DESTINY-Breast03 Trial: T-DXd vs TDM1

DESTINY-Breast03 (ClinicalTrials.gov Identifier: NCT03529110) is an international phase 3 study designed to assess how trastuzumab deruxtecan (T-DXd) compares with T-DM1 in the second-line setting. The study enrolled patients with HER2+, unresectable or mBC previously treated with trastuzumab and a taxane. Patients with clinically stable brain metastasis were eligible.

The 524 patients were randomly assigned to receive 5.4 mg/kg of T-DXd (n=261) or 3.6 mg/kg of T-DM1 (n=263) intravenously every 3 weeks. Stratification factors were HR status, prior pertuzumab treatment, and history of visceral disease.


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At ESMO 2021, the study’s primary analysis showed that T-DXd significantly improved the overall response rate (ORR) and PFS over T-DM1.5

The median PFS was not reached for T-DXd and was 6.8 months for T-DM1 (HR, 0.28; 95%CI, 0.22-0.37; P=7.8 x 10-22). The ORR was 79.7% for T-DXd and 34.2% for T-DM1.

The results presented at SABCS 2021 provided key subgroup analyses, including the relative efficacy of the 2 antibody-drug conjugates in patients with brain metastases.3 These results were presented by Sara Hurvitz, MD, of the Jonsson Comprehensive Cancer Center at University of California, Los Angeles.

For patients with stable brain metastasis at baseline (n=82), the median PFS was 15.0 months with T-DXd and 3.0 months with T-DM1 (HR, 0.25; 95% CI, 0.31-0.45). 

The extracranial ORR was 67.4% for T-DXd and 20.5% for T-DM1. The intracranial ORR was 63.9% and 33.3%, respectively. The complete response rates were 27.8% and 2.8%, respectively.

Consistent benefit was observed for T-DXd across other subgroups as well.

Overall, T-DXd demonstrated a manageable and tolerable safety profile, according to Dr Hurvitz. The median treatment duration was 14.3 months for T-DXd and 6.9 months for T-DM1.

Adjudicated drug-related interstitial lung disease/pneumonitis was reported in 10.5% of patients treated with T-DXd and 1.9% treated with T-DM1. There were no grade 4 or 5 cases.

The investigators concluded that T-DXd was superior to T-DM1 and should become standard second-line care in patients with HER2+ mBC.

Implications and Future Directions

For those clinicians who did not already adopt T-DXd for initial relapses of HER2+ mBC after ESMO 2021, the detailed analysis of the DESTINY-Breast03 study was practice-changing.  

For most patients with disease progression on taxanes plus anti-HER2 therapy, T-DXd is preferred over T-DM1, based on the impressive PFS and ORR data.

Future research will inform how making T-DXd the second-line treatment will influence responses to subsequent therapies (T-DM1 and TKIs) and whether there are practical strategies to reverse resistance to anti-HER2 therapies.

Important questions remain about the impact of second-line T-DXd on OS, the likelihood of developing brain metastases in patients without them, and the incidence of radiation necrosis in brain metastases that require radiation.

Despite the limitations and requirements for additional study, the foregoing phase 3 drug trials presented at SABCS 2021 gave oncologists a glimpse into an exciting future, one in which the use of genomics and continued dedication to personalized therapy will have even more relevance to second- and later-line therapy for all subtypes of mBC than currently. 

With continued expansion of the treatment options for all breast cancer subtypes, choosing the appropriate sequence of therapies will continue to require balancing anticipated toxicities of each available agent, comorbid conditions that could adversely affect the patient’s experience, the presence or absence of special metastatic sites, and scrutiny for molecular mediators of resistance to 1 or more agents that might otherwise be chosen.

Disclosures: The EMERALD study was sponsored by Radius Health and co-funded by Menarini Group. The PHOEBE study was sponsored by Jiangsu Hengrui Pharmaceuticals Company Ltd. The DESTINY-Breast03 study was sponsored by Daiichi Sankyo, Inc., in collaboration with AstraZeneca. All 3 presenters declared affiliations with biotech, pharmaceutical, and/or device companies. 

References

  1. Bardia A, Neven P, Streich G, et al. Elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of the EMERALD phase 3 trial. Presented at SABCS 2021; December 7-10, 2021; San Antonio, TX. Abstract GS2-02.
  2. Xu B, Yan M, Ma F, et al. Updated overall survival (OS) results from the phase 3 PHOEBE trial of pyrotinib versus lapatinib in combination with capecitabine in patients with HER2-positive metastatic breast cancer. Presented at SABCS 2021; December 7-10, 2021; San Antonio, TX. Abstract GS3-02.
  3. Hurvitz S, Kim S-B, Chung W-P, et al. Trastuzumab deruxtecan (T-DXd; DS-8201a) vs. trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): Subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Presented at SABCS 2021; December 7-10, 2021; San Antonio, TX. Abstract GS3-01.
  4. Xu B, Yan M, Ma F, et al. Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): A multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 22(3):351-360. doi:10.1016/S1470-2045(20)30702-6
  5. Cortés J, Kim S, Chung W, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): Results of the randomized phase III DESTINY-Breast03 study. Presented at ESMO Congress 2021; September 16-21, 2021. Abstract LBA1.