The European Society of Medical Oncology (ESMO) Congress 2021 was exceptional this year with so much to be excited about in the advancement of cancer treatment. At MEDSIR, we are particularly thrilled about the astonishing results from the DESTINY-Breast03 trial presented during ESMO's Presidential Session by one of MEDSIR’s founders, Dr. Javier Cortés. (1)
The DESTINY-Breast03 trial is a phase III, open label, randomized trial that is evaluating the efficacy and safety of trastuzumab deruxtecan (T-DXd) vs. the standard of care, trastuzumab emtansine (T-DM1), in 524 patients with previously treated human epidermal growth factor receptor 2 positive (HER2+) unresectable and/or metastatic breast cancer. The trial was sponsored and designed by Daiichi Sankyo and in collaboration with AstraZeneca.
Previous data from the CLEOPATRA, EMILIA, and DESTINY-Breast01 have established the value of trastuzumab, T-DM1, and T-DXd for HER2+ metastatic breast cancer. Both T-DM1 and T-DXd are antibody drug conjugates (ADCs) that target HER2. ADCs are biological drugs that are linked to chemotherapy to provide more specific drug delivery. T-DXd delivers deruxtecan (DXd) to the tumor, whereas T-DM1 delivering emtansine (DM1). The two chemotherapies have different mechanisms of action, with DM1 working as an anti-microtubule and DXd acting as an inhibitor of topoisomerase I. T-DXd has a greater drug-to-antibody ratio compared to T-DM1, is a tumor selective cleavable linker, and has demonstrated evidence of a bystander anti-tumor effect. (2-6) It was therefore selected to be compared head-to-head against T-DM1.
Patients enrolled in the study were between the ages of 20 and 83 years old and 99.6% were female. Roughly half of those enrolled in each arm (49.8% for T-DXd, 46.8% for T-DM1) had received 1 prior treatment in the metastatic setting. Patients with clinically stable, treated brain mets were eligible for the study, however, patients previously treated with endocrine therapy were not included.
The primary endpoint of progression free survival (PFS) demonstrated an impressive 72% reduction in risk of cancer progression or death with T-DXd treatment compared to T-DM1 (HR = 0.28, p=7.8 x 10-22). The 12-month PFS rate was 75.8% for T-DXd (95% CI, 69.8%-80.7%) versus only 34.1% for T-DM1 (95% CI, 27.7%-40.5%). Commenting on the PFS Kaplan-Meier curves, Dr. Cortés notes that there is a “clear and early separation of the curves starting at time of first scan after treatment and proceeding throughout.”
The overall response rate (ORR) was also significantly improved (P < .0001) with T-DXd treatment having an ORR of 79.7% (95% CI, 74.3%-84.4%) compared to 34.2% for T-DM1 (95% CI, 28.5%-40.3%). 96.6% of patients treated with T-DXd had either a complete response, partial response, or stable disease compared to 76% of patients treated with T-DM1.
The median overall survival (OS) at the data cutoff date of May 21, 2021 was not achieved in either arm (HR, 0.56; 95% CI, 0.36-0.86; P = .007172) and the 12-month OS rates were 94.1% for T-DXd (95% CI, 90.3%-96.4%) vs. 85.9% for T-DM1 (95% CI, 80.9%-89.7%). While the OS did not meet the pre-determined boundary for significant, it is expected to improve as the data matures given the strong improvement in PFS.
The safety profile was similar to earlier studies, with no deaths due to treatment in either group. The most common adverse event leading to discontinuation for T-DXd was interstitial lung disease (ILD)/pneumonitis (8.2%) and thrombocytopenia (2.7%) for T-DM1. Most cases of ILD/pneumonitis related to T-DXd treatment were mild or moderate, with less than 1% experiences moderately severe ILD.
Ultimately, this compelling data shows a clinically meaningful improvement in PFS for T-DXd over T-DM1 for the treatment of HER2+ breast cancer which was previously treated with trastuzumab and taxane. This evidence, along with T-DXd demonstrating a manageable toxicity profile and an improvement in interstitial lung disease when compared to previous studies in more heavily treated patients, has established T-DXd as the new standard of care for 2L HER2+ metastatic breast cancer.
At MEDSIR we are also contributing to the search of the best treatment combination in terms of efficacy and patient’s quality of life. Specifically, our PHERGAIN-2 trial is chemotherapy-free combination for treatment of HER2+ early breast cancer. Contact us to learn more about this trial or any of our other exciting trials!
References:
1. Cortes J, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM) in patients (Pts) with HER2+ metastatic breast cancer (mBC): results of the randomized phase III DESTINY-Breast03 study. Presented at: European Society for Medical Oncology Annual Congress 2021. September 16-21, 2021; virtual. Abstract LBA1.
2. Nakada T et al. Chem Pharm Bull (Tokyo), 2019:67:173-85
3. Ogitani Y et al, Clin Cancer Res 2016:22:5097-108
4. Trail PA et al. Pharmacol Ther 2018; 181:126-42
5. Ogitani Y et al. Cancer Sci 2016; 107:1039-46
6. LoRusso PM et al. Clin Cancer Res. 2011; 17:6437-47
