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AstraZeneca, Daiichi Sankyo's Enhertu Scores FDA Accelerated Approval in HER2-Mutant Lung Cancer

NEW YORK – The US Food and Drug Administration on Friday granted accelerated approval to AstraZeneca and Daiichi Sankyo's antibody-drug conjugate Enhertu (trastuzumab deruxtecan) for previously treated advanced non-small cell lung cancer patients whose tumors harbor activating HER2 (ERBB2) mutations.

The FDA based its approval on the results of the Phase II DESTINY-Lung02 trial, in which 58 percent of 52 previously treated HER2-mutated NSCLC patients responded to Enhertu. Less than 2 percent of patients had a complete response to the drug, while around 56 percent had a partial response. The median duration of response was 8.7 months.

The FDA on Friday also approved two companion diagnostic tests to identify NSCLC patients eligible for Enhertu based on their HER2 mutation status in tumor tissue and blood samples: Thermo Fisher Scientific's Oncomine Dx Target Test and Guardant Health's Guardant360 CDx liquid biopsy test. Between 2 percent and 4 percent of patients with non-squamous NSCLC harbor HER2 mutations.

Thermo Fisher's Oncomine Dx Target is a tissue-based next-generation sequencing test that detects alterations in 23 genes associated with NSCLC. Guardant's Guardant360 CDx, meanwhile, is a blood-based liquid biopsy assay that detects genomic alterations in circulating tumor DNA across 55 genes. When it comes to HER2, both tests gauge activating single nucleotide variants and exon 20 insertions.

Enhertu is also approved in the US for HER2-positive gastric cancers and HER2-positive and HER2-low breast cancers. Friday's FDA approval is the first time a drug has been approved for HER2-mutated lung cancer.

With advice from the FDA's Project Optimus, AstraZeneca and Daiichi Sankyo conducted a dose randomization study, based on which the agency approved a 5.4 mg/kg dose of Enhertu given every three weeks instead of a 6.4 mg/kg dose. Project Optimus is a program at the FDA's Oncology Center of Excellence that aims to refine dosing for molecularly targeted treatments, so patients aren't exposed to unnecessary toxicities from drugs they are likely to receive for extended periods. 

Some of the most common adverse reactions seen with Enhertu treatment in the DESTINY-Lung02 trial were nausea and decreased white blood cell count, hemoglobin, and neutrophil count. The drug's label contains a boxed warning for interstitial lung disease and embryo-fetal toxicity.