A supplemental new drug application has been submitted to Japan’s Ministry of Health, Labour, and Welfare or the use of fam-trastuzumab deruxtecan-nxki as a treatment in select patients with HER2-positive unresectable or recurrent breast cancer.
A supplemental new drug application (sNDA) has been submitted to Japan’s Ministry of Health, Labour, and Welfare (MHLW) for the use of fam-trastuzumab deruxtecan-nxki (Enhertu) as a treatment in patients with HER2-positive unresectable or recurrent breast cancer that has been previously treated with trastuzumab (Herceptin) and a taxane.1
The sNDA is based on findings from the pivotal phase 3 DESTINY-Breast03 trial (NCT03529110) that were presented at the 2021 ESMO Congress.2 The results showed that trastuzumab deruxtecan resulted in a 72% reduction in the risk of disease progression or death vs ado-trastuzumab emtansine (T-DM1; Kadcyla) in patients with HER2-positive unresectable and/or metastatic breast cancer that had been previously treated with trastuzumab and a taxane (HR, 0.28; 95% CI, 0.22-0.37; P = 7.8 x 10-22).
“There is a continued need in Japan for new therapeutic options for patients with HER2 positive metastatic breast cancer who often experience disease progression after initial treatment with available standards of care,” Wataru Takasaki, PhD, executive officer and head of the R&D Division of Daiichi Sankyo in Japan, stated in a news release. “We look forward to working with the Japan MHLW on this submission, as it marks a significant step towards bringing this important medicine to an earlier use in the metastatic setting for patients with HER2-positive breast cancer.”
In the global, head-to-head, randomized, open-label DESTINY-Breast03 trial, patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane were randomized to receive 5.4 mg/kg of trastuzumab deruxtecan every 3 weeks (n = 261) or 3.6 mg/kg of T-DM1 every 3 weeks (n = 263).
Patients with clinically stable, treated brain metastases were eligible for enrollment.
The primary end point of the trial was progression-free survival (PFS) per blinded independent central review (BICR). Secondary end points included overall survival (OS), objective response rate (ORR), duration of response, PFS per investigator, and safety.
At the time of the primary analysis, the median follow-up was 16.2 months in the trastuzumab deruxtecan arm and 15.3 months in the T-DM1 arm.
Additional findings from the primary analysis showed that the median PFS was not yet reached with trastuzumab deruxtecan (95% CI, 18.5–not evaluable [NE]) vs 6.8 months with T-DM1 (95% CI, 5.6-8.2) per BICR. The 12-month PFS rates in the investigative and control arms were 75.8% (95% CI, 69.8%-80.7%) and 34.1% (95% CI, 27.7%-40.5%), respectively.
The secondary end point of PFS per investigator assessment was 25.1 months (95% CI, 22.1-NE) with trastuzumab deruxtecan vs 7.2 months (95% CI, 6.8-8.3) with T-DM1 (HR, 0.26; 95% CI, 0.20-0.35; P = 6.5 x 10-24).
Although OS data were immature at the data cutoff, a trend toward improved OS was reported with trastuzumab deruxtecan (HR, 0.56; 95% CI, 0.36-0.86; P = .007172).
The median OS was NE in both arms (HR, 0.56; 95% CI, 0.36-0.86; P = .007172). Notably, the 1-year OS rate was 94.1% (95% CI, 90.3%-96.4%) with trastuzumab deruxtecan vs 85.9% (95% CI, 80.9%-89.7%) with T-DM1.
Moreover, the confirmed ORR was 79.7% (n = 208; 95% CI, 74.3%-84.4%) with trastuzumab deruxtecan vs 34.2% (n = 90; 95% CI, 28.5%-40.3%) with T-DM1 (P < .0001); the complete response (CR) rates were 16.1% and 8.7%, respectively.
Updated findings from the study, which were presented at the 2021 San Antonio Breast Cancer Symposium, showed that the median PFS was 15.0 months (95% CI, 12.5-22.2) with trastuzumab deruxtecan vs 3.0 months (95% CI, 2.8-5.8) with T-DM1 in patients with baseline brain metastases (HR, 0.25; 95% CI, 0.13-0.45).3 The 12-month PFS rates were 72.0% (95% CI, 55.0%-83.5%) and 20.9% (95% CI, 8.7%-36.6%), respectively.
Moreover, the median PFS was NE (95% CI, 22.2-NE) with trastuzumab deruxtecan vs 7.1 months (95% CI, 5.6-9.7) with T-DM1 in patients without baseline brain metastases (HR, 0.30; 95% CI, 0.22-0.40). The 12-month PFS rates were 76.5% (95% CI, 70.0%-81.8%) and 36.4% (95% CI, 29.4%-43.4%), respectively.
Additionally, the PFS and confirmed ORR data also favored trastuzumab deruxtecan across the following patient subgroups: hormone receptor status (positive vs negative), prior pertuzumab (Perjeta) treatment (yes vs no), visceral disease (yes vs no), prior lines of therapy (0-1 vs ≥ 2), and patients with brain metastases (yes vs no).
Regarding intracranial responses, the CR rate was 27.8% with trastuzumab deruxtecan vs 2.8% with T-DM1; the intracranial partial response rates were 36.1% and 30.6%, respectively. Trastuzumab deruxtecan also resulted in a lower rate of intracranial progressive disease vs T-DM1, at 2.8% and 22.2%, respectively.
In terms of safety, the most common adverse effects (AEs) reported with trastuzumab deruxtecan were consistent with prior trial data, and no new safety signals were reported.
The most common grade 3 or higher drug-related treatment-emergent AEs (TEAEs) in the trastuzumab deruxtecan arm were neutropenia (19.1%), thrombocytopenia (7.0%), leukopenia (6.6%), nausea (6.6%), anemia (5.8%), fatigue (5.1%), vomiting (1.6%), increase in alanine aminotransferase (ALT; 1.6%), decreased appetite (1.2%), increase in aspartate aminotransferase (AST; 0.8%), diarrhea (0.4%) and alopecia (0.4%).
The most common grade 3 or higher TEAEs with T-DM1 were thrombocytopenia (24.9%), AST increase (5.0%), ALT increase (4.6%), and anemia (4.2%).
Overall, 10.5% of patients in the trastuzumab deruxtecan arm reported interstitial lung disease (ILD) or pneumonitis related to treatment vs 1.9% of those in the T-DM1 arm. Most ILD events (9.7%) were low grade (grade 1, 2.7%; grade 2, 7.0%); 2 grade 3 (0.8%) events occurred, and no grade 4 or grade 5 drug-related ILD or pneumonitis events were reported with trastuzumab deruxtecan.
Trastuzumab deruxtecan is currently approved in over 30 countries for the treatment of patients with unresectable or metastatic HER2-positive breast cancer who have received at least 2 prior anti-HER2–based regimens based on findings from the DESTINY-Breast01 trial (NCT03248492).
Trastuzumab deruxtecan is also approved in several countries for the treatment of patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on findings from the DESTINY-Gastric01 trial (NCT03329690).
A Type II Variation is also currently under review by the European Medicines Agency for the treatment of patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior anti-HER2–based regimen.