First-in-Human Study of Osimertinib Plus Datopotamab Deruxtecan Shows ‘Promising’ Efficacy in Pretreated NSCLC

Osimertinib plus datopotamab deruxtecan showed “promising efficacy and manageable safety” in patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) who experienced disease progression on first-line osimertinib, according to results from the ORCHARD trial.

Xiuning Le, MD, PhD, of the University of Texas MD Anderson Cancer Center, presented the results from the trial during the 2025 European Lung Cancer Congress in Paris, France. The phase 2 ORCHARD trial is a non-randomized platform study evaluating novel treatment combinations in patients with EGFR-mutated advanced NSCLC who progressed on first-line osimertinib. Module 10 of the ORCHARD study is the first-in-human study to evaluate the combination of osimertinib plus datopotamab deruxtecan.

A total of 69 patients received oral osimertinib 80 mg once a day with intravenous datopotamab deruxtecan at a dose of 4 mg/kg (n=35) or 6 mg/kg (n=34) every three weeks. The study began enrolling patients in the 4 mg cohort and then extended enrollment to the 6 mg cohort, followed by simultaneous enrollment to both dose level cohorts. The primary endpoint of the study was the overall response rate ORR, with secondary endpoints including duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety.

The median treatment duration was 9 months among those receiving the 4 mg/kg dose, with a median follow-up of 13.4 months. Among patients receiving the 6 mg/kg dose, the median treatment duration was 9.8 months, with a median follow-up of 13.8 months.

Among the 68 patients the researchers evaluated, the ORR was 43% in patients receiving the 4 mg dose and 36% among those receiving the 6 mg dose. At 9 months, 15% of patients receiving the 4 mg dose remained in response, compared with 64% of those receiving the 6 mg dose. The median PFS was 9.5 months in patients receiving the 4 mg dose, compared with 11.7 months in those receiving the 6 mg dose.

However, a higher proportion (56%) of patients receiving the 6 mg dose had grade ≥3 adverse events (AEs) related to any treatment than those receiving the 4 mg dose (34%). AEs leading to datopotamab deruxtecan dose reduction also occurred in a higher proportion of patients receiving 6 mg (59%) than 4 mg (23%), as did adjudicated interstitial lung disease/pneumonitis (4 mg vs 6 mg: any grade, 3% vs 15%; grade ≥3, 3% vs 6%). The investigators reported “no new safety signals.”

While “longer-term follow-up data are awaited,” Dr. Li and colleagues explained that “considering the overall benefit/risk profile, 6 mg/kg should be the preferred” starting dose of datopotamab deruxtecan for combination with osimertinib 80 mg.

Reference

Le X. Osimertinib (osi) + datopotamab deruxtecan (Dato-DXd) in patients (pts) with EGFR-mutated (EGFRm) advanced NSCLC (aNSCLC) whose disease progressed on first-line (1L) osi: ORCHARD. Abstract #1O. Presented at the European Lung Cancer Congress 2025, March 26-29, 2025; Paris, France.