FDA Grants Priority Review to Trastuzumab Deruxtecan for HER2-Low Metastatic Breast Cancer

FDA

The FDA has accepted and granted priority review to a supplemental biologics license application (sBLA) for the use of fam-trastuzumab deruxtecan-nxki (Enhertu) in the treatment of adult patients with unresectable or metastatic HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+ and in-situ hybridization [ISH]–negative) breast cancer who have received 1 prior therapy in the metastatic setting.¹

The application is based on data from the phase 3 DESTINY-Breast04 trial (NCT03734029), in which the antibody-drug conjugate demonstrated a median progression-free survival (PFS) of 10.1 months (95% CI, 9.5-11.5) vs 5.4 months (95% CI, 4.4-7.1) with physician’s choice of chemotherapy in patients with hormone receptor–positive, HER2-low metastatic breast cancer (HR, 0.51; 95% CI, 0.40-0.64; P < .0001).^2,3 The median overall survival (OS) in this population was 23.9 months (95% CI, 20.8-24.8) with trastuzumab deruxtecan vs 17.5 months (95% CI, 15.2-22.4) with chemotherapy (HR, 0.64; 95% CI, 0.48-0.86; P = .003).

The regulatory agency is scheduled to decide on the sBLA during the fourth quarter of 2022, under the Prescription Drug User Fee Act.

“The results seen in the DESTINY-Breast04 trial represent a significant advance and reinforce the potential for trastuzumab deruxtecan tobecome a new standard of care for patients with previously treated HER2 low metastatic breast cancer,” Ken Takeshita, MD, global head of R&D at Daiichi Sankyo, stated in a press release. “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 trastuzumab deruxtecan to patients with HER2-low metastatic breast cancer as quickly as possible.”

Previously in April 2022, the FDA granted a breakthrough therapy designation to trastuzumab deruxtecan for the treatment of adult patients with unresectable or metastatic HER2-low 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.⁴

The global, randomized, open-label, pivotal DESTINY-Breast04 trial enrolled 557 patients with hormone receptor–positive or –negative, HER2-low unresectable and/or metastatic breast cancer previously treated with 1 or 2 prior lines of chemotherapy.

Eligible patients were randomized 2:1 to receive 5.4 mg/kg of trastuzumab deruxtecan every 3 weeks (n = 373) or physician’s choice of chemotherapy at locally approved dosing (n = 184) consisting of capecitabine (Xeloda), eribulin, gemcitabine, paclitaxel, or nab-paclitaxel (Abraxane).

The primary end point was PFS in patients with hormone receptor–positive disease based on blinded independent central review (BICR). Key secondary end points include PFS based on BICR in all randomized patients, OS in patients with hormone receptor–positive disease and OS in all randomized patients. Other secondary end points include PFS based on investigator assessment, objective response rate based on BICR and on investigator assessment, duration of response based on BICR and safety.

Additional findings from the study, which were presented at the 2022 ASCO Annual Meeting and published in the New England Journal of Medicine demonstrated a median PFS of 9.9 months (95% CI, 9.0-11.3) with trastuzumab deruxtecan vs 5.1 months (95% CI, 4.2-6.8) with chemotherapy in all randomized patients (HR, 0.50; 95% CI, 0.40-0.63). The median OS in this population was 23.4 months (95% CI, 20.0-24.8) with trastuzumab deruxtecan vs 16.8 months (95% CI, 14.5-20.0) with chemotherapy (HR, 0.64; 95% CI, 0.49-0.84; P = .001).

Among 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) with chemotherapy (HR, 0.46; 95% CI, 0.24-0.89). The median OS in this population was 18.2 months (95% CI, 13.6–not estimable) with trastuzumab deruxtecan vs 8.3 months (95% CI, 5.6-20.6) with chemotherapy (HR, 0.48; 95% CI, 0.24-0.95).

Among patients with hormone receptor–positive disease who received prior treatment with a CDK4/6 inhibitor, the median PFS was 10.0 months (95% CI, 8.3-11.4) with trastuzumab deruxtecan vs 5.4 months (95% CI, 4.0-7.8) with chemotherapy (HR, 0.55; 95% CI, 0.42-0.73). Patients with hormone receptor–positive disease who did not receive a CDK4/6 inhibitor experienced a median PFS of 11.7 months (95% CI, 9.5-17.7) with trastuzumab deruxtecan vs 5.9 months (95% CI, 4.3-8.2) with chemotherapy (HR, 0.42; 95% CI, 0.28-0.64).

In terms of safety, treatment-emergent adverse effects (TEAEs) occurred in 99.5% of patients in the trastuzumab deruxtecan arm vs 98.3% of those treated with physician’s choice of therapy. Fewer grade 3 or greater AEs were reported with trastuzumab deruxtecan vs chemotherapy, at 52.6% and 67.4%, respectively. Serious AEs occurred in 27.8% of patients treated with trastuzumab deruxtecan vs 25.0% with physician’s choice.

The most common treatment-related AEs for trastuzumab deruxtecan and chemotherapy, respectively, 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%).

Notably, 14 drug-related deaths occurred with trastuzumab deruxtecan (3.8%) vs 5 for physician’s choice of therapy (2.9%). Adjudicated interstitial lung disease (ILD)/pneumonitis occurred in 45 patients treated with trastuzumab deruxtecan (12.1%), with 5 patients having a grade 3 event and 3 having a grade 5 event.

“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,” Susan Galbraith, MBBChir, PhD, executive vice president, Oncology R&D, AstraZeneca, said. “For more than two decades, only patients with HER2-positive breast cancer have been able to benefit from HER2 targeted therapies. If approved, trastuzumab deruxtecan 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.”

References

1. ENHERTU® granted priority review in the U.S. for patients with HER2 low metastatic breast cancer. News release. Daiichi Sankyo. July 25, 2022. Accessed July 25, 2022. https://bit.ly/3S1wWHs
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):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. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690
4. ENHERTU granted breakthrough therapy designation in US for patients with HER2 low metastatic breast cancer. News release. Daiichi Sankyo. April 26, 2022. Accessed July 25, 2022. https://bit.ly/3MvIbEE