FDA Grants Breakthrough Therapy Designation to Trastuzumab Deruxtecan for HER2+ mBC


Based on results from the DESTINY-Breast03 clinical trial, trastuzumab deruxtecan has been granted another breakthrough therapy designation by the FDA.

The FDA has granted a breakthrough therapy designation to trastuzumab deruxtecan (Enhertu) for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer (HER2-positive mBC) who have received one or more prior anti-HER2-based regimens, according to a press release issued by AstraZeneca and Daiichi Sankyo.

Results from the DESTINY-Breast03 clinical trial (NCT03529110), which were recently presented during the European Society of Medical Oncology (ESMO) Congress 2021 led the FDA to grant this designation. The study showed a highly statistically significant and clinically meaningful improvement in progression-free survival with trastuzumab deruxtecan versus T-DM1 in patients with HER2-positive mBC who were previously treated with trastuzumab and a taxane. The treatment was also tolerable in these patients.

“This is an important step in bringing Enhertu as a potential new option in earlier lines of treatment for HER2-positive metastatic breast cancer, given the urgent need to improve outcomes. This recognition by the FDA underscores the transformative possibility of Enhertu seen with the remarkable DESTINY-Breast03 results presented at ESMO just two weeks ago, said Susan Galbraith, executive vice president, Oncology R&D at AstraZeneca, in a press release.

In DESTINY-Breast03, 524 patients were randomized 1:1 to receive either trastuzumab deruxtecan or T-DM1. The primary end point evaluated in the study was PFS by blinded independent central review (BICR), and secondary end points included overall survival (OS), objective response rate (ORR), duration of response (DOR), PFS by investigator assessment, and safety.

At baseline, the study population had a median age of 54.3 years (range 27.9-83.1) in the experimental arm versus 54.2 years (range 20.2-83.0) in the control arm. The majority of patients were from Asian countries including 57.1% of the trastuzumab deruxtecan arm versus 60.8% of the T-DM1 arm. Most patients in the trastuzumab deruxtecan arm versus the T-DM1 arm also had an ECOG performance status of 0 (59.0% vs 66.5%), hormone-receptor-positive disease (50.2% vs 51.0%), no presence of brain metastases (76.3% vs 80.2%), and most had visceral disease (70.5% vs 70.3%), respectively.

In terms of prior therapy, 92.0% of the trastuzumab deruxtecan arm compared with 89.0% of the T-DM1 arm were previously treated. Most patients in the study had 1 prior line of therapy including 49.8% of the experimental arm versus 46.8% of the control arm. More than 21% of the experimental arm versus 24.7% of the control arm had received 2 prior lines of therapy, however. The cohort also included a small number of patients who received 5 or more prior lines of therapy. Prior therapy for cancer was predominantly trastuzumab, but 62.1% of the trastuzumab deruxtecan arm versus 60.1% of the T-DM1 arm received prior pertuzumab (Perjeta), and the remaining patient received other anti-HER2 therapies.

At a median follow up of 15.5 months (range, 15.1-16.6) in the experimental arm and 13.9 months (range, 11.8-15.1) in the control arms, the median PFS by BICR was not reached (95% CI, 18.5 to not evaluable [NE]) versus 6.8 months (95% CI, 5.6-8.2), respectively (HR, 0.28; 95% CI, 0.22-0.37; P 7.8 x 10-22. The 12-month PFS rate by BICR was 75/8% (95% CI, 69.8%-80.7%) in the trastuzumab deruxtecan arm compared with 34.1% (95% CI, 27.7%-40.5%) in the T-DM1 arm.

PFS by investigator assessment was a median of 25.1 months (95% CI, 22.1-NE) with the experimental therapy compared with 7.2 months (95% CI, 6.8-8.3) in the T-DM1 arm (HR, 0.21; 95% CI, 0.20-0.35; P – 6.5 x 10-24. At 12 months, the PFS rate in the trastuzumab deruxtecan group was 76.3% (95% CI, 70.4%-81.2%) compared with 34.9% (95% CI, 28.8%-41.2%) in the control arm.

PFS results were in favor of trastuzumab deruxtecan across all key subgroups evaluated.

In terms of the other secondary end points, the median OS was not evaluable at the time of the analysis. The 12-month PFS rate with trastuzumab deruxtecan was 94.1 months (95% CI, 90.3%-96.4%) compared with 85.9% (95% CI, 80.9%-89.7%) in the T-DM1 arm (HR, 0.56; 95% CI, 0.36-0.86); =.007172).

The confirmed ORR in the trastuzumab deruxtecan-treated population was 79.7% (95% C 74.3%-84.4%) compared with only 34.2% (95% CI, 28.5%-40.3%) in the T-DM1 arm (P <.0001). Complete responses were observed in 16.1% of the experimental arm versus 8.7% of the control arm, and partial responses and stable disease 63.6% and 16.9% versus 25.5% and 42.6%, respectively. Further, progressive disease was seen in only 1.1% of patients in the trastuzumab deruxtecan arm versus 17.5% of the control arm. Twenty-one patients in the study were not evaluable for response. The disease control rates were 96.6% in the trastuzumab deruxtecan versus 76.8% in the T-DM1 arm.

Patients were treated in the study for a median duration of 14.3 months (range, 0.7-29.8) with trastuzumab deruxtecan and 6.9 months (range, 0.7-25.1) with T-DM1. Treatment-emergent adverse events (TEAEs) were observed in 98.1% of the trastuzumab deruxtecan arm versus 86.6% of the T-DM1 arm. Events were grade 3 or higher for 45.1% of the experimental arm versus 39.8% of the control arm. Treatment discontinuation related to a study drug occurred in 12.8% of the trastuzumab deruxtecan arm versus 5.0% of the T-DM1 arm, and dose reductions occurred in 21.4% versus 12.6%, respectively. There were no deaths in either treatment arm.

It was noted during the ESMO presentation of the results that the most common TEAE that lead to treatment discontinuation of trastuzumab deruxtecan was ILD/pneumonitis, which occurred in 8.2% of patients. In the T-DM1 arm, thrombocytopenia mostly lead to treatment discontinuation, which occurred in 2.7% of patients.

With a breakthrough therapy designation from the FDA, the development of trastuzumab deruxtecan will be accelerated to serve an unmet medical need in the field.

“By granting a fourth breakthrough therapy designation to Enhertu, the FDA continues to recognize the significant potential of this medicine across multiple HER2-targetable tumors. With the unprecedented data recently reported from the DESTINY-Breast03 trial, we look forward to working closely with the FDA to bring Enhertu to patients who have been previously treated for HER2-positive metastatic breast cancer as soon as possible,” said Ken Takeshita, global head of at R&D, Daiichi Sankyo, in the press release.


1. Enhertu granted breakthrough therapy designation in US for patients with HER2-positive metastatic breast cancer treated with one or more prior anti-HER2-based regimens. News release. October 4, 2021. Accessed October 4, 2021. https://bit.ly/3BbYMIf

2. Cortes J, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients with her2+ metastatic breast cancer: results of the randomized, phase 3 study DESTINY-Breast03. Presented at: 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract LBA1.

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