TROPION-Lung14: A phase 3 study of osimertinib ± datopotamab deruxtecan (Dato-DXd) as first-line (1L) treatment for patients with <i>EGFR</i> -mutated locally advanced or metastatic (LA/M) non-small cell lung cancer (NSCLC).

TPS8647 Background: Despite the benefit observed with osimertinib, most patients with LA/M EGFR -mutated NSCLC develop resistance and treatment options on or after disease progression are limited. Phase 3 clinical trial data, using agents with broad antitumor activity, have demonstrated the potential to extend the clinical benefit of 1L osimertinib and delay the onset of resistance. Dato-DXd, an antibody-drug conjugate composed of a humanized anti-TROP2 monoclonal antibody conjugated to a potent topoisomerase I inhibitor, has demonstrated efficacy as monotherapy in NSCLC in TROPION-Lung01, including in patients with EGFR -mutated advanced NSCLC. TROPION-Lung14 is evaluating the efficacy and safety of osimertinib ± Dato-DXd as 1L therapy in patients with EGFR -mutated LA/M NSCLC. Methods: TROPION-Lung14 (NCT06350097) is an ongoing phase 3, open-label, multicentre, randomized study. The study is enrolling patients (aged ≥18 years) with histologically or cytologically confirmed stage IIIB/IIIC or IV non-squamous, EGFR -mutated (exon 19 deletion or L858R) NSCLC, no prior EGFR tyrosine kinase inhibitor or other systemic therapy for stage IIIB/IIIC or IV disease, at least one measurable lesion per RECIST 1.1, and WHO performance status (PS) of 0 or 1. Prior to the randomized study period, ~20 patients will receive osimertinib + Dato-DXd in a non-randomized single-arm safety run-in . Following safety run-in, ~562 patients will be randomized 1:1 to osimertinib (80 mg orally [PO] QD) or osimertinib (80 mg PO QD) + Dato-DXd (6 mg/kg IV Q3W). Patients will be stratified by EGFR mutation type (Ex19Del vs L858R), WHO PS (0 vs 1) and central nervous system (CNS) metastasis status (yes vs no). Treatment will continue until RECIST v1.1-defined progression or unacceptable toxicity. The primary study endpoint is progression-free survival (PFS) assessed by blinded independent central review. Overall survival is a key secondary endpoint; other secondary endpoints include PFS by investigator, objective response rate, duration of response, PFS2, safety, pharmacokinetics and immunogenicity. Enrollment is ongoing. Clinical trial information: NCT06350097 .