Trastuzumab Deruxtecan Approved in Japan for HER2+ Metastatic Breast Cancer

In Clinical Studies News by Barbara Jacoby

By: Jason M. Broderick


The Japanese Ministry of Health, Labor, and Welfare (MHLW) has approved trastuzumab deruxtecan (Enhertu) for the treatment of patients with HER2-positive unresectable or recurrent breast cancer who have had prior chemotherapy and are refractory or intolerant to standard treatments.

The approval is based on findings from the phase II DESTINY-Breast01 trial, in which the antibody-drug conjugate (ADC) trastuzumab deruxtecan induced a confirmed objective response rate (ORR) of 64.1% (107 of 167 evaluable patients; 95% CI, 56.3-71.3).

“Our researchers in Japan have worked diligently on our ADC technology and we are excited to bring Enhertu, the first of many ADCs we have in development, to patients with HER2-positive metastatic breast cancer in Japan. Results seen with Enhertu are impressive as most women benefited from treatment with durable responses lasting a median duration of more than 14 months,” Wataru Takasaki, PhD, corporate officer, head of Oncology Function and Head of R&D Division in Japan, Daiichi Sankyo, said in a press release.

The safety population evaluated by the MHLW included 184 patients, 182 (98.9%) of whom experienced at least 1 adverse event (AE). The most common AEs were nausea (76.1%), alopecia (46.2%), fatigue (44.0%), vomiting (42.4%), neutrophil count decreased (29.9%), decreased appetite (28.3%), anemia (21.7%) and diarrhea (21.7%). Interstitial lung disease (ILD) occurred in 8.2% of patients, but there were no grade ≥3 events.

In the United States the FDA granted an accelerated approval to fam-trastuzumab deruxtecan-nxki in December 2019 for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received ≥2 prior anti–HER2-based regimens in the metastatic setting.

The available data from the phase II DESTINY-Breast01 trial at the time of the approval showed that trastuzumab deruxtecan induced a confirmed ORR of 60.3% (95% CI, 52.9-67.4) per independent central review (ICR), including a 4.3% complete response (CR) rate, and a 56% partial response (PR) rate.2 Sixty-seven patients had stable disease (SD; 36.4%), and 3 had progressive disease (PD; 1.6%). Two patients were not evaluable. ORRs were consistent across subgroups, including those with prior treatment with pertuzumab (Perjeta; 64%) and those with ≥ 3 prior regimens (59%).

In the open-label, international, multicenter phase II registration study, investigators enrolled 184 patients with HER2-positive breast cancer who were heavily pretreated, including with T-DM1 (Kadcyla) and other HER2-targeted treatments. The trial consisted of part 1 to evaluate pharmacokinetics (n= 65) and to determine recommended dose (RP2D; n = 54) for part 2 (n = 134): 5.4 mg/kg fam-trastuzumab deruxtecan-nxki. Data from this study were published simultaneously in the New England Journal of Medicine.3

ORR per ICR served as the primary endpoint. Secondary endpoints included DCR, DOR, and PFS.

Inclusion criteria included ≥18 years of age, unresectable and/or metastatic breast cancer, HER2-positive (centrally confirmed on archival tissue), prior T-DM1 therapy. Patients with a history of significant interstitial lung disease (ILD) were excluded. Those with stable, treated brain metastases were allowed.

All patients were female, the majority were white (55%), and 38% were Asian. Median age was 56 years (range, 28-96 years). Fifty-three percent were hormone receptor (HR)-positive and 45% were HR-negative. At baseline, the median number of prior treatment regimens was 6 (range, 2-27), including trastuzumab (Herceptin; 100%), T-DM1 (100%), pertuzumab (65.8%), and other HER2-targeted regimens (54.3%). The reported best response to T-DM1 before enrollment on the study were a CR and PR rate of 22%, 21% of patients with SD, and 36% with PD. Twenty-one percent were not evaluable.

As of the data cutoff (August 1, 2019), 79 patients (42.9%) are still on treatment, while 105 patients (57.1%) discontinued treatment, primarily for progressive disease (28.8%). In total, 184 patients enrolled on the study have received 5.4 mg/kg T-DXd for a median treatment duration of 6.9 months (range, 0.7-16 months).

Moreover, the investigational HER2-targeted antibody-drug conjugate yielded a median duration of response (DOR) of 14.8 months (95% CI, 13.8-16.9), and a disease control rate (DCR) of 97.3% (95% CI, 93.8-99.1). Clinical benefit ratio at 6 months was 76.1% (95% CI, 69.3%-82.1%), and median time to response was 1.6 months (95% CI, 1.4-2.6 months). Activity of fam-trastuzumab deruxtecan-nxki across all major subgroups appeared consistent.

After a median follow-up of 11.1 months (range, 0.7-19.9 months), median progression-free survival (PFS) of 16.4 months (95% CI, 12.7-NE). Median PFS in the 24 patients with brain metastases was 18.1 months (95% CI, 6.7-18.1 months). Median overall survival was not reached (95% CI, NE-NE).

For the approval, the FDA evaluated the safety of fam-trastuzumab deruxtecan-nxki in a pooled analysis of 234 patients in the DESTINY-Breast01 and Study DS8201-A-J101 trials.

Specifically, in DESTINY-Breast01, treatment-emergent AEs (TEAEs) occurred in 99% of patients, 51% being grade ≥ 3. The most common any-grade TEAEs were nausea (77%), alopecia (48%), fatigue (48%), vomiting (45%), constipation (34%), decreased neutrophil count (31%), decreased appetite (29%), diarrhea (27%), and anemia (26%). The most common grade ≥ 3 AEs were decreased neutrophil count (in 31% of the patients), nausea (7.6%), and anemia (in 26%).

Of note, 25 patients (13.6%) experienced ILD related to fam-trastuzumab deruxtecan-nxki by an independent adjudication committee. However, ILD was primarily grade 1 (2.7%) or 2 (8.2%). Median time to investigator-reported onset of ILD was 193 days (range, 42-535 days), and 13 of the 20 patients with grade ≥2 ILD received corticosteroids. Overall, 7 patients recovered, 2 were recovering at data cutoff, 12 were either outcome unknown or not followed until resolution, and 4 died. Of the 4 fatal cases, onset was from 63 to 148 days, of which 3 received steroids as part of their treatment, and death occurred 9 to 60 days after ILD diagnosis.


  1. ENHERTU® Approved in Japan for Treatment of Patients with HER2 Positive Unresectable or Metastatic Breast Cancer. Published online March 25, 2020. Accessed March 25, 2020.
  2. Krop IE, Saura C, Yamashita T, et al. [Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) in subjects with HER2-positive metastatic breast cancer previouslytreated with T-DM1: A phase 2, multicenter, open-label study (DESTINY-Breast01). Presented at: the San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, Texas. Abstract GS1-03.
  3. Modi S, Saura C, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Eng J Med. doi:10.1056/NEJMoa1914510.