From Pages to Practice

By Roma Bhatia, MD

Published July 19, 2022


A 66-year-old woman with metastatic HER2-positive breast cancer returns to her oncologist after treatment with trastuzumab and pertuzumab, the standard first-line treatment, only to learn that her disease has progressed. The oncologist offers her two choices for second-line treatment: trastuzumab deruxtecan (T-DXd), a HER2 antibody and topoisomerase inhibitor conjugate, respectively, or trastuzumab emtansine (T-DM1), a combination of HER2 antibody and the cytotoxic agent DM1. Which should she choose? Is there an evidence-based superior option?

Recently published interim results of the ongoing phase 3 DESTINY-Breast03 trial shed some light on this question. Investigators randomized 524 individuals with metastatic HER2-positive breast cancer to receive either T-DXd or T-DM1. Roughly half the patients in both groups had metastatic disease for which they had received one previous line of therapy.

After a median follow up of 16 months in the T-DXd group and 15 months in the T-DM1 group, T-DXd showed a clear benefit as compared with T-DM1 for the primary end point of progression-free survival (76% vs. 34% at 12 months)  Furthermore, 16% vs. 9% of patients, respectively, had complete responses. Median progression-free survival was not yet reached in the T-DXd group versus a median of 6.8 months in the T-DM1 group, equating to a 72% reduction in the risk of progression or death with T-DXd treatment (hazard ratio, 0.28). In fact, nearly all patients (97%) who received T-DXd had disease control. The benefit of T-DXd was evident across subgroups, including those defined by tumor hormone receptor status, history of stable brain metastases, and number of lines of previous therapies.

Adverse events were comparable with the two treatments (approximately 15% of participants in each group had grade 3 or more serious adverse events). The most common treatment-related adverse event was interstitial lung disease with T-DXd (approximately 8% of the patients) and thrombocytopenia with T-DM1 (25%).

These results are clearly practice changing and support the use of T-DXd over T-DM1 as second-line treatment for metastatic, unresectable HER2-positive breast cancer. For the patient described above who does not have a history of underlying lung disease, it would be wise to counsel her to choose T-DXd as the next treatment for metastatic HER-2 positive breast cancer.

The following NEJM Journal Watch summary explains more details of the study.

DESTINY-Breast03: Improving Outcomes in Metastatic HER2-Positive Breast Cancer

William J. Gradishar, MD, reviewing Cortés J et al. N Engl J Med 2022 Mar 24

The treatment of metastatic, HER2-positive breast cancer has improved dramatically in recent years as more effective therapies have been introduced. The standard first-line therapy remains a taxane combined with dual HER2 targeting with trastuzumab and pertuzumab, the so-called Cleopatra regimen. On disease progression, most patients would receive the antibody-drug conjugate trastuzumab-emtansine (T-DM1). Thereafter, a variety of HER2 therapies could be considered, including recently approved trastuzumab deruxtecan (T-DXd) and the triplet of trastuzumab, tucatinib, and capecitabine.

The DESTINY-Breast03 study is an industry-sponsored, phase 3, multicenter randomized trial comparing T-DXd to T-DM1 in patients with HER2-positive metastatic breast cancer who had previously been treated with a taxane and trastuzumab. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), response rate (RR), and safety. Of 524 patients, median age was 54 years, 51% had ER-positive tumors, 61% had received pertuzumab, and 22% had stable brain metastases.

At 12 months, the PFS rate was 75.8% in patients receiving T-DX-d versus 34.1% in those receiving T-DM1 (P<0.001). RR was 79.7% in those receiving T-DX-d versus 34.2% in those receiving T-DM-1. Overall survival data were immature at the time of the analysis. Drug-related interstitial lung disease, a concern from early trials of T-DXd, was reported in 10.5% of patients on T-DX-d versus 1.9% on T-DM1, though no cases were grade 4 or 5. 

Comment: The results of DESTINY-Breast03 are practice changing. The efficacy of T-DXd in comparison to T-DM1 will move T-DXd up as a preferred treatment choice for patients who develop progressive disease after treatment with a taxane and trastuzumab (and pertuzumab). There may be individual patients, such as those with significant preexisting inflammatory lung disease, for whom another second-line treatment may be chosen, but for the majority of patients, T-DXd will be the “go-to” choice as second-line treatment.

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Roma Bhatia, MD, is a 2021–2022 NEJM Editorial Fellow.