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Published on: November 22, 2021
Osimertinib plus datopotamab deruxtecan in patients with EGFR-mutated advanced NSCLC after progression on first-line
1Internal Medicine - Hematology/Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, USA.
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% to 55%] and 36% (80% CI 25% to 49%); median PFS was 9.5 months (95% CI 7.2-9.8 months) and 11.7 months (95% CI 8.3-21.7 months); median DoR was 6.3 months (95% CI 3.8-8.1 months) and 20.5 months [95% CI 6.2 months-not calculable (NC); estimated median of at least 16 months]; and median OS was 19.8 months (95% CI 13.5-23.3 months) and 26.2 months (95% CI 14.8 months-NC; estimated median greater than or equal to the 4 mg/kg cohort). 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.
Clinical Trial Number:
ClinicalTrials.govNCT03944772.
Insights
Osimertinib plus datopotamab deruxtecan showed clinical benefit in advanced EGFR-mutated NSCLC patients after first-line osimertinib. The 6 mg/kg dose demonstrated a favorable benefit-risk profile, suggesting it as a preferred starting dose.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- The ORCHARD study evaluated novel combinations for EGFR-mutated NSCLC following progression on first-line osimertinib.
- Datopotamab deruxtecan (Dato-DXd) is an anti-TROP2 ADC approved for advanced EGFR-mutated NSCLC.
Purpose of the Study:
- To report final data from the phase II ORCHARD study module evaluating osimertinib plus Dato-DXd.
- To characterize resistance mechanisms and treatment outcomes in advanced NSCLC patients.
Main Methods:
- Phase II platform study in EGFR-mutated advanced NSCLC patients with prior first-line osimertinib.
- Patients received osimertinib plus Dato-DXd at 4 mg/kg or 6 mg/kg.
- Primary endpoint: objective response rate (ORR); Secondary endpoints: PFS, DoR, OS, and safety.
Main Results:
- 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).
- Higher grade ≥3 AEs (76%) and dose reductions (59%) were observed in the 6 mg/kg cohort, with 15% experiencing pneumonitis.
Conclusions:
- Osimertinib plus Dato-DXd demonstrated clinical benefit in patients progressing on first-line osimertinib.
- The 6 mg/kg Dato-DXd dose, despite higher AEs, is suggested as the preferred starting dose due to its overall benefit-risk profile.
- AEs were manageable with prophylaxis, monitoring, and dose reduction, consistent with individual drug profiles.
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