EMA starts twin reviews of AZ, Daiichi’s Dato-DXd

The clock has started ticking in the EU on two marketing applications for AstraZeneca and Daiichi Sankyo’s TROP2-targeting antibody-drug conjugate datopotamab deruxtecan in breast and lung cancer.

The EMA has validated the two parallel applications for the drug, also known as Dato-DXd, in adults with previously treated non-small cell lung cancer (NSCLC) and hormone receptor-positive, HER2-negative breast cancer.

The lung cancer filing is based on the TROPION-Lung01 study, which involved adults with locally advanced or metastatic non-squamous NSCLC, with and without genomic alterations, who needed systemic therapy after prior treatment.

Treatment with Dato-DXd significantly improved median progression-free survival (PFS) from 3.7 months to 5.6 months in the non-squamous NSCLC group, with a trend towards improved overall survival (OS) over chemo.

If approved, the ADC would become the first alternative to chemotherapy in the second-line setting. Some analysts have questioned whether the efficacy results are sufficiently clinically meaningful to drive uptake, particularly as treatment also introduces a risk of serious side effects, including interstitial lung disease (ILD), but others have suggested the lung cancer indication alone could be worth $3 billion in sales at peak.

The breast cancer filing, meanwhile, comes on the back of the TROPION-Breast01 study in adults with unresectable or metastatic HR-positive, HER2-negative breast cancer who have progressed on and are not suitable for endocrine therapy and have been treated with one additional systemic therapy. That found a median PFS of 6.9 months for Dato-DXd vs 4.9 months for chemo.

The issue of ILD does not seem to be as great in breast cancer – perhaps because damage to the lungs makes NSCLC patients more vulnerable – and AZ has said that, in both breast and lung cancers, the tolerability of DAT-DXd is better than chemo.

There is direct competition already in place for the breast cancer indication, as Gilead Sciences’ TROP2 ADC Trodelvy (sacituzumab govitecan) is already approved for previously treated HR-positive/HER2-negative metastatic breast cancer, as well as triple-negative breast cancer (TNBC) and metastatic urothelial cancer.

“Our ambition is for datopotamab deruxtecan to improve upon and replace conventional chemotherapy in the treatment of multiple cancer types,” said Susan Galbraith, AZ’s head of oncology R&D, in a statement.

“Today’s dual validation of our applications in lung and breast cancers brings this potential medicine a meaningful step closer to redefining treatment expectations for patients with two of the most common cancers in Europe,” she added.

In the US, the regulatory filing for Dato-DXd in lung cancer has been accepted by the FDA – with a decision due in December – while the filing for breast cancer is underway, said Daiichi Sankyo’s global head of R&D, Ken Takeshita. He added that the applications underscore their "commitment to changing the standard of care by developing new medicines to help as many patients worldwide as possible.”

AZ licensed rights to Dato-DXd in July 2020 for $1 billion upfront, plus up to $5 billion in regulatory and sales milestones. It was the second major licensing deal between the two companies, coming after a $6.9 billion deal for HER2-directed ADC Enhertu (trastuzumab deruxtecan) in the previous year.