Daiichi Sankyo has announced that Japan’s Ministry of Health, Labour and Welfare (MHLW) has approved two new first-line indications for its Antibody-Drug Conjugates (ADCs), Enhertu (trastuzumab deruxtecan) and Datroway (datopotamab deruxtecan), in patients with metastatic breast cancer.

Under the new approvals, Enhertu in combination with pertuzumab is indicated for adult patients with HER2-positive unresectable or recurrent breast cancer. Datroway has been approved for adult patients with Hormone Receptor (HR)-negative and HER2-negative unresectable or recurrent breast cancer, commonly referred to as Triple-Negative Breast Cancer (TNBC).

Both medicines are DXd ADCs discovered by Daiichi Sankyo. The company develops and commercialises the medicines globally with AstraZeneca, while Daiichi Sankyo retains exclusive rights to Enhertu and Datroway in Japan. 

Breast cancer is the most common cancer among women in Japan. HER2-positive and TNBC are among the more aggressive breast cancer subtypes, highlighting the need for effective first-line treatments for patients with metastatic disease.

The Enhertu approval is based on results from the DESTINY-Breast09 Phase 3 trial, which evaluated Enhertu alone or in combination with pertuzumab against standard treatment with a taxane, trastuzumab and pertuzumab.

In the trial, Enhertu plus pertuzumab reduced the risk of disease progression or death by 44 percent compared with THP, with a hazard ratio (HR) of 0.56. 

Median Progression-Free Survival (PFS) was 40.7 months with Enhertu plus pertuzumab compared with 26.9 months with THP, as assessed by blinded independent central review.

DESTINY-Breast09 enrolled 1,157 patients across sites in Africa, Asia, Europe, North America and South America. Patients were randomised to receive Enhertu monotherapy, Enhertu plus pertuzumab or THP. The trial's primary endpoint was PFS, while secondary endpoints included Overall Survival (OS), overall response rate, duration of response, pharmacokinetics and safety.

The safety profile of Enhertu plus pertuzumab was consistent with previous clinical studies, with no new safety concerns identified. Among patients treated with Enhertu 5.4 mg/kg in combination with pertuzumab, adverse reactions included nausea, diarrhoea, alopecia, vomiting and anaemia. Interstitial lung disease (ILD) was also observed, including among Japanese patients.

The Datroway approval is based on results from the TROPION-Breast02 Phase 3 trial, which evaluated Datroway against investigator's choice of chemotherapy in patients with previously untreated locally recurrent inoperable or metastatic TNBC for whom immunotherapy was not an option.

Datroway demonstrated a statistically significant improvement in overall survival. Median OS was 23.7 months with Datroway compared with 18.7 months with chemotherapy, representing a 5.0-month improvement and a reduced risk of death of 21 percent.

Datroway also reduced the risk of disease progression or death by 43%, with an HR of 0.57. Median PFS was 10.8 months with Datroway compared with 5.6 months with chemotherapy.

TROPION-Breast02 enrolled 644 patients across Africa, Asia, Europe, North America and South America. Its dual primary endpoints were OS and PFS assessed by blinded independent central review, while secondary endpoints included objective response rate, duration of response, disease control rate, pharmacokinetics and safety.

The safety profile of Datroway was consistent with earlier clinical trials. The most frequently reported adverse reactions included stomatitis, nausea, alopecia, dry eye and constipation. ILD was not observed among the 17 Japanese patients treated with Datroway in the trial.

Both Enhertu and Datroway carry warnings regarding interstitial lung disease in Japan. Daiichi Sankyo states that ILD, including fatal cases, has occurred in patients treated with both medicines. Their use requires close collaboration with respiratory disease specialists, along with monitoring for symptoms such as dyspnoea, cough and fever and periodic assessment using oxygen saturation tests and chest imaging. The Japanese prescribing information and safety materials provide further precautions for patient selection and monitoring. 

Enhertu is a HER2-directed ADC consisting of a HER2 monoclonal antibody linked to multiple topoisomerase I inhibitor payloads through tetrapeptide-based cleavable linkers. Datroway is a TROP2-directed ADC built using the same DXd ADC technology platform. Its antibody component targets TROP2.

The two medicines form part of Daiichi Sankyo's broader ADC development portfolio. Enhertu is being studied across multiple tumour types, including breast, lung, gastric, colorectal, biliary tract, ovarian and endometrial cancers. Datroway is being evaluated in clinical programmes covering cancers including breast, lung and urothelial cancer.

The latest Japanese approvals further expand the use of the company's DXd ADC medicines in metastatic breast cancer. Daiichi Sankyo continues to evaluate both medicines in additional clinical settings and tumour types through ongoing global Phase 3 and earlier-stage studies.