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). We report final data from the osimertinib plus Dato-DXd module. Methods: Eligible patients had EGFR-mutated advanced NSCLC and PD on first-line osimertinib. Patients received oral osimertinib (80 mg once 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. Among patients in the 4 mg/kg (N = 35) and 6 mg/kg (N = 34) cohorts, respectively: confirmed ORR was 43% (80% confidence interval [CI] 32-55) and 36% (80% CI 25-49); median PFS was 9.5 (95% CI 7.2-9.8) and 11.7 (95% CI 8.3-21.7) months; median DoR was 6.3 (95% CI 3.8-8.1) and 20.5 (95% CI 6.2-not calculable [NC]; estimated median of at least 16) months; median OS was 19.8 (95% CI 13.5-23.3) and 26.2 (95% CI 14.8-NC; estimated median greater than or equal to the 4 mg/kg cohort) months. In the 4 mg/kg and 6 mg/kg cohorts, respectively, grade ≥3 adverse events (AEs) were reported in 49% and 76% of patients; AEs leading to Dato-DXd dose reduction in 23% and 59%; and adjudicated 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 safety profile was consistent with the known profiles of the individual drugs. Considering the overall benefit-risk profile, 6 mg/kg is suggested as the preferred Dato-DXd starting dose for combining with osimertinib 80 mg.
Osimertinib plus datopotamab deruxtecan in patients with EGFR-mutated advanced NSCLC post-progression on first-line osimertinib: ORCHARD
Bonanno, L.;
2026
Abstract
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). We report final data from the osimertinib plus Dato-DXd module. Methods: Eligible patients had EGFR-mutated advanced NSCLC and PD on first-line osimertinib. Patients received oral osimertinib (80 mg once 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. Among patients in the 4 mg/kg (N = 35) and 6 mg/kg (N = 34) cohorts, respectively: confirmed ORR was 43% (80% confidence interval [CI] 32-55) and 36% (80% CI 25-49); median PFS was 9.5 (95% CI 7.2-9.8) and 11.7 (95% CI 8.3-21.7) months; median DoR was 6.3 (95% CI 3.8-8.1) and 20.5 (95% CI 6.2-not calculable [NC]; estimated median of at least 16) months; median OS was 19.8 (95% CI 13.5-23.3) and 26.2 (95% CI 14.8-NC; estimated median greater than or equal to the 4 mg/kg cohort) months. In the 4 mg/kg and 6 mg/kg cohorts, respectively, grade ≥3 adverse events (AEs) were reported in 49% and 76% of patients; AEs leading to Dato-DXd dose reduction in 23% and 59%; and adjudicated 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 safety profile was consistent with the known profiles of the individual drugs. Considering the overall benefit-risk profile, 6 mg/kg is suggested as the preferred Dato-DXd starting dose for combining with osimertinib 80 mg.
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