FDA Accepts BLA for Trastuzumab Deruxtecan in HER2-Low Metastatic Breast Cancer

The FDA has accepted an application for the approval of fam-trastuzumab deruxtecan-nxki for the treatment of select adult patients with unresectable or metastatic HER2-low breast cancer.

The FDA has accepted the biologics license application (BLA) for fam-trastuzumab deruxtecan-nxki (Enhertu) for the treatment of adult patients with unresectable or metastatic HER2-low breast cancer who have received a prior therapy in the metastatic setting, according to an announcement by AstraZeneca.1

Trastuzumab deruxtecan is a HER-2 directed antibody-drug conjugate (ADC) that was previously granted breakthrough therapy designation in April 2022 for patients with metastatic HER2-low breast cancer. Previously the FDA also granted accelerated approval for adult patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior anti–HER2-based regimens in the metastatic setting in 2019, and this accelerated approval was transitioned to a full regulatory approval on May 4, 2022.

Acceptance of the BLA by was based on data from the phase 3 DESTINY-Breast04 study (NCT03734029), in which trastuzumab deruxtecan demonstrated doubled progression-free survival (PFS) for patients with HER2-low, hormone receptor–positive metastatic breast cancer (MBC) treated with the ADC, and it also reduced the risk of death by 36% compared to physician's choice of chemotherapy.2,3 These data were presented at the 2022 ASCO Annual Meeting and simultaneously published in the New England Journal of Medicine.

“The data from DESTINY-Breast04 represent the first time a HER2-targeted therapy has shown a survival benefit in patients with HER2-low metastatic breast cancer. For more than 2 decades, only patients with HER2-positive breast cancer have been able to benefit from HER2-targeted therapies. If approved, Enhertu will redefine how we classify and treat metastatic breast cancer, enabling patients whose tumors have lower levels of HER2 expression the opportunity to benefit from a HER2-directed therapy,” stated Susan Galbraith, executive vice president, oncology R&D of AstraZeneca, in the press release.

Within the DESTINY-Breast04 study, 557 patients were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan at 5.4 mg/kg every 3 weeks (n = 373) or physician’s choice of chemotherapy at locally approved dosing (n = 184). Patients administered chemotherapy received capecitabine (Xeloda; 20.1%), eribulin (Halaven; 51.1%), gemcitabine (10.3%), paclitaxel (8.2%), or nab-paclitaxel (Abraxane; 10.3%).

Of those enrolled in the trial, patient characteristics were balanced between each arm and representative of the overall population of patients with HER2-negative breast cancer. The median age of patients in the trastuzumab deruxtecan arm was 57.5 years (range, 31.5-80.2) with 99.5% being female.

According to investigators, low expression of HER2 was defined as an IHC score of 1+ or 2+ with a negative in situ hybridization (ISH) test, and this represented approximately 65% of breast cancer diagnoses. In the study, 88.7% of patients were hormone receptor–positive while 11.3% were negative. HER2-low was IHC 1+ for 57.6% of patients and IHC 2+ and ISH-negative for 42.4%.

Further, ECOG performance status was split between 0 (53.6%) and 1 (46.4%), and the primary locations of metastases were the brain (6.4%), liver (71.3%), and lung (32.2%). Patients had received a median of 3 (range, 1-9) prior lines of therapy, consisting of targeted or immunotherapy (74.8%), endocrine therapy (93.0%), and chemotherapy (100%).

Findings revealed that among all enrolled in the study, the median PFS was 9.9 months (95% CI, 9.0-11.3) with trastuzumab deruxtecan vs 5.1 months (95% CI, 4.2-6.8) with chemotherapy (HR, 0.50; 95% CI, 0.40-0.63). In this group, the median OS was 23.4 months (95% CI, 20.0-24.8) with trastuzumab deruxtecan and 16.8 months (95% CI, 14.5-20.0) for chemotherapy. These data showed a 6.6-month improvement in survival with the agent (HR, 0.64; 95% CI, 0.49-0.84; P = .001).

For patients with hormone receptor–negative disease, the median PFS was 8.5 months (95% CI, 4.3-11.7) with trastuzumab deruxtecan vs 2.9 months (95% CI, 1.4-5.1) for chemotherapy (HR, 0.46; 95% CI, 0.24-0.89). In the hormone receptor–negative cohort, the median OS was 18.2 months (95% CI, 13.6-not estimable) with trastuzumab deruxtecan compared with 8.3 months (95% CI, 5.6-20.6) with chemotherapy (HR, 0.48; 95% CI, 0.24-0.95).

The overall response rate (ORR) was 52.3% (95% CI, 47.1%-57.4%) for patients treated with trastuzumab deruxtecan compared with 16.3% (95% CI, 11.3%-22.5%) with those given chemotherapy. Then in the hormone receptor–negative arm, the ORRs demonstrated were 50.0% (95% CI, 33.8%-66.2%) for trastuzumab deruxtecan (n = 40) vs 16.7% (95% CI, 3.6%-41.4%) for chemotherapy (n = 18). The ORR for patients with hormone receptor–positive disease was 52.6% (95% CI, 47.0%-58.0%) for trastuzumab deruxtecan (n = 333) vs 16.3% (95% CI, 11.0%-22.8%) for chemotherapy (n = 166). Median duration of response for patients in this group was 10.7 months with trastuzumab deruxtecan vs 6.8 months for physician's choice of chemotherapy.

