Osimertinib plus datopotamab deruxtecan in patients with EGFR-mutated advanced NSCLC after progression on first-line osimertinib: ORCHARD.
Summary
The phase II ORCHARD study investigated the efficacy and safety of combining osimertinib with datopotamab deruxtecan (Dato-DXd) in patients with advanced EGFR-mutated non-small-cell lung cancer (NSCLC) who had progressed on first-line osimertinib. Two Dato-DXd doses (4 mg/kg and 6 mg/kg) were evaluated. Both cohorts demonstrated clinical benefit, with objective response rates (ORR) of 43% and 36% respectively. Median progression-free survival (PFS) was 9.5 months for the 4 mg/kg dose and 11.7 months for 6 mg/kg, while median overall survival (OS) reached 19.8 months and 26.2 months. Although the 6 mg/kg dose was associated with higher toxicity, it was manageable, and this dose is suggested as the preferred starting dose given the overall benefit-risk profile.
Analysis
This phase II study evaluates a novel therapeutic combination for patients with advanced EGFR-mutated NSCLC who have progressed on first-line osimertinib, a population with limited treatment options. The results demonstrate promising clinical benefit with ORRs of 43% and 36%, median PFS of 9.5 and 11.7 months, and median OS of 19.8 and 26.2 months for the 4 mg/kg and 6 mg/kg Dato-DXd doses, respectively. The 6 mg/kg dose, despite higher grade ≥3 toxicity (76% vs 49%), is considered preferable due to better efficacy and manageable adverse events. These phase II data are encouraging and could justify phase III trials to confirm these results and potentially change clinical practice within 3 to 5 years, offering a new option for this patient population with treatment failure.