FDA Grants Trastuzumab Deruxtecan Orphan Drug Status in Gastric Cancer


The FDA has granted an orphan drug designation to fam-trastuzumab deruxtecan-nxki for the treatment of patients with gastric cancer, including gastroesophageal junction cancer.

The FDA has granted an orphan drug designation to fam-trastuzumab deruxtecan-nxki (Enhertu) for the treatment of patients with gastric cancer, including gastroesophageal junction (GEJ) cancer.1

Trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, previously demonstrated a statistically significant and clinically meaningful improvement in objective response rate (ORR) and overall survival (OS) versus physician’s choice of chemotherapy in patients with HER2-positive metastatic gastric or gastroesophageal cancer in the phase 2 DESTINY-Gastric01 trial.2

Full findings of the phase 2 study will be presented at the 2020 ASCO Virtual Scientific Program.

Based on these data, as well as results from a phase 1 study, the FDA granted the agent a breakthrough therapy designation in May 2020 for the treatment of patients with HER2-positive unresectable or metastatic gastric or GEJ adenocarcinoma who have received 2 or more prior regimens, including trastuzumab (Herceptin).

In the open-label, multicenter phase 2 DESTINY-Gastric01 trial, investigators enrolled 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-fluouracil and platinum-based chemotherapy. Patients were randomized 2:1 to receive 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 primary end point of ORR, secondary end points included OS, progression-free survival (PFS), duration of response, disease control rate, time to treatment failure, and safety/pharmacokinetics.

Moreover, Daiichi Sankyo, which jointly develops trastuzumab deruxtecan with AstraZeneca, reported that safety data showed that the tolerability of trastuzumab deruxtecan was consistent with reports from a phase 1 study.

The most common adverse events (AEs; ≥30%) included hematologic and gastrointestinal, including neutrophil count decrease, anemia, nausea and decreased appetite. Cases of drug-related interstitial lung disease (ILD) and pneumonitis were mostly grade 1/2 with 2 grade 3 and 1 grade 4 AE. No ILD-related deaths occurred in patients with gastric cancer in the phase 1 trial nor in the DESTINY-Gastric01 trial.

In the phase 1 trial, which is part of the basis for the breakthrough therapy designation, results 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 treatment with irinotecan, 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 AEs (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 or more prior anti—HER2-based regimens in the metastatic setting.

Orphan drug designation is designated for agents intended for the treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in United States. In the press release, Daiichi Sankyo noted that an estimated 27,600 new cases of gastric cancer will be diagnosed in 2020, and the disease could also lead to more than 11,000 deaths this year.


  1. Enhertu granted orphan drug designation in the U.S. for gastric cancer [news release]. Daiichi Sankyo Company; May 22, 2020. Accessed May 22, 2020.
  2. Phase II DESTINY-Gastric01 trial of Enhertu versus chemotherapy met primary endpoint [news release]. AstraZeneca; January 27, 2020. 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. doi10.1016/S1470-2045(19)30088-9
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