AstraZeneca-Daiichi's Dato-DXd fails to show overall survival benefit in phase 3

Daiichi Sankyo and AstraZeneca are championing their TROP2-directed antibody-drug conjugate (ADC), datopotamab deruxtecan (Dato-DXd), as a promising treatment for nonsquamous non-small cell lung cancer (NSCLC). The companies have highlighted data from the phase 3 TROPION-Lung01 trial, which bolsters their ongoing approval applications with U.S. and EU regulatory authorities. However, the recent clinical findings have also introduced some uncertainties.

Earlier this year, the FDA accepted an application for Dato-DXd's use in treating nonsquamous NSCLC, based on phase 3 trial data showing a median progression-free survival (PFS) of 5.6 months for Dato-DXd, compared to 3.7 months for the chemotherapy docetaxel. A separate application for the drug as a treatment for HR-positive, HER2-negative breast cancer has also been submitted. Notably, Dato-DXd did not demonstrate a PFS benefit in patients with squamous NSCLC, necessitating a more focused application in the nonsquamous subgroup.

Recently, high-level overall survival (OS) data from the TROPION-Lung01 trial came to light, showing that while survival outcomes "numerically favored" Dato-DXd, they did not achieve statistical significance. Despite this, the companies emphasize that a "clinically meaningful" OS improvement was observed in the nonsquamous NSCLC subgroup.

Daiichi Sankyo and AstraZeneca remain optimistic about their approval prospects. In a statement, Ken Takeshita, M.D., Daiichi's global head of R&D, pointed out that the combined data on OS improvement, PFS, overall response rates, and the duration of response indicate that Dato-DXd could become a significant new treatment for advanced nonsquamous NSCLC. He added that these findings would support ongoing discussions with global regulatory authorities, aiming for expedited patient access.

Susan Galbraith, Ph.D., AstraZeneca's executive vice president of oncology R&D, echoed this sentiment, suggesting that Dato-DXd could replace conventional chemotherapy in later treatment stages and expressing confidence in ongoing first-line lung cancer trials. David Fredrickson, executive vice president of AstraZeneca’s oncology business unit, noted in a February interview that maintaining the positive trend observed so far would be advantageous, although adverse results would necessitate further discussion with the agency.

Nonetheless, the TROPION-Lung01 trial has faced challenges. Last year, at the European Society for Medical Oncology (ESMO) Congress, AstraZeneca and Daiichi reported an indeterminate number of deaths due to interstitial lung disease—a serious adverse event that remains a concern. Fredrickson acknowledged these incidents, stressing the importance of understanding and monitoring interstitial lung disease, similar to the protocols developed for the companies' blockbuster ADC, Enhertu.

Dato-DXd aims to be the first TROP2-targeted ADC approved for NSCLC, a title that also saw Gilead Sciences' Trodelvy vying for, albeit unsuccessfully, as it failed to show a statistically significant OS benefit in its phase 3 trial.

In conclusion, while Dato-DXd has demonstrated promising potential as a treatment for advanced nonsquamous NSCLC, it still faces hurdles in its approval process. The companies are focused on presenting a compelling case to regulatory authorities, armed with robust clinical data and a proactive approach to managing associated risks such as interstitial lung disease.

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