ORCHARD: Osimertinib Plus Necitumumab in Patients With Epidermal Growth Factor Receptor-Mutated Advanced Non-Small Cell Lung Cancer With a Secondary Epidermal Growth Factor Receptor Alteration Whose Disease Had Progressed on First-Line Osimertinib.

Purpose: ORCHARD (ClinicalTrials.gov identifier: NCT03944772) is a phase II, biomarker-directed platform study designed to characterize resistance mechanisms and evaluate novel drug combinations in patients with epidermal growth factor receptor ()-mutated advanced non-small cell lung cancer who have progressed on first-line osimertinib. We report final results of the module assessing the efficacy and safety of osimertinib plus necitumumab (a monoclonal antibody that blocks EGFR) in patients with ≥one of the following: amplification or select secondary alterations (L718 or G724 mutation, or exon 20 insertion).

Materials And Methods: Patients received osimertinib (80 mg orally once daily) plus necitumumab (800 mg intravenously, days 1 and 8 of a 3-week cycle) until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR) per RECIST 1.1 by investigator assessment.

Results: Overall, 19 patients received osimertinib plus necitumumab; at data cutoff (April 18, 2023), all patients had discontinued treatment. The ORR was 11% (80% CI, 3 to 26); two patients had a confirmed partial response, with duration of response of 10.4 and 6.0 months; both patients had amplification. The median progression-free survival was 4.0 months (95% CI, 1.3 to 5.4) and the overall survival was 11.4 months (95% CI, 6.6 to 15.5). Ten patients (53%) had grade ≥3 adverse events, most commonly embolism (not otherwise specified, pulmonary embolism or deep vein thrombosis, reported in four patients; 21%). The safety profile of the combination was consistent with the known profiles of the two individual drugs, and no new signals were identified.

Conclusion: Osimertinib plus necitumumab demonstrated modest clinical benefit, and the overall risk-benefit analysis indicates that further evaluation of the regimen is not warranted in these molecularly defined subsets of osimertinib resistance.