Detailed results from the TROPION-Lung01 Phase III trial indicate a clinically meaningful trend toward improved overall survival (OS) with datopotamab deruxtecan (Dato-DXd) compared to docetaxel in adult patients with locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) who have undergone at least one prior line of therapy. These findings were presented at the IASLC 2024 World Conference on Lung Cancer (WCLC).
Datopotamab deruxtecan is a TROP2-directed DXd antibody drug conjugate discovered by Daiichi Sankyo and jointly developed by AstraZeneca and Daiichi Sankyo.
Overall Survival Results
In the overall trial population, OS results numerically favored datopotamab deruxtecan compared to docetaxel (12.9 vs. 11.8 months), but this difference did not reach statistical significance (hazard ratio [HR] 0.94; 95% confidence interval [CI] 0.78-1.14; p=0.530). However, in the prespecified subgroup of patients with nonsquamous NSCLC, datopotamab deruxtecan demonstrated a 2.3-month improvement in OS compared to docetaxel (14.6 vs. 12.3 months; HR 0.84; 95% CI 0.68-1.05). This OS improvement was observed regardless of the presence of actionable genomic alterations in patients with nonsquamous NSCLC. Datopotamab deruxtecan did not show an OS improvement in patients with squamous NSCLC, consistent with previous analysis.
Dr. Jacob Sands, MD, Dana-Farber Cancer Institute, and an investigator in the trial, noted, "Despite many efforts to surpass docetaxel with novel approaches in previously treated advanced or metastatic non-small cell lung cancer, patients only survive for about one year. For datopotamab deruxtecan to show a statistically significant improvement in progression-free survival along with improved response rate, duration of response and an overall survival improvement numerically consistent with progression-free survival is clinically meaningful for patients with nonsquamous lung cancer."
Safety Profile
The safety profile of datopotamab deruxtecan in TROPION-Lung01 was consistent with previous analyses, showing lower rates of dose reduction (20% vs. 30%) and discontinuation (8% vs. 12%) due to adverse events compared to docetaxel. The median treatment duration for datopotamab deruxtecan was 4.2 months versus 2.8 months for docetaxel. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 26% and 42% of patients in the datopotamab deruxtecan and docetaxel arms, respectively. The most common Grade 3 or higher TRAEs were neutropenia (1% vs. 23%), leukopenia (0% vs. 13%), stomatitis (7% vs. 1%), anemia (4% vs. 4%), interstitial lung disease (ILD) (4% vs. 1%), and asthenia (3% vs. 2%). No new ILD events of any grade were adjudicated as drug-related since the previous analysis.
NeoCOAST-2 Trial
Results from the NeoCOAST-2 Phase II platform trial, evaluating IMFINZI® (durvalumab) in multiple novel combinations before and after surgery in patients with early-stage (Stage IIA–IIIB) resectable NSCLC, were also presented at the WCLC. Preliminary results from the trial arm testing neoadjuvant IMFINZI plus datopotamab deruxtecan and carboplatin demonstrated a pathological complete response (pCR) rate of 34.1% (95% CI 20.5-49.9) and a major pathological response (mPR) rate of 65.9% (95% CI 50.1-79.5). While these response rates were numerically higher than those shown by other combination regimens tested, the trial was not powered to make direct statistical comparisons between arms.
The safety profile of IMFINZI plus datopotamab deruxtecan and carboplatin was consistent with the known safety profiles of these agents. Surgical rates across arms were comparable and in line with those shown in recent Phase III trials.
TROP2 Biomarker Analysis
Results from an exploratory analysis of TROPION-Lung01 showed that TROP2, as measured by AstraZeneca’s proprietary computational pathology platform, quantitative continuous scoring (QCS), was predictive of clinical outcomes in patients with advanced or metastatic NSCLC treated with datopotamab deruxtecan. In patients with TROP2-QCS biomarker-positive tumors, datopotamab deruxtecan demonstrated a meaningfully greater magnitude of efficacy versus docetaxel than in the overall trial population.
Roche Collaboration
AstraZeneca and Roche Tissue Diagnostics are extending their existing collaboration to co-develop a novel companion diagnostic incorporating AstraZeneca’s proprietary computational pathology platform, QCS, which will be deployed within Roche's navify® Digital Pathology image management system. This collaboration aims to aid pathologists in interpreting an investigational VENTANA TROP2 assay.
