Trastuzumab Deruxtecan Leads to Improved Response and OS in HER2+ Gastric Cancer

In this open-label, randomized, phase 2 trial, treatment with trastuzumab deruxtecan led to significant improvements in response and overall survival in patients with HER2-positive gastric cancer.

Treatment with trastuzumab deruxtecan (Enhertu) led to significant improvements in response and overall survival (OS) in patients with HER2-positive gastric cancer compared with standard therapies, according to a study published in the New England Journal of Medicine.

Unlike metastatic breast cancer, no other HER2-directed agent has shown a significant benefit in this patient population thus far.

“The findings of this trial confirm those observed in a phase 1 trial of trastuzumab deruxtecan in patients with advanced HER2-positive gastric cancer (response according to investigator assessment, 43.2%; median progression-free survival [PFS], 5.6 months),” the authors wrote.

In this open-label, randomized, phase 2 trial, patients with centrally confirmed HER2-positive gastric or gastroesophageal junction adenocarcinoma that had progressed while they were receiving at least 2 previous therapies, including trastuzumab, were randomly assigned in a 2:1 ratio to receive either 6.4 mg per kilogram of body weight of trastuzumab deruxtecan every 3 weeks or physician’s choice of chemotherapy.

The primary end point was the objective response, per independent central view, and secondary endpoints included overall survival (OS), response duration, progression-free survival (PFS), confirmed response (response persisting ≥4 weeks), and safety. In the overall study cohort of 187 patients treated, 125 received trastuzumab deruxtecan and 62 chemotherapy (55 received irinotecan [Camptosar] and 7 paclitaxel [Taxol]).

An objective response was reported in 51% of the patients in the trastuzumab deruxtecan arm compared with 14% of those in the chemotherapy choice arm (P < 0.001). Moreover, OS was longer with trastuzumab deruxtecan than with chemotherapy (median, 12.5 months vs. 8.4 months; HR, 0.59; 95% CI, 0.3900.88; P = 0.01, which crossed the prespecified O’Brien–Fleming boundary [0.0202 on the basis of number of deaths]).

“From the data obtained in this trial, lower levels of HER2 expression seem to be likely to result in lower percentages of patients with a response,” the authors wrote. “Biomarker analyses of patients’ tumor and liquid biopsy samples will be needed to provide information about the mechanism of action of trastuzumab deruxtecan and potential resistance mechanisms.”

With regard to safety, the most common adverse events (AEs) of grade 3 or higher observed were a decreased neutrophil count (51% in the trastuzumab deruxtecan arm; 24% in the chemotherapy arm), anemia (38% and 23%, respectively), and decreased white-cell count (21% and 11%). In addition, 12 patients experienced trastuzumab deruxtecan-related interstitial lung disease or pneumonitis (grade 1 or 2 in 9 patients; grade 3 or 4 in 3), as determined by an independent committee. One drug-related death due to pneumonia was also noted in the trastuzumab deruxtecan arm and no drug-related deaths occurred in the chemotherapy arm.

“These toxic effects were often addressed with dose modification. Although HER2-targeted therapies, including trastuzumab, have been associated with cardiotoxic effects, this was not observed in our trial,” the authors noted. “If interstitial lung disease is suspected, useful evaluations include high-resolution computed tomography, consultation with a pulmonologist, and testing of pulmonary function and oxygen saturation, as well as other tests as needed.”

A single-group, phase 2 trial is currently under way in the US and Europe to evaluate trastuzumab deruxtecan as a second-line therapy, following the receipt of first-line trastuzumab (NCT04014075).


Shitara K, Bang YJ, Iwasa S, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med. doi:10.1056/NEJMoa2004413.