DESTINY-Lung06: trastuzumab deruxtecan and pembrolizumab as first-line treatment for HER2-overexpressing, PD-L1 TPS <50% NSCLC
In brief
Phase III study enrolls 686 HER2-positive, low-PD-L1 NSCLC patients
The DESTINY-Lung06 trial will randomize about 686 adults with non-small cell lung cancer that overexpresses HER2 (at least 25% staining) and has PD-L1 tumor proportion scores below 50% to receive either trastuzumab deruxtecan plus pembrolizumab or pembrolizumab with pemetrexed and platinum chemotherapy. The primary goal is to see if the antibody-drug conjugate improves progression-free survival, with overall survival as a key secondary endpoint.
- Journal
- Future oncology (London, England) (Q1)
- Published
- 2 September 2026
- Study design
- Randomized controlled trial
- Evidence level
- Level 1, High (CEBM 1b)
- Authors
- Pasi A Jänne, Cai-Cun Zhou, Egbert F Smit, Enriqueta Felip, George Blumenschein, Koichi Goto, et al.
- PMID
- 42682104
- DOI
- 10.1080/14796694.2026.2724696
Why clinicians should know about it
- Picked for Radiation Oncology (top studies of the week, 6 September 2026): DESTINY-Lung06 trial design for HER2 NSCLC
Abstract
Non-small cell lung cancer (NSCLC) that overexpresses human epidermal growth factor receptor 2 (HER2) is associated with poor prognosis, and no HER2-targeting therapies for HER2-overexpressing NSCLC are currently approved in the first-line setting. Pembrolizumab plus pemetrexed and platinum-based chemotherapy is a recommended first-line treatment option for nonsquamous NSCLC with no actionable genomic alterations. However, improved outcomes with pembrolizumab-based therapies correlate with higher programmed death-ligand 1 (PD-L1) levels, underscoring the need for more targeted treatment options for patients with lower PD-L1 tumor proportion scores (TPS; <50%). DESTINY-Lung06 is a multicenter, open-label, randomized, phase III trial evaluating the efficacy and safety of trastuzumab deruxtecan (T-DXd) in combination with pembrolizumab in the first-line setting in patients with HER2-overexpressing (≥25% moderate/strong membrane staining), PD-L1 TPS <50% NSCLC. Planned enrollment will be approximately 686 patients randomly assigned to either T-DXd 5.4 mg/kg with pembrolizumab 200 mg intravenously every 3 weeks (Q3W) or pembrolizumab 200 mg plus pemetrexed 500 mg/m2 with platinum-based chemotherapy (cisplatin 75 mg/m2 or carboplatin under the concentration-time curve 5 mg min/mL) intravenously Q3W. Progression-free survival by blinded independent central review and overall survival are the primary and key secondary endpoints of the study, respectively.Clinical trial registration: www.ClinicalTrials.gov identifier is NCT06899126; EudraCT identifier is 2024-515658-26-00.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.