FDA Grants Priority Review to Fam-Trastuzumab Deruxtecan-Nxki for HER2+ mBC

The FDA has accepted a supplement biologics license application (sBLA) for fam-trastuzumab deruxtecan-nxki (Enhertu) and granted it priority review for the treatment of adult patients with unresectable or HER2-positive metastatic breast cancer (mBC) who have received a prior anti-HER2- based regimen, according to a press release issued by Daiichi Sankyo Company, Limited.¹

The sBLA will be evaluated under the FDA’s Real-Time Oncology Review and Project Orbis and a prescription drug user fee action date in the second quarter of 2022. Data from the phase 3 DESTINY-Breast03 support the application for approval.

“This regulatory review of Enhertu in the U.S. marks the first time this medicine is participating in both the Real-Time Oncology Review and Project Orbis programs,” said Ken Takeshita, MD, global head, R&D, Daiichi Sankyo, in a press release. “The FDA’s prioritization of our application underscores the potential of this medicine and the continued need to expedite the availability of new treatment options, while making it possible to potentially receive approvals in several countries concurrently.”

In the phase 3, multicenter, randomized, open-label, active-controlled study (NCT03529110), a highly statistically significant and clinically meaningful improvement in progression-free survival (PFS) was shown with trastuzumab deruxtecan versus ado trastuzumab emtansine (T-DM1; Kadcyla) in patients with HER2-positive mBC who were previously treated with trastuzumab and a taxane. The treatment was also found to be tolerable in this patient population.^2,3

The study randomized 524 patients 1:1 to receive either trastuzumab deruxtecan or T-DM1. The primary end point of 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.

Patients in the study had a median age of 54.3 years (range, 27.9-83.1) in the experimental arm compared with 54.2 years (range, 20.2-83.0) in the control arm. Most of the patients were from Asian countries including 57.1% of the trastuzumab deruxtecan arm versus 60.8% of the T-DM1 arm. Moreover, 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.

Baseline information showed that the majority of patients, including 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. Over 21% of the experimental arm versus 24.7% of the control arm had received 2 prior lines of therapy, however. Some of the study subjects also 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). Among the remaining patients, anti-HER2 therapies were received as prior therapy.

Patients with HER2-positive mBC in the study were followed for a median 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.

According to investigator assessment the median PFS was 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 was favorable for the experimental arm across all assessed subgroups.

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%) versus 85.9% (95% CI, 80.9%-89.7%) in the T-DM1 arm (HR, 0.56; 95% CI, 0.36-0.86); P =.007172).

The confirmed ORR in the trastuzumab deruxtecan-treated population was 79.7% (95% C 74.3%-84.4%) versus 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 compared with 8.7% of the control arm, and partial responses and stable disease 63.6% and 16.9% versus 25.5% and 42.6%, respectively. Progressive disease was seen in 1.1% of patients in the trastuzumab deruxtecan arm versus 17.5% of the control arm. Of those enrolled, 21 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.

Safety data showed that 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 compared with 86.6% of the T-DM1 arm. Events were grade 3 or higher for 45.1% of the experimental arm compared with 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. No deaths in the study were seen in either treatment arm.

“This review across geographies and the priority review in the U.S. as part of Project Orbis is so important because it speaks to the transformative potential of Enhertu based on the unprecedented progression-free survival benefit in this setting,” said Susan Galbraith, Executive vice president, Oncology R&D, AstraZeneca. “The news reinforces the importance of bringing this potential new option to patients as quickly as possible,” in the press release.¹

_References:

_{1. ENHERTU® granted priority review in the U.S. for patients with HER2 positive metastatic breast cancer treated with a prior anti-HER2-based regimen. News release. January 17, 2022. Accessed January 17, 2022.}

_{2. 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 January 17, 2022. https://bit.ly/3BbYMIf}

_{3. 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.}