US FDA grants priority review to Daiichi Sankyo and AstraZeneca’s sBLA of Enhertu

Daiichi Sankyo and AstraZeneca have received notification of acceptance by the US Food and Drug Administration (FDA) of the supplemental Biologics License Application (sBLA) of Enhertu (fam-trastuzumab deruxtecan-nxki) for the treatment of adult patients in the US with unresectable or metastatic HER2 positive breast cancer who have received a prior anti-HER2-based regimen. The application has also been granted Priority Review, Daiichi Sankyo informed in a statement.

Enhertu is a HER2-directed Antibody Drug Conjugate (ADC) being jointly developed by Daiichi Sankyo
and AstraZeneca, the statement added.

It also said that the FDA grants priority review to applications for medicines that, if approved, would offer significant improvements over available options by demonstrating safety or efficacy improvements, preventing serious conditions, or enhancing patient compliance. The Prescription Drug User Fee Act date (PDUFA), the FDA action date for their regulatory decision, is during the second quarter of the 2022 calendar year.

The sBLA is being reviewed under the Real-Time Oncology Review (RTOR) programme and Project Orbis, two initiatives of the FDA which are designed to bring effective cancer treatments to patients as early as possible. RTOR allows the FDA to review components of an application before submission of the complete application. Project Orbis provides a framework for concurrent submission and review of oncology medicines among participating international partners, the statement mentioned.

“This regulatory review of Enhertu in the US marks the first time this medicine is participating in both
the Real-Time Oncology Review and Project Orbis programmes,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo.

Takeshita added, “The FDA’s prioritisation 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.”

According to the statement, the sBLA is based on data from the pivotal Destiny-Breast03 phase-III trial that were presented at the 2021 European Society for Medical Oncology (ESMO) Congress. In the trial, Enhertu demonstrated a 72 per cent reduction in the risk of disease progression or death compared to T-DM1 (hazard ratio [HR] = 0.28; 95 per cent confidence interval [CI]: 0.22-0.37; p=7.8×10-22) in patients with HER2 positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane. The median Progression-Free Survival (PFS) for patients treated with Enhertu was not reached (95% CI: 18.5-NE) compared to 6.8 months for T-DM1 (95% CI: 5.6-8.2) as assessed by blinded independent central review (BICR). In the secondary endpoint analysis of PFS assessed by investigators, patients treated with Enhertu experienced an improvement in PFS of 25.1 months (95% CI: 22.1-NE) compared to 7.2 months (95% CI: 6.8-8.3) for T-DM1 (HR=0.26; 95% CI: 0.20-0.35). There was a strong trend towards improved overall survival (OS) with Enhertu (HR=0.56; 95% CI: 0.36-0.86; p=0.007172). However, this analysis is not yet mature and is not statistically significant. Nearly all patients treated with Enhertu during the trial were alive at one year (94.1%; 95% CI: 90.3-96.4) compared to 85.9 per cent of patients treated with T-DM1 (95% CI: 80.9-89.7). Confirmed Objective Response Rate (ORR) was more than doubled in the Enhertu arm versus the T-DM1 arm (79.7%; n=208; 95% CI: 74.3-84.4) versus 34.2% (n=90; 95% CI: 28.5-40.3; p<0.0001).

The statement also notified that the safety profile of the most common adverse events with Enhertu in Destiny-Breast03 was consistent with previous clinical trials with no new safety concerns identified. The most common grade 3 or higher drug-related treatment emergent adverse events in the Enhertu arm were neutropenia (19.1%), thrombocytopenia (seven per cent), leukopenia (6.6 per cent), nausea (6.6 per cent), anemia (5.8 per cent), fatigue (5.1 per cent), vomiting (1.6 per cent), increase in ALT (1.6 per cent), decreased appetite (1.2 per cent), increase in AST (0.8 per cent), diarrhoea (0.4 per cent) and alopecia (0.4 per cent). Overall, 10.5 per cent of patients had Interstitial Lung Disease (ILD) or pneumonitis related to treatment as determined by an independent adjudication committee. The majority of ILD events (9.7 per cent) were low grade (grade 1 (2.7 per cent) or grade 2 (7.0 per cent)) with two grade 3 (0.8 per cent) events reported. No grade 4 or grade 5 ILD or pneumonitis events occurred.