DESTINY Breast03: Second-Line Fam-Trastuzumab Deruxtecan-nxki for Metastatic HER2-Positive Breast Cancer

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Fam-trastuzumab deruxtecan-nxki (T-DXd) showed statistically significant improvement in progression-free survival vs trastuzumab emtansine (T-DM1) in second-line treatment for HER2-positive unresectable or metastatic breast cancer, according to results from the global phase III DESTINY-Breast03 trial, which was presented by Javier Cortés, MD, PhD, and colleagues at a Presidential Symposium during the European Society for Medical Oncology (ESMO) Congress 2021 (Abstract LBA1).

Treatment with T-DXd led to a highly significant 72% reduction in the risk of progression vs ado-trastuzumab emtansine (T-DM1) in patients who had received treatment with a taxane and trastuzumab (hazard ratio [HR] = 0.2840; P = 7.8 × 10−22), according to Dr. Cortés, Head of Breast Cancer and Gynecological Cancers at the Hospital Universitario Ramón y Cajal in Madrid, Spain.

The benefit was seen across subgroups and in other endpoints, and a trend has emerged as well in overall survival, though these data remain immature, he said.

Javier Cortés, MD, PhD

Javier Cortés, MD, PhD

Shanu Modi, MD

Shanu Modi, MD

“This is terrific news for patients…. In my opinion, based on these data, T-DXd should replace T-DM1 as the standard of care for patients who have previously received trastuzumab and a taxane,” Dr. Cortés said. 

Invited discussant Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center, agreed: “T-DXd is now my preferred antibody-drug conjugate in the second-line setting.”

Dr. Modi continued: “I think the progression-free survival curves from DESTINY-Breast03 are absolutely startling. I don’t believe I’ve seen a hazard ratio like this in HER2-positive breast cancer. The efficacy of T-DXd in this randomized trial is unprecedented, and secondary endpoints and subgroup analyses likewise favored T-DXd…. Most importantly, T-DXd delivered in this early-line setting was associated with less lung toxicity [than in DESTINY-Breast01], resetting the risk/benefit analysis in its favor.”

About DESTINY-Breast03

Fam-trastuzumab deruxtecan-nxki was approved by the U.S. Food and Drug Administration in December 2019 for the treatment of patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti–HER2-based regimens, based on results from the phase II DESTINY-Breast01 trial.

The open-label randomized DESTINY-Breast03 trial is the first global phase III head-to-head trial of T-DXd against an active control in patients with HER2-positive metastatic breast cancer following initial treatment with trastuzumab and a taxane. The study randomly assigned 524 previously treated patients from North America, South America, Europe, Asia, and Oceania to receive T-DXd at 5.4 mg/kg or T-DM1 at 3.6 mg/kg every 3 weeks. The primary endpoint was progression-free survival measured by blinded independent central review.

Progression-Free Survival: Primary Endpoint Met

At a median follow-up of about 16 months, median progression-free survival by blinded independent central review was not reached with T-DXd and was 6.8 months with T-DM1 (hazard ratio [HR] = 0.2840; P = 7.8 × 10−22). By investigator review, median progression-free survival was 25.1 months with T-DXd and 7.2 months with T-DM1 (HR = 0.2649; P = 6.5 × 10−24).

The benefit was observed across all prespecified subgroups, including patients with brain metastases (HR = 0.3796).


  • T-DXd led to a highly significant and clinically meaningful improvement in progression-free survival.
  • The rate of interstitial lung disease was 10.5%, almost all grade 1 or 2, which is notably less than seen in earlier studies of more heavily pretreated patients.

Confirmed responses were observed in 79.1% of those receiving T-DXd and 34.2% receiving T-DM1 (P < .0001). The estimated 12-month overall survival rate was 94.1% vs 85.9% (HR = 0.56; P = .007172), which did not cross the prespecified boundary for significance, “likely due to immature follow-up, in my opinion,” said Dr Cortés.

Safety results were consistent with prior clinical trials. Treatment-emergent adverse event rates were similar, and no new safety signals emerged. Adjudicated drug-related interstitial lung disease occurred in 10.5% of those in the T-DXd arm, 9.7% being grade 1 or 2 and none being grade 4 or 5. Interstitial lung disease, all grade 1 or 2, was diagnosed in 1.9% of patients in the T-DM1 arm. Left-ventricular ejection decreases, all grade 1 or 2, were seen in 2.7% and 0.4%, respectively.

The interstitial lung disease profile was significantly less concerning than was seen in previous trials of T-DXd in more heavily pretreated patients, emphasized Dr. Cortés.

In concluding their report, the study authors wrote, “T-DXd demonstrated a highly statistically significant and clinically meaningful improvement in progression-free survival vs T-DM1 in patients previously treated with trastuzumab and taxane for HER2-positive metastatic breast cancer. These data confirm that T-DXd is tolerable with manageable toxicity and a significant improvement in interstitial lung disease profile vs studies performed in more heavily pretreated patients. This study will lead to a paradigm shift in the treatment of HER2-positive metastatic breast cancer.”

Disclosure: For full disclosures of the study authors, visit


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