The results for the pivotal phase II DESTINY-Breast01 trial of Trastuzumab deruxtecan ( DS-8201 ).
The HER2-targeting antibody drug conjugate ( ADC ) was evaluated in patients with HER2-positive, unresectable and/or metastatic breast cancer previously treated with Trastuzumab emtansine ( Kadcyla ).
The response rate in DESTINY-Breast01, as assessed by an independent review committee, has confirmed in a heavily-pretreated, global patient population the clinical activity in the recently-published phase I trial.
The safety and tolerability profile of Trastuzumab deruxtecan was also consistent with previous experience.
DESTINY-Breast01 is a pivotal phase II, open-label, global, multicentre, two-part trial of Trastuzumab deruxtecan.
The optimal dose of 5.4mg/kg was previously identified in part one of the trial.
The results from part two evaluated the efficacy and safety of that dose in patients who have failed or discontinued previous treatment with Trastuzumab emtansine.
Trastuzumab deruxtecan has been granted US FDA Breakthrough Therapy Designation and Fast Track Designation for HER2-positive patients in the advanced or refractory breast cancer setting.
A publication in The Lancet Oncology reported long-term phase I safety and preliminary efficacy results in HER2-positive metastatic breast cancer.
HER2 is a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells that is associated with aggressive disease and poorer prognosis in breast cancer patients.
To be considered HER2-positive, tumour cancer cells are usually tested by one of two methods: immunohistochemistry ( IHC ) or fluorescent in situ hybridization ( FISH ). IHC test results are reported as: 0, IHC 1+, IHC 2+, or IHC 3+. A finding of IHC 3+ and/or FISH amplification is considered positive.
There are currently no targeted therapies for HER2-FISH-negative, IHC 2+ or IHC 1+ tumours.
The primary endpoint of DESTINY-Breast01 is objective response rate. Secondary objectives include duration of response, disease control rate, clinical benefit rate, progression-free survival and overall survival.
The first part of the trial has included a pharmacokinetic stage and a dose-finding stage to identify the recommended dose of Trastuzumab deruxtecan to be evaluated in the second part of the trial.
The second part enrolled patients into one of two cohorts: patients resistant or refractory to Trastuzumab emtansine ( part 2a ) and patients who discontinued treatment with Trastuzumab emtansine for reasons other than resistant or refractory disease ( part 2b ).
Enrolment into DESTINY-Breast01 was completed in September 2018, with 253 patients at more than 100 sites across North America, Europe, Japan and other countries in Asia.
The safety and tolerability profile of Trastuzumab deruxtecan in DESTINY-Breast01 is consistent with the recently-published phase I trial, in which the most common adverse events ( greater than or equal to 30%, any grade ) included nausea, decreased appetite, vomiting, alopecia, fatigue, anaemia, diarrhoea, and constipation.
Cases of drug-related pneumonitis, including grade 5 events, have also been reported in the clinical development programme. ( Xagena )
Source: AstraZeneca & Daiichi Sankyo, 2019