FDA Grants Trastuzumab Deruxtecan Breakthrough Designation in HER2+ Gastric Cancer

The FDA has granted a breakthrough therapy designation to fam-trastuzumab deruxtecan-nxki for the treatment of patients with HER2-positive unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma.

The FDA has granted a breakthrough therapy designation to fam-trastuzumab deruxtecan-nxki (Enhertu) for the treatment of patients with HER2-positive unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received 2 or more prior regimens including trastuzumab (Herceptin).1

The designation, which will expedite the development and review of trastuzumab deruxtecan in this setting, is supported by findings from the phase 2 DESTINY-Gastric01 trial,2 along with data from a phase 1 study. In the DESTINY-Gastric01 trial, trastuzumab deruxtecan improved overall survival (OS) versus chemotherapy in patients with heavily pretreated unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) cancer.Patients enrolled on the trial had tumors that progressed after at least 2 treatment regimens, including trastuzumab (Herceptin) and chemotherapy.

The antibody-drug conjugate trastuzumab deruxtecan also met the primary end point of the trial by inducing a clinically meaningful improvement in objective response rate (ORR) versus chemotherapy. The full results of the study are scheduled to be presented at the 2020 American Society of Clinical Oncology Annual Meeting.

“For patients with HER2 positive metastatic gastric cancer, current therapy options are limited, and for those who progress, there no approved HER2 targeted medicines,” José Baselga, MD, PhD, executive vice president, Oncology R&D, AstraZeneca, which codevelops trastuzumab deruxtecan with Daiichi Sankyo Company, stated in a press release. “We look forward to working with the FDA to further explore the potential of Enhertu to become an important new treatment and the first antibody drug conjugate for this devastating disease.”

The open-label, multicenter phase 2 DESTINY-Gastric01 trial included 189 Japanese and South Korean patients with HER2-expressing (IHC3+ or IHC2+/ISH+) advanced gastric/GEJ adenocarcinoma with progression on at least 2 prior regimens, including trastuzumab and 5-FU and platinum chemotherapy. In a 2:1 randomization, patients received either trastuzumab deruxtecan at 6.4 mg/kg once every 3 weeks or physician’s choice of paclitaxel or irinotecan monotherapy on the same schedule. Beyond the ORR primary end point, secondary outcome measures included OS, progression-free survival (PFS), duration of response, disease control rate, time to treatment failure, and safety/pharmacokinetics.

Data from the phase 1 trial included in the sNDA showed that trastuzumab deruxtecan induced a confirmed ORR of 43.2% (n = 19) and a disease control rate (DCR) of 79.5% among 44 evaluable patients with HER2-positive gastric/GEJ cancer.3 Among 24 patients who received prior irinotecan treatment, the ORR and DCR were 41.7% (n = 10) and 79.2%, respectively.

Patients received trastuzumab deruxtecan at a dose of 5.4 mg/kg or 6.4 mg/kg. The median patient age was 68 years, 73.3% had an ECOG performance status of 0, and 26.7% had an ECOG performance status of 1.

HER2 expression per IHC was 3+ in 82% of patients and 2+ in 18% of patients. More than one-fourth (26.7%) of patients had received 5 or more prior anticancer regimens. All patients had prior trastuzumab. The median number of prior lines of therapy was 3.

At the data cutoff, the median OS was 12.8 months, the median PFS was 5.6 months, and the median duration of response was 7.0 months. The vast majority (80%) of patients experienced tumor shrinkage.

Most treatment-emergent adverse events (TEAEs) were grade 3 or lower. The most common (≥5%) grade 3 nonhematologic AEs included decreased appetite (7%), hypokalemia (7%), hyponatremia (7%), and cholangitis (5%). Grade 4 nonhematologic TEAEs included 2 cases of grade 4 hypokalemia.

Grade 3 hematologic TEAEs included anemia (30%), decreased platelet count (14%), decreased WBC count (11%), decreased neutrophil count (16%), and decreased lymphocyte count (9%). Grade 4 hematologic TEAEs included 2 cases each of grade 4 decreased platelet count, decreased WBC count, and decreased neutrophil count.

Drug-related TEAEs led to treatment discontinuation in 5 patients: pneumonitis (n = 3), decreased appetite (n = 1), and decreased platelet count (n = 1).

Trastuzumab deruxtecan is currently approved by the FDA for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received ≥2 prior anti–HER2-based regimens in the metastatic setting


  1. ENHERTU® Granted Breakthrough Therapy Designation in the U.S. for HER2 Positive Metastatic Gastric Cancer. https://bit.ly/2AjGb2D. Published May 11, 2020. Accessed May 11, 2020.
  2. Phase II DESTINY-Gastric01 trial of Enhertu versus chemotherapy met primary endpoint [news release]. AstraZeneca; January 27, 2020. bit.ly/37HPmG1. Accessed January 27, 2020.
  3. Shitara K, Iwata H, Takahashi S, et al. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study. Lancet Oncol. 2019;20(6):827-836. doi: 10.1016/S1470-2045(19)30088-9.