In a global, phase II, single-arm, open-label TROPION-Lung05 study, a novel TROP2-directed antibody drug conjugate (ADC) datopotamab deruxtecan elicited promising objective response rate (ORR), durable responses, and an acceptable safety profile in heavily pretreated patients with advanced non-small cell lung cancer (NSCLC) and actionable genomic alterations, including in the two predominant EGFR mutation and ALK rearrangement subgroups.
These results support recent findings from the pivotal TROPION-Lung01 study, comparing datopotamab deruxtecan with docetaxel in patients with pretreated advanced/metastatic NSCLC, that demonstrated clinically meaningful benefit for patients with non-squamous NSCLC, both with and without actionable genomic alterations. The findings from the TROPION-Lung05 study were published by Dr. Jacob Sands of the Dana-Farber Cancer Institute in Boston, MA, USA and colleagues on 6 January 2025 in the JCO.
First- and second-line treatment approaches for NSCLC with actionable genomic alterations consist mostly of targeted treatment with tyrosine kinase inhibitors. Targeted therapies have significantly improved outcomes compared with conventional chemotherapy; however, resistance eventually develops, and subsequent treatment options remain limited.
TROP2 is broadly expressed in various tumour types, including NSCLC. In the first-in-human TROPION-PanTumor01 study, datopotamab deruxtecan showed promising efficacy and manageable safety in patients with NSCLC, including those with actionable genomic alterations. In the latest article published in the JCO, the investigators describe the efficacy and safety of datopotamab deruxtecan in patients with pretreated advanced/metastatic NSCLC with actionable genomic alterations, progressing on or after targeted therapy and platinum-based chemotherapy, enrolled in the phase II TROPION-Lung05 study.
Patients received datopotamab deruxtecan 6 mg/kg once every 3 weeks. The primary endpoint was ORR by blinded independent central review. Secondary endpoints included duration of response (DoR), safety, tolerability, and survival. Among 137 patients who received at least one dose of datopotamab deruxtecan, 71.5% received at least three lines of prior therapies for advanced/metastatic disease. Overall, 56.9% had EGFR mutations and 24.8% had ALK rearrangements. Median treatment duration was 4.4 months (range, 0.7-20.6).
The confirmed ORR was 35.8% (95% confidence interval [CI] 27.8 to 44.4) overall, and 43.6% (95% CI 32.4 to 55.3) and 23.5% (95% CI 10.7 to 41.2) in those with EGFR mutations and ALK rearrangements. The median DoR was 7.0 months (95% CI 4.2 to 9.8), and the overall disease control rate was 78.8% (95% CI 71.0 to 85.3). Median progression-free survival was 5.4 months and median overall survival 13.6 months.
Datopotamab deruxtecan also exhibited a manageable safety profile, consistent with previously reported data in patients with NSCLC, and no new safety signals were identified. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 28.5% of patients. The most common TRAE was stomatitis (any grade occuring in 56.2%, grade ≥3 in 9.5%); five patients (3.6%) experienced adjudicated treatment-related interstitial lung disease/pneumonitis with 1 (0.7%) grade 5 event.
These findings suggest that this novel TROP2-directed ADC may provide clinically meaningful benefit in a difficult-to-treat population with poor prognosis and lack of effective therapies. Currently, trastuzumab deruxtecan is the only approved ADC in NSCLC, indicated for patients with activating HER2 mutations. Several other ADCs are undergoing clinical investigation.
Sacituzumab govitecan and SKB-264 are two other TROP2-directed ADCs that are currently being evaluated in patients with NSCLC with and without actionable genomic alterations. Patritumab deruxtecan is a HER3-directed ADC being investigated in patients with EGFR-mutated NSCLC. Furthermore, the EGFR × HER3 bispecific ADC BL-B01D1 is under phase I investigation in locally advanced/metastatic tumours, including the patients with EGFR-mutated NSCLC.
The TROPION-Lung05 study results were previously presented at the ESMO 2023 Congress.
The study was supported by Daiichi Sankyo, Inc. In July 2020, AstraZeneca entered into a global development and commercialisation collaboration agreement with Daiichi Sankyo, Inc for datopotamab deruxtecan.
Reference
Sands J, Ahn M-J, Lisberg A, et al. Datopotamab Deruxtecan in Advanced or Metastatic Non–Small Cell Lung Cancer With Actionable Genomic Alterations: Results From the Phase II TROPION-Lung05 Study. JCO; Published online 6 January 2025. DOI: https://doi.org/10.1200/JCO-24-01349