FDA Approves Trastuzumab Deruxtecan for Certain Patients With HER2-Positive Metastatic Breast Cancer

The FDA has granted a full approval to trastuzumab deruxtecan (Enhertu; AstraZeneca and Daiichi Sankyo) for adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer who were previously administered an anti–HER2-based regimen in the metastatic setting, in the neoadjuvant setting, or adjuvant setting, and who developed disease recurrence during or within 6 months of completing therapy.¹

“Enhertu has demonstrated significant progression-free survival in the earlier metastatic setting, potentially establishing it as a new standard of care in previously treated patients with HER2-positive metastatic breast cancer,” Erika Hamilton, MD, director of the Breast Cancer and Gynecological Cancer Research Program for Sarah Cannon Research Institute, said in a press release. “[The] approval is an important milestone for the clinical community as we will now be able to offer Enhertu to these patients earlier in their treatment.”

In December 2019, the FDA granted trastuzumab deruxtecan an accelerated approval for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer previously administered 2 or more prior anti–HER2-based regimens in the metastatic setting.

The approval was based on the multicenter, open-label, DESTINY-Breast03 trial (NCT03529110).² To be eligible for enrollment, patients needed to have HER2-positive, unresectable or metastatic breast cancer that progressed during or after treatment with trastuzumab (Herceptin) and a taxane in the context of advanced or metastatic disease or that had progressed within 6 months after neoadjuvant or adjuvant therapy with trastuzumab or a taxane. Patients were also permitted with clinically stable, previously treated brain metastases.

Patients were excluded if they had brain metastases that were symptomatic or needed treatment; if they were previously administered a HER2-targeted antibody drug conjugate, including trastuzumab emtansine (Kadcyla; T-DM1), for metastatic disease; or if they had a history of noninfectious interstitial lung disease for which they were administered glucocorticoids.

The study randomized 524 patients 1:1 to receive intravenous (IV) trastuzumab deruxtecan at 5.4 mg/kg every 3 weeks (n = 261) or IV T-DM1 at 3.6 mg/kg every 3 weeks (n = 263). Treatment was administered until disease progression or intolerable toxicity. Stratification factors included hormone receptor status (positive or negative), previous treatment with pertuzumab (Perjeta; yes or no), and history of visceral disease (yes or no).

The trial’s primary end point of was progression-free survival (PFS) per blinded independent central review (BICR), and overall survival (OS) served as a key secondary end point. Other end points included overall response per BICR and investigator assessment, investigator-assessed PFS, and safety.

Among patients in the trial, 49.8% of those in the investigative cohort and 46.8% of those in the control cohort had received 1 prior line of therapy, not including endocrine therapy, for metastatic disease. Further, 62.1% of patients in the trastuzumab deruxtecan cohort previously received pertuzumab compared with 60.1% of patients in the T-DM1 cohort. Stable brain metatases were observed in 23.8% in the trastuzumab deruxtecan cohort and 19.8% of patients in the T-DM1 cohort.

The median follow-up in the investigative cohort was 16.2 months (range, 0-32.7) compared with 15.3 months (range, 0-31.3) in the control group. Trastuzumab deruxtecan was found to significantly improve PFS compared with T-DM1, with the median PFS not yet reached (95% CI, 18.5–not estimable [NE]) in the investigative group compared with 6.8 months (95% CI, 5.6-8.2) in the control group (HR, 0.28; 95% CI, 0.22-0.37; P <.0001).

At 12 months, 75.8% (95% CI, 69.8%-80.7%) of patients administered trastuzumab deruxtecan were still alive and free of disease progression compared with 34.1% (95% CI, 27.7%-40.5%) of patients administered T-DM1. Per investigator assessment, median PFS in the investigative cohort was 25.1 months (95% CI, 22.1-NE) compared with 7.2 months (95% CI, 6.8-8.3) in the control group (HR, 0.26; 95% CI, 0.20-0.35; P <.001).

The PFS benefit of trastuzumab deruxtecan compared with T-DM1 was noted across all subsets of patients examined, irrespective of prior lines of therapy received. At the interim analysis data cutoff of May 21, 2021, 94.1% (95% CI, 90.3%-96.4%) of patients in the investigative cohort were still alive at 12 months compared with 85.9% (95% CI, 80.9%-89.7%) of those in the control arm (HR, 0.55; 95% CI, 0.36-0.86; P =.007).

"Data from DESTINY-Breast03 not only confirmed the results of DESTINY-Breast01, but also demonstrated the superiority of Enhertu in prolonging progression-free survival compared to T-DM1 in an earlier setting of HER2-positive metastatic breast cancer,” Ken Keller, global head, Oncology Business and president and CEO, Daiichi Sankyo, Inc, said in the press release.

The objective response rate based on the patients with measurable disease assessed by BICR at baseline was 82.7% (95% CI, 77.4%-87.2%) in the trastuzumab deruxtecan cohort compared with 36.1% (95% CI, 30.0%-42.5%) in the T-DM1 cohort.

The most frequent toxicities experienced by patients administered trastuzumab deruxtecan were nausea, fatigue, vomiting, alopecia, constipation, anemia, and musculoskeletal pain.

Serious adverse effects reported in more than 1% of patients administered trastuzumab deruxtecan included vomiting, interstitial lung disease, pneumonia, pyrexia, and urinary tract infection. The FDA noted that prescribing information for trastuzumab deruxtecan includes a Boxed Warning for the risk of interstitial lung disease and embryo-fetal toxicity.

Last month, the FDA granted trastuzumab deruxtecan Breakthrough Therapy Designation for the treatment of patients with HER2-low metastatic breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.

“Enhertu is already established in the later-line treatment of patients with HER2-positive metastatic breast cancer, and we are thrilled that with this approval, patients in the US will now be able to access the transformative potential of Enhertu earlier in their treatment,” Dave Fredrickson, executive vice president, Oncology Business Unit, AstraZeneca, said in a press release.

References

1. Enhertu approved in the US for patients with HER2-positive metastatic breast cancer treated with a prior anti-HER2-based regimen. AstraZeneca. News release. May 5, 2022. https://www.astrazeneca.com/media-centre/press-releases/2022/enhertu-approved-in-us-for-2l-her2-positive-breast-cancer.html
2. Cortés J, Kim S-B, Chung W-P, et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022;386(12):1143-1154. doi:10.1056/NEJMoa2115022