Osimertinib Plus Datopotamab Deruxtecan in EGFR-Mutated Advanced NSCLC

Key Clinical Summary:

• Design/Population: This phase 2 platform substudy evaluated osimertinib plus datopotamab deruxtecan in patients with EGFR-mutated advanced NSCLC who experience progression on first-line osimertinib.
• Key Outcomes: The combination demonstrated meaningful response rates and durable responses, with evidence of activity across dosing cohorts and a manageable safety profile.
• Clinical Relevance: These results support a chemotherapy-sparing, targeted combination approach following EGFR TKI resistance and are being further evaluated in ongoing randomized trials.

Jonathan Riess, MD, UC Davis Comprehensive Cancer Center, Sacramento, California, discusses results from the ORCHARD study evaluating osimertinib plus datopotamab deruxtecan among patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) who experienced disease progression on first-line osimertinib. 

The combination demonstrated meaningful antitumor activity with durable responses and manageable safety, and supports continued development of this strategy in randomized trials.

Transcript:

My name is Dr Jonathan Riess. I’m a medical oncologist and director of thoracic oncology and early phase therapeutics at UC Davis Comprehensive Cancer Center. I’m going to be discussing our recently published study of osimertinib plus datopotamab deruxtecan in patients with EGFR-mutated advanced non-small cell lung cancer post-progression on first-line osimertinib.

This was an ORCHARD platform substudy. ORCHARD is an overarching phase 2 platform study that assessed resistance mechanisms and novel treatment combinations of treatment in patients with EGFR-mutated advanced non-small cell lung cancer following progression on first-line osimertinib.

This osimertinib plus datopotamab deruxtecan study was one of the biomarker nonmatched modules within the ORCHARD platform that based on next-generation sequencing, patients with matched resistance mechanisms were assigned to matched precision treatment combinations. Those without a match, such as in this substudy, were assigned to an unmatched treatment arm—here, continuing osimertinib, a next-generation EGFR TKI, with the anti-TROP2-directed antibody-drug conjugate datopotamab deruxtecan, which is approved as a single agent in EGFR-mutated non-small cell lung cancer after progression on EGFR TKI and platinum-based chemotherapy.

This study evaluates the combination after progression on first-line osimertinib while continuing osimertinib and adding datopotamab deruxtecan. Potential reasons for doing so include nonoverlapping potential mechanisms of resistance between an antibody-drug conjugate and an EGFR TKI, as well as potential enhanced CNS penetration from continuing osimertinib, which is CNS-penetrant. 

Patients were treated with osimertinib 80 mg daily and assigned to one of two cohorts: datopotamab deruxtecan at 4 mg/kg every 3 weeks or 6 mg/kg every 3 weeks. The primary end point was overall response rate by investigator assessment using RECIST 1.1. Secondary end points included safety and tolerability, progression-free survival, duration of response, and overall survival.

In terms of efficacy, in the 4 mg/kg cohort, 35 patients were enrolled and the overall response rate was 43%. Twenty percent of patients had a duration of response of 12 months or more. In the 6 mg/kg cohort, 33 patients were enrolled, with an overall response rate of 36%, and 50% of patients had a duration of response of 12 months or more. Median duration of response was 6.3 months in the 4 mg/kg arm and 20.5 months in the 6 mg/kg arm. Median progression-free survival was 9.5 and 11.7 months in the 4 and 6 mg/kg arms, respectively. Median overall survival was 19.8 months in the 4 mg/kg arm and 26.2 months in the 6 mg/kg arm.

In terms of safety, there were differences between the dose levels. Grade ≥3 adverse events occurred in 49% of patients in the 4 mg/kg cohort and 76% in the 6 mg/kg cohort. Serious adverse events occurred in 31% and 44% of patients, respectively. Adverse events leading to dose reduction occurred in 23% and 59% of patients, respectively. Adjudicated interstitial lung disease occurred in about 3% of patients in the 4 mg/kg group and 15% in the 6 mg/kg group. Safety was consistent with the known profiles of the individual drugs, but at the 6 mg/kg dose, which is the single-agent FDA-approved dose, there was increased toxicity compared with 4 mg/kg, including higher rates of grade ≥3 adverse events, dose reductions, and a higher incidence of interstitial lung disease/pneumonitis.

Overall, the take-home message is that the combination demonstrated clinical benefit in patients with EGFR-mutated advanced non-small cell lung cancer who progressed on first-line osimertinib. Adverse events were manageable with prophylaxis, such as dexamethasone mouthwash for stomatitis, as well as monitoring and dose modification.The difference in duration of response, in particular, was intriguing and suggests that early dose intensity may matter for datopotamab deruxtecan. There are 2 ongoing randomized trials, TROPION-Lung14 and TROPION-Lung15, evaluating this combination in the first- and second-line settings. Based on the duration of response data, the 6 mg/kg dose of datopotamab deruxtecan is being taken forward in these studies, alongside osimertinib 80 mg daily.

Overall, these are intriguing efficacy results, particularly for duration of response with the 6 mg/kg dose, and this combination is being further explored in randomized trials.

Source: 

Riess J, Yu HA, Le X, et al. Osimertinib plus datopotamab deruxtecan in patients with EGFR-mutated advanced NSCLC after progression on first-line osimertinib: ORCHARD. Ann Oncol. Published online: March 2, 2026. doi: 10.1016/j.annonc.2026.02.014