Additionally, a consistent improvement in PFS across subgroups was demonstrated with trastuzumab deruxtecan as patients with hormone receptor–positive disease with a HER2 IHC score of 1+ had a median PFS of 10.3 months (95% CI, 8.6-12.3) with trastuzumab deruxtecan compared with 5.3 months (95% CI, 4.1-7.8) with chemotherapy (HR, 0.48; 95% CI, 0.35-0.65). For patients with hormone receptor–positive HER2 IHC 2+ and ISH-negative disease, the median PFS was 10.1 months (95% CI, 8.2-12.2) for trastuzumab deruxtecan compared with 5.9 months (95% CI, 4.3-7.9) for chemotherapy (HR, 0.55; 95% CI, 0.38-0.80).

Patients with hormone receptor–positive disease who had received prior treatment with a CDK4/6 inhibitor had a median PFS of 10.0 months (95% CI, 8.3-11.4) with trastuzumab deruxtecan vs 5.4 months (95% CI, 4.0-7.8) for chemotherapy (HR, 0.55; 95% CI, 0.42-0.73). Those with hormone receptor–positive disease who did not receive a CDK4/6 inhibitor demonstrated a median PFS of 11.7 months (95% CI, 9.5-17.7) with trastuzumab deruxtecan and 5.9 months (95% CI, 4.3-8.2) for chemotherapy (HR, 0.42; 95% CI, 0.28-0.64). Further, the median treatment duration was 8.2 months for trastuzumab deruxtecan and 3.5 months for chemotherapy at the time of the data cutoff.

In regard to safety, adverse events (AE) led to 16.2% of patients discontinuing treatment in the trastuzumab deruxtecan arm compared with 8.1% in the chemotherapy arm. Because of AEs found in 22.6% of patients in the trastuzumab deruxtecan group and 38.4% for chemotherapy, dose reductions were required. Treatment-emergent adverse events (TEAE) were also observed in 99.5% of those given trastuzumab deruxtecan vs 98.3% of those treated with physician’s choice of therapy. Exposure adjusted AE rates were 1.30 per patient year for trastuzumab deruxtecan and 2.66 for physician’s choice of chemotherapy. Additionally, serious AEs were reported in 27.8% of patients in the trastuzumab deruxtecan arm and for 25.0% in the physician’s choice arm.

The treatment-related AEs which were most frequently observed in each arm were nausea (73% vs 23.8%), fatigue (47.7% vs 42.4%), skin and subcutaneous tissue disorders, including alopecia (37.7% vs 32.6%), vomiting (34% vs 9.9%), neutropenia (33.2% vs 51.2%), and anemia (33.2% vs 22.7%). A total of 14 drug-related deaths were reported with trastuzumab deruxtecan (3.8%) vs 5 for physician’s choice of therapy (2.9%) and adjudicated interstitial lung disease (ILD)/pneumonitis occurred in 45 patients treated with trastuzumab deruxtecan (12.1%), including 5 patients who had a grade 3 event and 3 who had a grade 5 event.

Overall, the study showed trastuzumab deruxtecan to demonstrate superior and clinically meaningful efficacy in PFS and OS in patients with previously treated patients with HER2-low metastatic breast cancer with hormone receptor-positive or hormone receptor-negative disease vs standard of care physician’s choice of chemotherapy. The safety profile of trastuzumab deruxtecan was also consistent with what has been seen in previous clinical trials and no new safety concerns were identified.

The FDA has set a Prescription Drug User Fee Act date for their regulatory decision during the fourth quarter of 2022.

“The results seen in the DESTINY-Breast04 trial represent a significant advance and reinforce the potential for Enhertu to become a new standard of care for patients with previously treated HER2-low metastatic breast cancer. The prioritization of this application by the FDA and inclusion in both the Real-Time Oncology Review and Project Orbis initiatives support the importance of these data, and we look forward to working with the FDA to potentially bring Enhertu to patients with HER2-low metastatic breast cancer as quickly as possible,” added Ken Takeshita, global head, R&D of Daiichi Sankyo, in the press release.

References:
  1. Enhertu granted Priority Review in the US for patients with HER2-low metastatic breast cancer. News release. AstraZeneca. July 25, 2022. Accessed July 25, 2022. https://bit.ly/3J1Jt9X
  2. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): results of DESTINY-Breast04, a randomized, phase 3 study. J Clin Oncol. 2022;40 (suppl 17):abstr LBA3. doi: 10.1200/JCO.2022.40.17_suppl.LBA3
  3. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. Published online June 5, 2022. doi:10.1056/NEJMoa2203690