Breakthrough Clinical Results
Daiichi Sankyo announced positive late-breaking data from two phase 3 trials, DESTINY-Breast09 and DESTINY-Gastric04, highlighting ENHERTU (trastuzumab deruxtecan)'s superior efficacy in HER2-positive metastatic breast cancer (first-line) and gastric cancer (second-line). The company also presented updates on its broader oncology portfolio, including data on DATROWAY (datopotamab deruxtecan) in lung cancer and other investigational ADCs. An investor meeting will discuss these findings and future oncology development plans.
Key Highlights
- Superior progression-free survival of ENHERTU + pertuzumab vs. THP in first-line HER2-positive metastatic breast cancer (DESTINY-Breast09)
- Superior overall survival of ENHERTU vs. ramucirumab + paclitaxel in second-line HER2-positive metastatic gastric cancer (DESTINY-Gastric04)
- Multiple updates on Daiichi Sankyo's DXd ADC portfolio across various cancers, including lung cancer.
- Investor meeting scheduled to discuss ASCO presentations and oncology development updates.
Incidence and Prevalence
Latest Estimates of Metastatic Breast Cancer Incidence and Prevalence Globally
Metastatic breast cancer represents a significant global health challenge with poor survival outcomes. Based on available data:
Incidence and Mortality
- In 2023, an estimated 43,170 women died of breast cancer in the US
- Only about 28% five-year survival rate has been reported for stage IV breast cancer
- Metastasis is one of the most leading causes of death in breast cancer patients
Patient Demographics
According to study data from the Surveillance, Epidemiology, and End Results (SEER) database, 4,932 eligible metastatic breast cancer patients were identified between 2010-2013, including: - 850 younger patients (<50 years) - 2,540 middle-aged patients (50-69 years) - 1,542 elder patients (>69 years)
Metastatic Patterns
- The major sites of metastasis of breast cancer are the lymph nodes, bone, brain and lung
- Elder patients were more likely to have lung metastasis and less likely to have only distant lymphatic spread
- Higher proportion of younger (34.9%) and middle-aged (36.2%) patients had multiple metastatic sites than elder patients (28.3%)
Prognosis Factors
- Patients with bone metastasis only had superior survival compared to other metastatic patients
- Brain metastasis only group and multiple sites metastasis group had the poorest prognosis
- Age at diagnosis was an independent prognostic factor for metastatic breast cancer patients
- While early-stage breast cancer is curable in about 70% of patients, advanced breast cancer is largely incurable
Research Scale
- Researchers investigated the landscape of somatic alterations in 617 metastatic breast cancers
Study Design Parameters
Study Design Parameters and Endpoints in Key Trials for Metastatic Breast Cancer
Study Design Parameters
The key trials for metastatic breast cancer employed various study designs:
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MONALEESA trials (MONALEESA-2, MONALEESA-3, and MONALEESA-7): Randomized clinical trials evaluating intrinsic subtypes with progression-free survival in hormone receptor-positive, HER2-negative advanced breast cancer treated with endocrine therapy and ribociclib
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Docetaxel plus trastuzumab study: Evaluated docetaxel (75 mg/m²) every 3 weeks for 6 cycles plus trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly) in HER2-overexpressing advanced breast cancer
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Capecitabine dosing study: Used a standard three-patients-per-cohort dose-escalation scheme with a 7-day on/7-day off schedule, starting at 1,500 mg orally twice daily
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MARIANNE trial: Randomized 1095 patients with HER2-positive breast cancer with no prior therapy for advanced disease into three treatment arms: trastuzumab plus taxane (HT), T-DM1 plus placebo, or T-DM1 plus pertuzumab
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TH3RESA trial: Randomized, parallel assignment, open-label, phase 3 study enrolling 602 patients from 146 centers in 22 countries (404 to trastuzumab emtansine, 198 to physician's choice)
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Seated exercise trial: Randomized, controlled, longitudinal trial in an outpatient clinic setting with 38 women beginning outpatient chemotherapy
Patient Populations
- Women with advanced/metastatic breast cancer
- HER2-overexpressing advanced breast cancer (median age 53 years, range 36-73 years)
- Patients with measurable, metastatic breast cancer with no limit to prior treatments (capecitabine study)
- Hormone receptor-positive, HER2-negative advanced breast cancer (MONALEESA trials)
- In TH3RESA: HER2-positive advanced breast cancer previously treated with trastuzumab, lapatinib, and a taxane, with ECOG performance status 0-2 and LVEF ≥50%
Monitoring and Assessment
- Response evaluation using radiographic assessment every 12 weeks (capecitabine study)
- Toxicity assessment every 2 weeks (capecitabine study)
- Patient monitoring for 28 days before dose escalation to assess delayed toxicity
Endpoints
The trials measured various primary and secondary endpoints:
- Progression-free survival (PFS): Primary endpoint in multiple trials including MONALEESA and MARIANNE
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Overall survival (OS):
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TH3RESA trial showed significantly longer OS with trastuzumab emtansine vs. physician's choice (22.7 vs. 15.8 months)
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MARIANNE trial showed similar OS across groups (50.9, 53.7, and 51.8 months)
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Non-surgery vs. surgery group comparison (3.4 years vs. 3.5 years)
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Response rates:
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67% overall response rate in docetaxel/trastuzumab study
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Pooled response rate in pemetrexed analysis: 32.6% for first-line and 13.9% for second-line
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Safety measures:
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Toxicity and adverse events
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Maximum tolerated dose (MTD) - established as 2,000 mg twice daily for capecitabine 7/7 schedule
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Adverse effects including neutropenia, leukopenia, fatigue, and anemia in pemetrexed analysis
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Patient-reported outcomes:
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Time to clinically meaningful deterioration in neurotoxicity symptoms (MARIANNE)
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Exercise, fatigue, and quality of life using FACIT F assessment (seated exercise trial)
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Other endpoints:
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Time to treatment failure
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Duration of response
Biomarker Analysis
- PAM50-based intrinsic subtype analysis in MONALEESA trials
- Subtype distribution: luminal A (46.7%), luminal B (24.0%), normal-like (14.0%), HER2-enriched (12.7%), and basal-like (2.6%)
- All subtypes except basal-like demonstrated significant PFS benefit with ribociclib
Drug used in other indications
Based on the provided context, there is no specific information available about which other indications ENHERTU (trastuzumab deruxtecan) is being trialled for beyond metastatic breast cancer. The context only mentions ENHERTU in relation to HER2-positive advanced breast cancer treatment.
The available information indicates that: - Trastuzumab deruxtecan is recommended for second-line treatment of HER2-positive advanced breast cancer - It should be used preferentially in the second line, with the only caveat being patients with CNS involvement where an alternative regimen (tucatinib, capecitabine, and trastuzumab) could be considered - It was approved after showing unprecedented activity in a phase 2 trial for highly pretreated HER2+ ABC patients - It is discussed as a treatment option for the post-TDM1 setting in HER2-positive advanced breast cancer
Regarding intervention models for trials, the provided context does not contain any information about intervention models for ENHERTU trials for other indications.