Datopotamab deruxtecan

NeoCOAST-2 trial showed promising pathologic complete and major pathologic response rates with neoadjuvant datopotamab deruxtecan (Dato-DXd) plus durvalumab and single-agent platinum chemotherapy in early-stage NSCLC, surpassing historical benchmarks.

Marina Chiara Garassino discusses the predictive utility of TROP2 normalized membrane ratio (NMR) for clinical outcomes with datopotamab deruxtecan (Dato-DXd) in previously treated non–small cell lung cancer (NSCLC). Findings from the TROPION-Lung01 trial showed improved outcomes for TROP2-QCS-positive patients, particularly in nonsquamous NSCLC, with Dato-DXd reducing progression risk by 43% compared to docetaxel. TROP2-QCS NMR could identify patients benefiting from Dato-DXd, with similar toxicity rates across TROP2 expression levels.

ENHERTU granted Priority Review in the US for HER2-low or HER2-ultralow metastatic breast cancer patients who have received at least one line of endocrine therapy, based on the DESTINY-Breast06 Phase III trial demonstrating significant progression-free survival benefit. If approved, ENHERTU would be the first HER2-directed therapy and ADC for patients prior to chemotherapy. ENHERTU also received Breakthrough Therapy Designation for this patient population.

Lung cancer, a leading cause of cancer death globally, affects 2.4 million annually. TAGRISSO (osimertinib), a third-generation EGFR-TKI, is pivotal in treating EGFRm NSCLC, with extensive evidence supporting its use across various stages. AstraZeneca continues to innovate in lung cancer treatment, aiming to improve outcomes and redefine care.

Lung cancer is a leading cause of cancer death globally, with EGFRm NSCLC patients particularly sensitive to EGFR-TKI treatment. LAURA trial assessed Tagrisso in Stage III EGFRm NSCLC patients post-CRT, enrolling 216 patients across 15 countries. Tagrisso, a third-generation EGFR-TKI, has demonstrated efficacy in various NSCLC stages and is being explored in early-stage and resistant settings. AstraZeneca aims to improve lung cancer outcomes through early detection and innovative treatments.

Antibody-drug conjugates (ADCs) are emerging in oncology, with dozens approved by the FDA. ADCs offer a 'bystander effect' but can increase off-target toxicity. Aditya Bardia highlighted ADCs like sacituzumab govitecan, trastuzumab deruxtecan, and datopotamab deruxtecan, which show superiority over chemotherapy in metastatic settings. Domenica Lorusso noted over 260 ADCs in cancer trials, calling them a 'rising star' in ovarian cancer. Toon Van Gorp emphasized TROP2 as a key target in cervical cancer. Challenges include understanding ADC resistance mechanisms and managing toxicities, necessitating multidisciplinary approaches.

The TROPION-Breast01 phase III trial of datopotamab deruxtecan (Dato-DXd) did not achieve statistical significance in the final overall survival (OS) analysis for patients with inoperable or metastatic hormone receptor (HR)-positive, HER2-low or negative breast cancer. Despite this, the trial previously met the progression-free survival (PFS) endpoint, showing a significant improvement in PFS and patient-reported outcomes. The safety profile remained consistent with no new safety concerns. The treatment landscape's advancement with multiple antibody drug conjugates (ADCs) approved during the trial may have influenced the OS results.

The phase 3 TROPION-Breast01 study found datopotamab deruxtecan (Dato-DXd) did not significantly improve overall survival (OS) vs chemotherapy in HR-positive, HER2-low or HER2-negative breast cancer patients. However, Dato-DXd did significantly improve progression-free survival (PFS) with a median PFS of 6.9 months vs 4.9 months with chemotherapy. The FDA is currently evaluating a biologics license application for Dato-DXd in this patient population, with a decision expected in Q1 2025.

AstraZeneca and Daiichi Sankyo's datopotamab deruxtecan (Dato-DXd) missed overall survival (OS) goal in Phase III TROPION-Breast01 study, despite showing significant progression-free survival (PFS) benefits. The companies will continue regulatory discussions and apply study insights to inform future clinical development.

AstraZeneca's cancer drug Dato-DXd, acquired for up to $1 billion, failed to significantly improve overall survival in advanced breast cancer patients, following a similar setback in a lung cancer study, leading to a further decline in the company's share price.