SUMMARY: The FDA on May 4, 2022, approved ENHERTU® (Trastuzumab Deruxtecan) for adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy. In 2019, ENHERTU® received accelerated approval for adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. The following trial was the confirmatory trial for the accelerated approval. Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence.
The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. HER2-targeted therapies include HERCEPTIN® (Trastuzumab), TYKERB® (Lapatinib), PERJETA® (Pertuzumab) and KADCYLA® (ado-Trastuzumab emtansine). Dual HER2 blockade with HERCEPTIN® and PERJETA® given along with chemotherapy (with or without endocrine therapy), as first line treatment, in HER2 positive metastatic breast cancer patients, was shown to significantly improve Progression Free Survival (PFS) as well as Overall Survival (OS). The superior benefit with dual HER2 blockade has been attributed to differing mechanisms of action and synergistic interaction between HER2 targeted therapies. Patients progressing on Dual HER2 blockade often receive KADCYLA® which results in an Objective Response Rate (ORR) of 44% and a median PFS of 9.6 months, when administered after HERCEPTIN® and a taxane. There is however no standard treatment option for this patient population following progression on KADCYLA®.
ENHERTU® (Trastuzumab Deruxtecan) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). ENHERTU® has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike KADCYLA®, ENHERTU® has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life , thus minimizing systemic exposure. In the DESTINY-Breast 01 Phase II registration trial involving patients with HER2-positive metastatic breast cancer, who had received two or more prior HER2 targeted therapies including KADCYLA®, the Objective Response Rate (ORR) was 60.9%, with 6% Complete Responses and 54.9% Partial Response, with a median response duration of 14.8 months. The median PFS was 16.4 months. This benefit was consistent across all key subgroups, including patients who had previously received PERJETA® therapy.
The present FDA approval was based on DESTINY-Breast 03, which is a global, multicenter, open-label, randomized Phase III study, in which the efficacy and safety of ENHERTU® was compared with KADCYLA®, in patients with HER2-positive metastatic breast cancer previously treated with Trastuzumab and a Taxane or developed disease recurrence during or within 6 months of completing neoadjuvant or adjuvant therapy. In this study, 524 pts were randomized 1:1 to receive ENHERTU® 5.4 mg/kg (N=261) or KADCYLA® 3.6 mg/kg (N=263) once every 3 weeks. Randomization was stratified by hormone receptor status, prior treatment with Pertuzumab, and history of visceral disease. The median patient age was 54 years and patients in both treatment groups were comparable in terms of baseline characteristics including age, HER2-positivity status, ECOG Performance Status, prior treatment for breast cancer, brain metastases, and prior cancer therapy with agents including Trastuzumab. The Primary endpoint was Progression Free Survival (PFS) by Blinded Independent Central Review (BICR). Secondary endpoints include Overall Survival (OS), Objective Response Rate (ORR), Duration of Response, PFS by investigator, and Safety.
At the time of the prespecified interim analysis of this study, the median follow up was approximately 16 months and the median PFS by BICR review was Not Reached with ENHERTU® and was 6.8 months with KADCYLA® (HR=0.28; P= <0.0001). This represented a very statistically significant 72% reduction in the risk for progression or death with ENHERTU® compared to KADCYLA®. The investigator-assessed PFS was similar (25.1 versus 7.2 months, HR=0.26, P<0.0001). This PFS benefit was observed as early as 4 weeks and remained consistent throughout the follow up period. PFS was significantly higher with ENHERTU® in all prespecified key subgroups, including Hormone Receptor status, prior treatment with PERJETA®, visceral disease, number of prior lines of therapy, and the presence or absence of brain metastases. Majority of patients in the ENHERTU® group experienced a reduction in tumor size, and the ORR was significantly higher among patients in the ENHERTU® compared to those who received KADCYLA® (82.7% versus 36.1%; P<0.0001), with a near doubling of the Complete Response rate in the ENHERTU® group, at 16.1% compared to 8.7% in the KADCYLA® group. The estimated 12-month Overall Survival rate was 94.1% versus 85.9% respectively (HR=0.56; P=0.007), but was not considered significant as it did not cross the prespecified boundary for significance, likely due to the immaturity of the dataset.
Adjudicated treatment related Interstitial Lung Disease/pneumonitis was more common in the ENHERTU® compared with the KADCYLA® treatment arm, at rates of 10.5% and 1.9%, respectively and most of the events were Grade 1 or 2 in severity, and none at Grade 4 or 5 in either treatment group. Interstitial Lung Disease profile was of less concern, than was seen in previous trials of ENHERTU® in more heavily pretreated patients. All Left Ventricular Ejection Fraction decreases were Grade 1 or 2 and were seen in 2.7% of the ENHERTU® group and in 0.4% of KADCYLA® group. Other serious adverse reactions in patients who received ENHERTU® included, vomiting, pyrexia, and urinary tract infection.
The researchers concluded that ENHERTU® demonstrated a highly statistically significant and clinically meaningful improvement in Progression Free Survival, when compared to KADCYLA®, in patients previously treated with Trastuzumab and Taxane for HER2-positive metastatic Breast cancer, with manageable toxicities.
Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (Pts) with HER2+ metastatic breast cancer (mBC): Results of the randomized phase III DESTINY-Breast03 study. Cortés J, Kim SB, Chung WP, et al. Presented at: European Society for Medical Oncology 2021 Virtual Congress. September 16-21, 2021; virtual. Abstract LBA1.