Osimertinib plus datopotamab deruxtecan in patients with EGFR-mutated advanced NSCLC after progression on first-line osimertinib: ORCHARD
Osimertinib plus datopotamab deruxtecan demonstrated clinical benefit in patients with EGFR-mutated advanced NSCLC who progressed on first-line osimertinib.
Background: ORCHARD (NCT03944772) was a phase II platform study conducted to characterize resistance mechanisms and evaluate novel treatment combinations following progressive disease (PD) on first-line osimertinib. Datopotamab deruxtecan (Dato‑DXd) is an anti‑TROP2 antibody‑drug conjugate approved as monotherapy in EGFR‑mutated advanced non‑small‑cell lung cancer (NSCLC). Methods: Eligible patients had EGFR‑mutated advanced NSCLC and PD on first‑line osimertinib. Patients received oral osimertinib (80 mg daily) plus intravenous Dato‑DXd (4 or 6 mg/kg every 3 weeks). The primary endpoint was investigator‑assessed confirmed objective response rate (ORR) per RECIST v1.1. Secondary endpoints were progression‑free survival (PFS), duration of response (DoR), overall survival (OS), and safety. Results: Sixty‑nine patients received study treatment. Confirmed ORR was 43% (4 mg/kg) and 36% (6 mg/kg). Median PFS was 9.5 months (4 mg/kg) and 11.7 months (6 mg/kg). Median DoR was 6.3 months (4 mg/kg) and 20.5 months (6 mg/kg). Median OS was 19.8 months (4 mg/kg) and 26.2 months (6 mg/kg). Grade ≥ 3 adverse events were reported in 49% and 76% of patients; AEs leading to dose reduction in 23% and 59%; interstitial lung disease/pneumonitis in 3% and 15%. Conclusions: Osimertinib plus Dato‑DXd demonstrated clinical benefit in patients with EGFR‑mutated advanced NSCLC who progressed on first‑line osimertinib. AEs in the 6 mg/kg cohort were of higher frequency and severity but could be managed with prophylaxis, careful monitoring, and dose reduction.
The combination shows activity in a population with limited therapeutic options after progression on first‑line osimertinib, supporting a new strategy for EGFR‑mutated NSCLC patients.
Evidence level: Korai humán adat. Kis vagy feltáró emberi adat.
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