FDA Grants Breakthrough Therapy Designation to Trastuzumab Deruxtecan in HER2+ Gastric Cancer

Trastuzumab deruxtecan received Breakthrough Therapy Designation for the treatment of patients with HER2-positive unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma who have received two or more prior regimens including trastuzumab.

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, announced AstraZeneca and Daiichi Sankyo, in a press release.1

“Current therapy options are limited for patients with HER2-positive metastatic gastric cancer and for those who relapse, there are no approved HER2-targeted medicines. 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,” José Baselga, executive vice president, R&D Oncology, stated.

This designation was influenced by data from the phase II DESTINY-Gastric01 trial and the phase I DESTINY-Gastric01 trial. The phase II results showed a statistically significant and clinically meaningful improvement in the objective response rate, as well as overall survival (OS), which are the primary and secondary end points of the study, respectively. The activity of trastuzumab deruxtecan was compared to the investigator’s choice of irinotecan or paclitaxel monotherapy.

The safety profile was consistent with the profile observed in the phase I study. The most common adverse events (AEs) included neutrophil count decrease, anemia, nausea, and decreased appetite. Cases of drug-related interstitial lung disease (ILD) and pneumonitis occurred but were predominantly grade 1/2 in severity, except for 2 patients who experienced grade 3/4 events. No cases of ILD led to death in either study.

The full results from the phase II study will be presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Annual Meeting.

The phase I data were published in the Lancet Oncology and reported preliminary activity with a manageable safety profile. At least 1 dose of trastuzumab deruxtecan was given to 274 patients in the study, of whom 44 had HER2-positive disease. A total of 19 patients received the 5.4mg/kg dose of trastuzumab deruxtecan, and 25 patients received the 6.4 mg/kg dose. Treatment lasted for a median duration of 4.4 months (range, 2.5-8.2).2

After a median follow up of 5.5 months (range, 2.8-13.1), 19 out of 44 patients achieved an objective response (43.2%; 95% CI, 28.3-59.0), with disease control in 33 patients (79.5%, 64.7-90.2). The median time to response was 1.4 months (95% CI 1.3-1.6), and the response lasted for a median duration of 7.0 months (range, 4.4-16.6).

In terms of survival, a 5.6-month median progression-free survival (PFS) was achieved with trastuzumab deruxtecan (range, 3.0-8.3). The median OS was 12.8 months at data cutoff (95% CI not estimable, range 1.4-25.4 [with censoring]). Objective responses were observed more so at the lower dose level of trastuzumab deruxtecan than the higher dose level. Specifically, 6 patients who received the 6.4 mg/kg dose achieved an objective response, whereas 19 patients who received the 5.4mg/kg dose achieved an objective response. Eighty percent of patients in the study (n = 35) also displayed tumor shrinkage first 6-week postbaseline tumor assessment.

At least 1 treatment-emergent AE of any grade was seen in each patient in the study. In 28 patients (64%), at least one grade 3 or higher treatment-emergent AE was observed and 48% of them were determined to be drug related. At least 1 serious treatment-emergent AE also occurred in every patient and of these, 9% were considered drug related. The most commonly seen grade 3 or higher treatment-emergent AEs included anemia (30%), neutrophil decrease (20%), platelet count decrease (18%), and white blood cell decrease (16%) counts.

In the open-label, dose-escalation, and dose-expansion phase I trial, the 2 recommended doses of trastuzumab deruxtecan were administered once every 3 weeks until a withdrawal of consent, unacceptable toxicity, or progressive disease. The co-primary end points include the number of patients with AEs and tumor response.

As of the time these data were published, the study had completed enrollment of patients with gastric or gastro-oesophageal junction cancer.

In the phase II multicenter, open-label study, trastuzumab deruxtecan will be evaluated against 3 other arms to determine efficacy, which is defined as the percentage of randomized participants with objective response. The other secondary end points of the study are OS, duration of response, disease control rate, and time to treatment failure.

“DESTINY-Gastric01 represents the first randomized trial of Enhertu to demonstrate clinically meaningful and statistically significant results, including objective response and survival increases compared to the physician’s choice of chemotherapy. We are thrilled that the FDA has granted Enhertu a second Breakthrough Therapy Designation, said Gilles Gallant, senior vice president, and global head, Oncology Development, Oncology R&D, Daiichi Sankyo.


1. Enhertu granted Breakthrough Therapy Designation in the US for HER2-positive metastatic gastric cancer [news release]. Cambridge, United Kingdom; AstraZeneca; May 11, 2020. https://bit.ly/3bqI9Lk. Accessed May 11, 2020.

2. Shitarak 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: 827-36.