AstraZeneca details AI-driven TROP2 biomarker plan for Daiichi ADC after weak lung cancer results

AstraZeneca has projected that Dato-DXd could achieve peak sales of over $5 billion, largely driven by its potential use in first-line non-small cell lung cancer (NSCLC). The company has leveraged artificial intelligence to create a unique biomarker for its drug, datopotamab deruxtecan (Dato-DXd), which aims to distinguish it from competitors and elucidate why the TROP2-directed therapy is effective only for some NSCLC patients. This new biomarker, termed normalized membrane ratio of TROP2 by quantitative continuous scoring (NMR-QCS), is quite intricate.

The NMR-QCS biomarker measures the ratio of TROP2 expression in the membrane compared to the cytoplasm of tumor cells, unlike traditional biomarkers like HER2 which are determined by cell surface expression. To qualify as NMR-QCS-positive under AstraZeneca’s model, a patient's sample needs at least 75% of tumor cells with a TROP2 normalized membrane ratio of no more than 0.5585.

In a retrospective analysis of the phase 3 TROPION-Lung01 trial for previously treated NSCLC, Dato-DXd showed significantly better efficacy in patients with QCS-NMR-positive tumors compared to those who were QCS-NMR-negative. Specifically, Dato-DXd reduced the risk of tumor progression or death by 43% in QCS-NMR-positive patients, whereas it performed worse than the chemotherapy drug docetaxel in QCS-NMR-negative patients, who faced a 16% higher risk.

AstraZeneca is now collaborating with Roche to co-develop and commercialize the TROP2-QCS biomarker companion diagnostic and digital pathology algorithm. This combines AstraZeneca’s computational pathology platform with Roche’s navify digital pathology image management system.

To develop this biomarker, AstraZeneca employed AI to sift through thousands of factors before identifying a combination most predictive of Dato-DXd’s progression-free survival (PFS) benefit in second-line nonsquamous NSCLC without actionable genomic alterations. This process began with a hypothesis-free exploration in the phase 1 TROPION-PanTumor01 study, eventually identifying QCS-NMR as the most promising feature correlated with PFS.

The exact thresholds for determining biomarker status were fine-tuned using data from cases of nonsquamous NSCLC without actionable mutations in the phase 3 TROPION-Lung01 trial. This search for a biomarker came following a setback in the TROPION-Lung01 trial, where Dato-DXd’s benefit was observed only in patients with nonsquamous histology, prompting an FDA application for previously treated nonsquamous NSCLC.

In the TROPION-Lung01 trial, QCS-NMR-positive tumors were more common in nonsquamous (66%) than in squamous disease (44%), offering a potentially better explanation for the varying efficacy than histology alone. The 43% PFS improvement in QCS-NMR-positive tumors surpassed the 37% improvement seen in nonsquamous disease, suggesting QCS-NMR could serve as a predictive biomarker for Dato-DXd response.

AstraZeneca is incorporating the biomarker into the phase 3 AVANZAR trial, which evaluates Dato-DXd in combination with Imfinzi and chemotherapy as first-line treatment for advanced NSCLC without actionable genomic alterations. The trial’s primary endpoints focus on PFS and overall survival in the “TROP2 biomarker positive population” as indicated on ClinicalTrials.gov.

Despite this, there remains regulatory uncertainty. The QCS-NMR biomarker might not be the only approach for Dato-DXd in NSCLC; it is one of several potential strategies. AstraZeneca has retrospectively used the biomarker in other large phase 3 studies, revealing similar histology prevalence in nonsquamous populations. However, the biomarker complicates Dato-DXd's FDA application in second-line nonsquamous NSCLC.

The QCS-NMR test utilizes a common immunohistochemistry (IHC) assay to assess TROP2 expression. Despite requiring additional digital infrastructure, AstraZeneca is preparing labs for this advanced diagnostic process, highlighting its commitment to replacing conventional chemotherapy with more effective treatments.