European Commission Approves Trastuzumab Deruxtecan in Pretreated HER2+ Advanced Gastric/GEJ Cancer

The European Commission has approved fam-trastuzumab deruxtecan-nxki as monotherapy for the treatment of patients with advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.

Eric Van Cutsem, MD, PhD

The European Commission has approved fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) as monotherapy for the treatment of patients with advanced HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab (Herceptin)-based regimen.

T-DXd is the first approved HER2-directed therapy in the European Union for patients with metastatic gastric cancer with disease progression following first-line therapy with a trastuzumab-based regimen. The approval follows a positive opinion from the Committee for Medicinal Products for Human Use issued in November 2022, and is based on results from the phase 2 DESTINY-Gastric02 (NCT04014075) and DESTINY-Gastric01 (NCT03329690) trials.

In DESTINY-Gastric02, treatment with 6.4 mg/kg of T-DXd led to a confirmed objective response rate (ORR) of 41.8% (95% CI, 30.8%-53.4%) in European and North American patients as assessed by independent central review (ICR). The median duration of response (DOR) was 8.1 months (95% CI, 5.9-not evaluable).

In DESTINY-Gastric01, the antibody-drug conjugate (ADC) elicited an ORR of 40.5% vs 11.3% with irinotecan or paclitaxel in Japanese and South Korean patients as assessed by ICR. The median DOR was 11.3 months with trastuzumab deruxtecan vs 3.9 months with chemotherapy. The median overall survival (OS) was 12.5 months (95% CI, 9.6-14.3) vs 8.4 months (95% CI, 6.9-10.7) with T-DXd and chemotherapy, respectively (HR, 0.59; 95% CI, 0.39-0.88; P =.0097).

“Today’s news is a welcome advance for patients with HER2 positive advanced gastric cancer,” Eric Van Cutsem, MD, PhD, head of the Department of Oncology at the University of Leuven in Belgium, said in a press release. “Patients with this disease face poor outcomes following progression on initial treatment with a HER2-directed medicine as many do not respond to further treatment, and even those that do respond often do not have durable responses. Data from the DESTINY-Gastric02 and DESTINY-Gastric01 trials support Enhertu becoming a new standard of care for patients in this setting.”

The open-label, single-arm phase 2 DESTINY-Gastric02 trial evaluated 6.4 mg/kg T-DXd in patients with HER2-positive metastatic and/or unresectable gastric or GEJ adenocarcinoma with disease progression on or after a trastuzumab-containing regimen.

The primary end point of DESTINY-Gastric02 was confirmed ORR based on ICR. Secondary end points include progression-free survival (PFS), OS, DOR, and safety. Primary results from the DESTINY-Gastric02 phase 2 trial were presented at the ESMO Congress 2021 with updated data presented at 2022 ESMO.

The randomized, open-label, phase 2 DESTINY-Gastric01 trial enrolled patients with HER2-positive advanced gastric cancer or GEJ adenocarcinoma with disease progression following at least 2 prior treatment regimens including fluoropyrimidine (5-FU), platinum chemotherapy, and trastuzumab. HER2 positivity was defined as immunohistochemistry (IHC) 3+ or IHC 2+/in-situ hybridization positive. Eligible patients received trastuzumab deruxtecan at a dose of 6.4 mg/kg.

The primary end point of DESTINY-Gastric01 was ORR. Secondary end points include OS, PFS, DOR, disease control rate, time to treatment failure, pharmacokinetics, and safety. The primary analysis was published in the New England Journal of Medicine with updated data presented at the 2022 Gastrointestinal Cancers Symposium.

“Enhertu is the first [ADC] to be approved in Europe for advanced gastric cancer, representing a major advance in treating this difficult-to-treat cancer,” said Ken Keller, global head of Oncology Business and president and chief executive officer of Daiichi Sankyo, Inc. “With this approval, we can now offer patients with previously treated HER2-positive gastric cancer a treatment with clinically meaningful efficacy.”

In both trials, trastuzumab deruxtecan demonstrated a similar safety profile as reported in other trials evaluating the agent, with no newly identified safety signals.

In a pooled safety analysis of patients spanning several tumor types who received 6.4 mg/kg of T-DXd, common grade 3/4 treatment-related adverse effects (TRAEs) included neutropenia (27.9%), anemia (23.1%), leukopenia (12.9%), thrombocytopenia (9.0%), fatigue (8.2%), decreased appetite (8.1%), lymphopenia (7.4%), nausea (5.8%), increased transaminases (4.7%), hypokalemia (4.2%), pneumonia (2.9%), febrile neutropenia (2.9%), vomiting (2.4%), diarrhea (2.1%), decreased weight (2.1%), increased blood alkaline phosphate (1.8%), interstitial lung disease (ILD) (1.6%), dyspnea (1.3%) and decrease ejection fraction (1.1%).

Grade 5 TRAEs occurred in 2.6% of patients including interstitial lung disease (1.9%).


ENHERTU® approved in the EU for patients with previously treated HER2 positive advanced gastric cancer. News release. Daiichi Sankyo. December 19, 2022. Accessed December 19, 2022.

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