 years old in Japan and had advanced solid tumours (regardless of HER2 expression in dose escalation or HER2 expression or mutation in dose expansion). The recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg trastuzumab deruxtecan were administered intravenously to patients once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. In this Article, all patients with HER2-positive gastric or gastro-oesophageal junction cancer with previous trastuzumab treatment who received trastuzumab deruxtecan were analysed together. The primary endpoints of the study were safety and preliminary activity (proportion of patients who achieved an objective response as assessed by the investigators). The activity evaluable set included all patients who received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion, and for whom both baseline and post-treatment activity data were available. The safety analysis set included all patients who received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion. Enrolment for patients with gastric or gastro-oesophageal junction cancer has completed. This trial is registered at ClinicalTrials.gov, number NCT02564900, and ClinicalTrials.jp, number JapicCTI-152978. FINDINGS: Between Aug 28, 2015, and Aug 10, 2018, 44 patients with HER2-positive gastric or gastro-oesophageal junction cancer received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion. All patients had at least one treatment-emergent adverse event. The most frequent grade 3 or worse treatment-emergent adverse events included anaemia (13 [30%]) and decreases in neutrophil (nine [20%]), platelet (eight [18%]), and white blood cell (seven [16%]) counts. Serious treatment-emergent adverse events occurred in 11 (25%) patients. There were four pneumonitis cases (three grade 2 and one grade 3). There were no drug-related deaths due to treatment-emergent adverse events. 19 (43·2%; 95% CI 28·3-59·0) of 44 patients had a confirmed objective response. INTERPRETATION: Trastuzumab deruxtecan had a manageable safety profile and showed preliminary activity in heavily pretreated patients with HER2-positive gastric or gastro-oesophageal junction cancer. These results support further investigation of trastuzumab deruxtecan for HER2-positive gastric or gastro-oesophageal junction cancer post-trastuzumab. FUNDING: Daiichi Sankyo Co, Ltd.
BACKGROUND:Trastuzumabderuxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanised anti-HER2 antibody, cleavable peptide-based linker, and topoisomerase I inhibitor payload. A phase 1, non-randomised, open-label, multiple-dose study was done to assess the safety, tolerability, and activity of trastuzumabderuxtecan in HER2-expressing advanced solid tumours. The dose escalation (part 1) has previously been reported and the recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg were established. In this Article, we report the safety and preliminary activity results from this phase 1 trial in all patients with HER2-positive gastric or gastro-oesophageal junction cancer who received trastuzumabderuxtecan at the recommended doses for expansion. METHODS: This was an open-label, dose-escalation and dose-expansion phase 1 trial done at eight hospitals and clinics in the USA and six in Japan. Eligible patients were at least 18 years old in the USA and at least 20 years old in Japan and had advanced solid tumours (regardless of HER2 expression in dose escalation or HER2 expression or mutation in dose expansion). The recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg trastuzumabderuxtecan were administered intravenously to patients once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. In this Article, all patients with HER2-positive gastric or gastro-oesophageal junction cancer with previous trastuzumab treatment who received trastuzumabderuxtecan were analysed together. The primary endpoints of the study were safety and preliminary activity (proportion of patients who achieved an objective response as assessed by the investigators). The activity evaluable set included all patients who received at least one dose of trastuzumabderuxtecan at the recommended doses for expansion, and for whom both baseline and post-treatment activity data were available. The safety analysis set included all patients who received at least one dose of trastuzumabderuxtecan at the recommended doses for expansion. Enrolment for patients with gastric or gastro-oesophageal junction cancer has completed. This trial is registered at ClinicalTrials.gov, number NCT02564900, and ClinicalTrials.jp, number JapicCTI-152978. FINDINGS: Between Aug 28, 2015, and Aug 10, 2018, 44 patients with HER2-positive gastric or gastro-oesophageal junction cancer received at least one dose of trastuzumabderuxtecan at the recommended doses for expansion. All patients had at least one treatment-emergent adverse event. The most frequent grade 3 or worse treatment-emergent adverse events included anaemia (13 [30%]) and decreases in neutrophil (nine [20%]), platelet (eight [18%]), and white blood cell (seven [16%]) counts. Serious treatment-emergent adverse events occurred in 11 (25%) patients. There were four pneumonitis cases (three grade 2 and one grade 3). There were no drug-related deaths due to treatment-emergent adverse events. 19 (43·2%; 95% CI 28·3-59·0) of 44 patients had a confirmed objective response. INTERPRETATION:Trastuzumabderuxtecan had a manageable safety profile and showed preliminary activity in heavily pretreated patients with HER2-positive gastric or gastro-oesophageal junction cancer. These results support further investigation of trastuzumabderuxtecan for HER2-positive gastric or gastro-oesophageal junction cancer post-trastuzumab. FUNDING: Daiichi Sankyo Co, Ltd.
Authors: Giandomenico Roviello; Giuseppe Aprile; Alberto D'Angelo; Luigi Francesco Iannone; Franco Roviello; Karol Polom; Enrico Mini; Martina Catalano Journal: Gastric Cancer Date: 2021-03-19 Impact factor: 7.370
Authors: Virginia S Hahn; Kathleen W Zhang; Lova Sun; Vivek Narayan; Daniel J Lenihan; Bonnie Ky Journal: Circ Res Date: 2021-05-13 Impact factor: 17.367