Supported via arm's length funding from Gilead.

Highlights from

SABCS 2021

San Antonio Breast Cancer Symposium

San Antonio, Texas, 7 - 10 December 2021

DESTINY-Breast03 trial: survival outcomes with T-DXd versus T-DM1 in patients with HER2+ unresectable or metastatic breast cancer

Take-home messages
  • Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) provides a survival benefit for patients with HER2+ unresectable or metastatic breast cancer
  • T-DXd shows greater efficacy compared with T-DM1 in patients with or without brain metastases
  • The intracranial response in patients with brain metastases is considerably higher with T-DXd compared with T-DM1
"My opinion is that these data support the use of T-DXd in second-line setting as a standard of care."

Dr Sara Hurvitz from David Geffen School of Medicine, UCLA, Los Angeles, CA, US

The interim progression-free survival (PFS) results from the DESTINY-Breast03 trial, the first randomised phase III clinical trial of T-DXd, were reported at the ESMO Congress earlier this year. Dr Sara Hurvitz from David Geffen School of Medicine, UCLA, Los Angeles, CA, US was at SABCS 2021 on 9 December to talk about the subgroup analysis results.

In the trial, patients with unresectable or metastatic HER2+ breast cancer that had previously been treated with trastuzumab and a taxane (N=524) were randomised 1:1 to receive T-DXd (n=261) or T-DM1 (n=263). Patients who had clinically stable, treatable brain metastases were eligible for the study as long as there were at least 2 weeks between the end of whole brain radiotherapy and study enrolment. Patients were required to have recovered from toxicities of any local treatment.

Stratification factors were hormone receptor status, prior treatment with pertuzumab and history of visceral disease. Of the patient population, ~20% had a history of brain metastases and "those patients who had brain metastases at baseline on imaging comprised about 15% of the patient population and that is going to be the population I discuss in my coming slides" commented Dr Hurvitz.

Dr Hurvitz first reminded the audience of the primary endpoint results previously presented at the ESMO Congress: the 12-month PFS rates were 75.8% (95% CI: 69.8-80.7) in the T-DXd arm and 34.1% (95% CI: 27.7-40.5) in the T-DM1 arm (HR: 0.28, 95% CI: 0.22-0.37, p=7.8x10-22). The PFS benefit was consistent across all subgroups and patients benefited from T-DXd regardless of hormone receptor status, prior pertuzumab treatment, presence or absence of visceral disease, number of prior lines of therapy and brain metastases.

The trend with PFS rates was also observed with objective response rate (ORR); patients who received T-DXd showed higher objective response (79.7%) compared with those who received T-DM1 (34.2%) in the overall population, and ORR in the T-DXd arm was at least ~40% higher in the T-DXd arm in all subgroups.

The Kaplan-Meier estimate of median PFS in patients who had brain metastases at baseline was 15.0 months in the T-DXd arm (n=43) and 3.0 months in the T-DM1 arm (n=39; HR: 0.25, 95% CI: 0.13-0.45). In patients with no brain metastases at baseline, median PFS was not reached in the T-DXd arm (n=218) and was 7.1 months in the T-DM1 arm (n=224; HR: 0.30, 95% CI: 0.22-0.40).

Overall ORR in patients who had a history of brain metastases was 67.4% in the T-DXd group and 20.5% in the T-DM1 group. In patients who had brain metastases at baseline, the intracranial ORR was 63.9% in the T-DXd group compared with 33.4% in the T-DM1 group. Intracranial response per BICR using RECIST 1.1 showed that the complete response in the T-DXd group was 27.8% versus 2.8% in the T-DM1 group. Partial response rates were 36.1% and 30.6% in the T-DXd and T-DM1 groups respectively.

Median treatment duration was 14.3 months for the patients receiving T-DXd and 6.9 months for the patients receiving T‑DM1. Treatment-emergent adverse event rates (TEAEs) of any grade and of grade ≥3 were observed at similar rates in both study arms, with grade ≥3 TEAEs in 52.1% versus 48.3% of patients in the T‑DXd and T‑DM1 groups, respectively. Exposure-adjusted incidence rates (EAIRs) were lower with T-DXd compared with T‑DM1. Although rates of TEAEs associated with discontinuation were greater with T‑DXd versus T-DM1, EAIRs were similar.

Nausea, vomiting and fatigue were the most commonly observed any-grade TEAEs observed in at least 20% of patients in both treatment arms.

Overall , data generated from DESTINY-Breast03 this year demonstrate that T-DXd can provide a consistent efficacy benefit over T-DM1, in both the PFS and ORR endpoints across patient subgroups. In patients with and without brain metastases, treatment with T-DXd resulted in greater efficacy compared with T-DM1. T-DXd was associated with substantial intracranial response and reduction in central nervous system disease. Treatment with T-DXd had a manageable safety profile.

During the Q&A following her presentation, Dr Hurvitz was asked for her thoughts on whether this could affect treatment sequencing, and where T-DXd would fit alongside tucatinib. "My opinion is that these data support the use of T-DXd in second-line setting as a standard of care. I don't think PFS of this long… it hasn’t yet been reached. By investigator assessment it was around 2 years for T-DXd, which exceeded that for tucatinib. I think for tucatinib the overall survival was around that, not the progression-free survival, so I would see T-DXd as being the standard second-line treatment for patients based on the data and tucatinib playing a very important role at this point in the third-line setting."

BICR: Blinded Independent Central Review; CI: confidence interval; ESMO: European Society for Medical Oncology; HER2: human epidermal growth factor receptor 2; HR: hazard ratio; RECIST: response evaluation criteria in solid tumours

Based on:
Hurvitz S, Kim S-B 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 (abstract GS3-01). Presented on Thursday 9 December 2021

Top image: rustycloud

Article image: Naeblys

The content and interpretation of these conference highlights are the views and comments of the speakers/ authors.

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