AstraZeneca points down disappointing drug trial results by Investing.com

Investing.com — Shares of AstraZeneca ( LON: ) fell on Thursday after disappointing final overall survival data from the TROPION-Lung-01 ( TL-01 ) trial were presented at the World Lung Cancer Conference in San Diego.

At 5:09am (0909 GMT), AstraZeneca was trading 4.8% lower at £12,108.

The study evaluated the company’s investigational drug, datopotamab deruxtecan (Dato-Dxd), as a second-line treatment for patients with non-small cell lung cancer (NSCLC).

Analysts at BofA Securities and Stifel expressed concern about the study’s results, which showed a lack of improvement in overall survival, raising questions about the drug’s regulatory approval prospects and its commercial potential.

The TL-01 study tested Dato-Dxd, an antibody-drug conjugate (ADC) targeting Trop-2, against docetaxel in patients who had progressed after first-line therapies such as pembrolizumab or chemotherapy.

Although there is an unmet medical need in this patient population, final OS data fell short of expectations, prompting analysts to warn of potential delays or even a rejection by the US Food and Drug Administration.

The OS hazard ratio for the non-squamous NSCLC subgroup has deteriorated since the previous interim data. In the European Society of Medical Oncology (ESMO) 2023, the HR was 0.77, but has now increased to 0.84.

More worryingly, the upper confidence interval (CI) has increased from 1.01 to 1.05, meaning that the survival benefit is no longer statistically significant, as crossing 1.0 suggests that the drug may not improve survival over the current standard of care.

Although patients in the non-squamous subgroup saw an absolute improvement in OS of 2.3 months (14.6 months for Dato-Dxd vs. 12.3 months for docetaxel), the data failed to reach nominal statistical significance.

This marginal benefit falls on the edge of what oncologists consider clinically significant and raises concerns about whether the FDA will see the results as sufficient for approval.

The trial data were particularly disappointing for patients in the AGA (non-squamous, non-actionable genomic alterations) subgroup, which represents the majority of NSCLC patients. This group only experienced an improvement in OS of 1.3 months (HR=0.89), while the HR for patients with AGA (17% of the study population) was stronger at 0.65.

Poor performance in non-GA patients suggests limited benefit for a large portion of the target population, reducing the overall potential impact of the drug.

AstraZeneca has been investigating the use of a biomarker test to better predict which patients are likely to respond to Dato-Dxd. The QCS-NMR test measures Trop-2 expression, with early analysis indicating that patients with higher levels of Trop-2 responded better to the drug.

However, the biomarker analysis remains exploratory and was applied retroactively in the TL-01 trial, raising questions about its validity in the regulatory review process.

Both BofA Securities and Stifel analysts expressed concern that the FDA may require additional studies to validate the biomarkers’ predictive power before granting approval.

The regulatory agency could either delay the decision or approve a narrower label limited to biomarker-positive patients. That would shrink the potential market for Dato-Dxd, which AstraZeneca originally hoped would benefit a broader NSCLC population.