Dato-DXd outperforms docetaxel in previously treated patients with metastatic NSCLC  

The TROP2-directed antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) is a potential new meaningful therapy for patients with previously treated non-squamous non-small cell lung cancer (NSCLC), as was shown in the TROPION-LUNG01 and TROPION-Lung05 trials.

The standard of care second-line chemotherapy for patients with metastatic NSCLC is associated with modest benefit and substantial toxicity. Dato-DXd, a TROP2-directed antibody-drug conjugate that selectively delivers a potent topoisomerase I inhibitor payload directly into tumour cells, is currently under clinical investigation in multiple tumour types. Promising antitumour activity was observed with Dato-DXd in patients with locally advanced or metastatic NSCLC in the phase 1 TROPION-PanTumor01 trial (NCT03401385) [1]. Both the phase 3 TROPION-LUNG01 (NCT04656652) and phase 2 TROPION-Lung05 (NCT04484142) trials further evaluated the efficacy and safety of Dato-DXd in previously treated participants with locally advanced or metastatic NSCLC.

The phase 3 TROPION-LUNG01 trial enrolled 604 participants (with or without actionable genomic alterations), who were randomised 1:1 to receive Dato-Dxd or docetaxel until disease progression. The dual primary endpoints were progression-free survival (PFS) and overall survival (OS). Dr Aaron Lisberg (University of California Los Angeles, CA, USA) presented the interim results [2]. Median PFS was significantly improved by treatment with Dato-DXd over docetaxel: 4.4 versus 3.7 months (HR 0.75; 95% CI 0.62–0.91; P=0.004). However, PFS benefit was exclusively observed in participants with non-squamous histology (HR 0.63 vs HR1.38 in participants with squamous histology). OS data are not yet mature.

The phase 2 TROPION-Lung05 trial enrolled 137 participants who had tumours with ≥1 actionable genomic alterations (e.g. EGFR, ALK, ROS1, NTRK). All participants were treated with Dato-DXd until progression. The primary endpoint was the objective response rate (ORR). Prof. Luis Paz-Ares (Hospital Universitario 12 de Octubre, Spain) presented the results [3]. ORR in all treated participants was 35.8% (95% CI 27.8–44.4), whereby 3% of participants achieved a complete response and 33% a partial response. The ORR was 43.6% (95% CI 32.4–55.3) in participants with EGFR mutations (57% of all participants) and 23.5% (95% CI 10.7–41.2) in participants with ALK alterations (25% of all participants). The median PFS in all participants was 5.4 months, and the median duration of response was 7.0 months.

In both trials, Data-DXd had a manageable safety profile, characterised by a low incidence of haematological or drug-related grade ≥3 toxicities. Nausea and stomatitis were the predominant adverse events observed. Grade ≥3 interstitial lung disease (ILD) was reported in 3% of participants, highlighting the need for careful monitoring and adherence to ILD management guidelines.

Based on these interim results, Dr Lisberg concluded that “Dato-DXd is a potential new meaningful therapy for patients with previously treated non-squamous NSCLC.”

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   1. Shimizu T, et al. J Clin Oncol. 2023;41(29):4678–4687.
   2. Ahn M-J, et al. L- Datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC): Results of the randomized phase III study TROPION-Lung01. Abstract LBA12, ESMO 2023, 20–24 October, Madrid, Spain.
   3. Paz-Ares L, et al. TROPION-Lung05: Datopotamab deruxtecan (Dato-DXd) in previously treated non-small cell lung cancer (NSCLC) with actionable genomic alterations (AGAs). Abstract 1314MO, ESMO 2023, 20–24 October, Madrid, Spain.

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Posted on 19 December 2023