Multicenter phase 2 trial of osimertinib plus dapopotamab deruxtecan for EGFR-mutated aNSCLC after progression on first-line osimertinib

The multicenter phase 2 ORCHARD study in the USA evaluated the combination of datopotamab deruxtecan (Dato-DXd; an anti-TROP2 antibody-drug conjugate) plus osimertinib (EGFR TKI) for EGFR-mutated advanced non-small cell lung cancer (aNSCLC) after progression on first-line osimertinib. Patients received oral osimertinib (60 mg once daily) plus intravenous Dato-DXd (4 or 6 mg/kg every 3 weeks. The primary endpoint was investigator-assessed objective response rate (ORR). Among 35 patients in the 4 mg/kg cohort the confirmed ORR was 43% (80% CI 32-55) whereas among 34 patients in the 6 mg/kg cohort the confirmed ORR was 36% (25-49); median progression-free survival was 9.5 months (95% CI 7.2-9.8) and 11.7 months (8.3-21.7); median duration of response was 6.3 months (3.8-8.1) and 20.5 months (6.2-NC); and median overall survival was 19.8 months (13.5-23.3) and 26.2 months (14.8-NC). In the 4 mg/kg and the 6 mg/kg cohorts, respectively, grade ≥ 3 adverse events were reported in 49% and 76% of patients; AEs leaded to Dato-DXd dose reduction in 23% and 59%, and adjudicated interstitial lung disease/pneumonitis in 3% and 15%. The authors conclude that osimertinib plus Dato-DXd demonstrated clinical benefit in patients with EGFR-mutated aNSCLCwho progressed on first-line osimertinib; AEs in the 6 mg/kg cohort were of higher frequency and severity than in the 4mg/kg cohort but could be managed with prophylaxis, careful monitoring, and dose reduction. Considering the overall benefit-risk profile, 6 mg/kg is suggested as the preferred Dato-DXd starting dose combined with osimertinib 60 mg.