Daiichi Sankyo Company, Limited announced that it has submitted a supplemental New Drug Application (sNDA) to Japan’s Ministry of Health, Labour and Welfare (MHLW) for trastuzumab deruxtecan, a HER2 directed antibody drug conjugate (ADC), for the treatment of adult patients with HER2 positive unresectable or recurrent breast cancer previously treated with trastuzumab and a taxane.

Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide, resulting in nearly 685,000 deaths globally. In Japan, breast cancer is the most common cancer in women, with approximately 92,000 cases of breast cancer diagnosed in 2020. Approximately one in five cases of breast cancer are considered HER2 positive. Despite initial treatment with trastuzumab and a taxane, patients with HER2 positive metastatic breast cancer will often experience disease progression. More treatment options are needed to further delay progression and extend survival.

“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,” said Wataru Takasaki, PhD, executive officer, head of R&D division in Japan, Daiichi Sankyo. “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.”

The sNDA is based on data from the pivotal DESTINY-Breast03 phase 3 trial that were presented at the 2021 European Society for Medical Oncology (ESMO) Congress. In the trial, trastuzumab deruxtecan demonstrated a 72% reduction in the risk of disease progression or death compared to trastuzumab emtansine (T-DM1) (hazard ratio [HR] = 0.28; 95% confidence interval [CI]: 0.22-0.37; p=7.8x10-22) in patients with HER2 positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane. The median progression-free survival (PFS) for patients treated with trastuzumab deruxtecan was not reached (95% CI: 18.5-NE) compared to 6.8 months for T-DM1 (95% CI: 5.6-8.2) as assessed by blinded independent central review (BICR).

In the secondary endpoint analysis of PFS assessed by investigators, patients treated with trastuzumab deruxtecan experienced a three-fold improvement in PFS of 25.1 months (95% CI: 22.1-NE) compared to 7.2 months (95% CI: 6.8-8.3) for T-DM1 (HR=0.26; 95% CI: 0.20-0.35; p=6.5x10-24). There was a strong trend towards improved overall survival (OS) with trastuzumab deruxtecan (HR=0.56; 95% CI: 0.36-0.86; p=0.007172), however, this analysis is not yet mature and is not statistically significant. Nearly all patients treated with trastuzumab deruxtecan were alive at one year (94.1%; 95% CI: 90.3-96.4) compared to 85.9% of patients treated with T-DM1 (95% CI: 80.9-89.7). Confirmed objective response rate (ORR) was more than doubled in the trastuzumab deruxtecan arm versus the T-DM1 arm (79.7% [n=208; 95% CI: 74.3-84.4] versus 34.2% [n=90; 95% CI: 28.5-40.3; p<0.0001]).

The safety profile of the most common adverse events with trastuzumab deruxtecan in DESTINY-Breast03 was consistent with previous clinical trials with no new safety concerns identified. The most common grade 3 or higher drug-related treatment emergent adverse events 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 ALT (1.6%), decreased appetite (1.2%), increase in AST (0.8%), diarrhea (0.4%) and alopecia (0.4%). Overall, 10.5% of patients had interstitial lung disease (ILD) or pneumonitis related to treatment as determined by an independent adjudication committee. The majority of ILD events (9.7%) were low grade (grade 1 (2.7%) or grade 2 (7.0%)) with two grade 3 (0.8%) events reported. No grade 4 or grade 5 ILD or pneumonitis events occurred.

Breast cancer is the most common cancer and is one of the leading causes of cancer-related deathsworldwide.  More than two million cases of breast cancer were diagnosed in 2020, resulting in nearly 685,000 deaths globally. In Japan, breast cancer is the most common cancer in women, with approximately 92,000 cases of breast cancer diagnosed in 2020.HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including breast, gastric, lung and colorectal cancers. HER2 protein overexpression may occur as a result of HER2 gene amplification and is often associated with aggressive disease and poor prognosis in breast cancer. Approximately one in five cases of breast cancer are considered HER2 positive.

Despite initial treatment with trastuzumab and a taxane, patients with HER2 positive metastatic breast cancer will often experience disease progression. More effective options are needed to further delay progression and extend survival.

DESTINY-Breast03 is a global, head-to-head, randomized, open-label, pivotal phase 3 trial evaluating the efficacy and safety of trastuzumab deruxtecan (5.4 mg/kg) versus T-DM1 in patients with HER2 positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane. The primary efficacy endpoint of DESTINY-Breast03 is PFS based on blinded independent central review. Secondary efficacy endpoints include OS, ORR, duration of response, PFS based on investigator assessment and safety.DESTINY-Breast03 enrolled 524 patients at multiple sites in Asia, Europe, North America, Oceania and South America.

Trastuzumab deruxtecan (fam-trastuzumab deruxtecan-nxki in the US only) is a HER2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, trastuzumab deruxtecan is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca’s ADC scientific platform. Trastuzumab deruxtecan consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

Trastuzumab deruxtecan (5.4 mg/kg) is approved in more than 30 countries for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received two or more prior anti-HER2 based regimens based on the results from the DESTINY-Breast01 trial.

Trastuzumab deruxtecan (6.4 mg/kg) is also approved in several countries for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 trial.

A Type II Variation is currently under review by the European Medicines Agency for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or GEJ adenocarcinoma who have received a prior anti-HER2-based regimen.

A comprehensive global development program is underway evaluating the efficacy and safety of trastuzumab deruxtecan monotherapy across multiple HER2 targetable cancers including breast, gastric, lung and colorectal cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

Trastuzumab deruxtecan was highlighted in the Clinical Cancer Advances 2021 report as one of two significant advancements in the “ASCO Clinical Advance of the Year: Molecular Profiling Driving Progress in GI Cancers,” based on data from both the DESTINY-Gastric01 and DESTINY-CRC01 trials, as well as one of the targeted therapy advances of the year in NSCLC based on the interim results of the HER2 mutated cohort of the DESTINY-Lung01 trial.

In September 2021, trastuzumab deruxtecan received its fourth Breakthrough Therapy Designation in the US for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received one or more prior anti-HER2-based regimens.