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Background There are currently no approved targeted therapies for non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 insertions (ins20), a subgroup of EGFR mutations that are generally refractory to first/second generation EGFR inhibitors. We report the final results of a phase II trial evaluating the activity of the Hsp90 inhibitor luminespib (AUY922) in NSCLC patients with EGFR ins20. Patients and methods Twenty-nine patients with stage IV NSCLC with EGFR ins20 identified on local testing and at least one prior therapy were enrolled on the trial between August 2013 and October 2016. The primary end point was objective response rate (ORR), with a pre-determined target rate of effectiveness [defined as the rate of partial response (PR) plus stable disease (SD) lasting ≥3 months] of 20%. Secondary end points were PFS, overall survival (OS), safety and response by EGFR ins20 subtype. Results Among the 29 patients (18 females, median age 60 years) the ORR was 17%, median progression-free survival was 2.9 months (95% CI 1.4–5.6) and median OS (mOS) was 13 months (95% CI 4.9–19.5). The results exceeded the pre-determined target rate of effectiveness with 11/29 (38%) patients having a PR or an SD ≥3 months. The most common luminespib-related toxicities were diarrhea (83%), visual changes (76%) and fatigue (45%). All study treatment was stopped on 28 February 2017 due to dissolution of study drug availability; 3 patients were on treatment at study termination. Conclusion The study met its primary end point, suggesting that luminespib may be an active therapy for advanced NSCLC patients with EGFR ins20. Luminespib is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of luminespib and other hsp90 inhibitors in this population is warranted. Study registration (ClinicalTrials.gov) NCT01854034. [ABSTRACT FROM AUTHOR]