Trastuzumab Deruxtecan Approved in Japan for HER2+ Metastatic Gastric Cancer

The Japanese Ministry of Health, Labor, and Welfare has approved the antibody-drug conjugate trastuzumab deruxtecan for the treatment of patients with HER2-positive unresectable advanced or recurrent gastric cancer that has progressed following chemotherapy.

The Japanese Ministry of Health, Labor, and Welfare has approved the antibody-drug conjugate (ADC) trastuzumab deruxtecan (Enhertu) for the treatment of patients with HER2-positive unresectable advanced or recurrent gastric cancer that has progressed following chemotherapy, according to an announcement from Daiichi Sankyo Company, Limited.1

The regulatory decision was based on data from the phase 2 DESTINY-Gastric01 trial (NCT03329690), which demonstrated that trastuzumab deruxtecan elicited a statistically significant improvement in objective response rate (ORR) per independent central review (ICR) compared with investigator’s choice of chemotherapy, at 51.3% (95% CI, 41.9-60.5) versus 14.3% (95% CI, 6.4-26.2), respectively.2 Eleven complete responses (CRs) were reported in the arm who received the ADC.

The ADC also led to a statistically significant improvement in overall survival (OS). The median OS with trastuzumab deruxtecan was 12.5 months (95% CI, 9.6-14.3) versus 8.4 months (95% CI, 6.9-10.7) with chemotherapy (HR, 0.59; 95% CI, 0.39-0.88; P = .0097). Moreover, 1-year OS rates with the ADC and chemotherapy were 52.1% and 28.9%, respectively; the 6-month OS rates were 80.3% and 66.4%, respectively.

“Today’s approval of [trastuzumab deruxtecan] in Japan is significant as it is the first HER2 directed therapy to demonstrate an improvement in OS compared to chemotherapy for previously treated patients with HER2-positive metastatic gastric cancer,” Wataru Takasaki, PhD, executive officer, head of R&D Division in Daiichi Sankyo, stated in a press release. “We are proud of the quality and speed in which we were able to deliver the second indication to patients and physicians in Japan as it highlights our commitment to transforming science into innovative therapies for patients with cancer.”

In the open-label, multicenter, randomized phase 2 trial, investigators set out to examine the efficacy of trastuzumab deruxtecan compared with physician’s choice of standard chemotherapy in patients with HER2-expressing advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma who had received at least 2 previous regimens, including fluoropyrimidine, a platinum-based agent, and trastuzumab (Herceptin) or an approved biosimilar.

DESTINY-Gastric01 enrolled a total of 187 participants; 125 were given the ADC, while 62 were given chemotherapy. Moreover, 86% of participants had received prior treatment with a taxane drug, 71% also received ramucirumab (Cyramza), and 31% had PD-1/PD-L1 inhibitors. At the November 8, 2019 data cutoff date, 22.4% of patients on the investigational arm were still on treatment compared with 4.8% of patients on the control arm.

The primary end point of the trial was ORR per independent central review (ICR), while secondary end points were comprised of OS, duration of response (DOR), progression-free survival (PFS), confirmed ORR, and safety.

Additional results presented during the 2020 ASCO Virtual Scientific Program showed that the confirmed ORR per ICR was 42.9% (n = 51; 95% CI, 33.8-91.5) in the experimental arm versus 12.5% (n = 7; 95% CI, 5.2-24.1) in the control arm. The confirmed disease control rates were 85.7% (n = 102; 95% CI, 78.1-91.5) and 62.5% (n = 35; 95% CI, 48.5-75.1) with the ADC and chemotherapy, respectively. Moreover, the median confirmed DOR was 11.3 months (95% CI, 5.6–not evaluable) compared with 3.9 months (95% CI, 3.0-4.9), respectively.

The median PFS achieved with the ADC was 5.6 months (95% CI, 4.3-6.9) versus 3.5 months (95% CI, 2.0-4.3) with chemotherapy (HR, 0.47; 95% CI, 0.31-0.71). The 1-year PFS rates in the experimental and control arms were 29.9% versus 0%, respectively; the 6-month PFS rates were 42.8% versus 20.6%, respectively.

With regard to safety, the most frequently reported adverse effects with the ADC that were grade 3 in severity or higher included neutropenia, decreased appetite, anemia, thrombocytopenia, and decreased white blood cell count. Treatment-emergent toxicities that were linked with drug discontinuation occurred in 15.2% of those on the ADC versus 6.5% of those on chemotherapy. Events associated with dose reductions occurred in 32.0% and 33.9% of those in the experimental and control arms, respectively. Events that resulted in dose interruptions occurred in 62.4% and 37.1%, respectively.

One treatment-related death, due to pneumonia was reported on the ADC arm versus none on the chemotherapy arm. Twelve patients experienced interstitial lung disease (ILD)/pneumonitis that was determined by an independent adjudication committee to be associated with trastuzumab deruxtecan.

The approval in Japan comes with a warning for ILD. The regulatory agency calls for close collaboration with a respiratory disease expert when prescribing the ADC. Patients should be closely monitored during treatment for early signs or symptoms associated with ILD and peripheral artery oxygen saturation tests, chest X-ray scans, and chest CT scans should be performed on a routine basis.

If such signs are observed, the administration of trastuzumab deruxtecan should be discontinued and appropriate measures should be taken to address the effect, such as the administration of corticosteroids.

Prior to administration, a chest CT scan should to performed and an interview should be conducted to confirm the absence of any comorbidity or history of ILD in the patient.


  1. Enhertu approved in Japan for the treatment of patients with HER2-positive metastatic gastric cancer. News release. Daiichi Sankyo Company, Limited. September 25, 2020. Accessed September 25, 2020.
  2. Shitara K, Bang Y-J, Iwasa S, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: a randomized, phase II, multicenter, open-label study (DESTINY-Gastric01). J Clin Oncol. 2020;38(suppl 15; abstr 4513). doi:10.1200/JCO.2020.38.15_suppl.4513