Background: EGFR exon 20 insertions (ins20) represent a rare subtype (4%) of EGFR mutations and are refractory to EGFR-specific tyrosine kinase inhibitors (TKIs). No effective targeted therapies exist for patients (pts) with ins20; median PFS on the irreversible EGFR TKI Afatinib is 2.8 months (mos). A pt with EGFR ins20 achieved a durable RECIST partial response (PR) to AUY922, a Heat Shock Protein 90 (Hsp90) inhibitor, in a previous study (NCT01124864), so we designed this phase II investigator-initiated trial to assess the activity of AUY922 in NSCLC pts with EGFR ins20. Methods: This was a single-arm, multi-center, open-label study of AUY922 in advanced NSCLC pts with EGFR ins20 mutations. A Simon two-stage design was used, with a plan to enroll 10 pts in the 1st stage and an additional 19 pts in the 2nd stage if >1 PR or stable disease (SD) lasting > 3 mos was observed in the 1st stage. All pts were treated with AUY922 at 70mg/m2 IV weekly. The primary aim was to evaluate objective response rate (ORR) to AUY922. Here we report the complete results of the 1st stage. Results: Ten pts, including 7 females and 3 males, average age 55 (range 44-69), were enrolled. Median number of prior therapies = 1 (range 1-6.) 3 had received a prior EGFR TKI; none responded to TKI monotherapy. The most common toxicities were grade 1-2 visual changes (9 pts), diarrhea (9) and fatigue (8.) The only treatment-related grade 3 toxicity was hypertension (2).Among the 10 pts, we observed one PR and three SD lasting > 3 mos, thus triggering full enrollment to the 2nd stage of the study (Table). Median PFS estimate is 6.1 mos (95% CI, 1.2 to NR). Updated results and correlation with specific ins20 mutations will be presented. Conclusions: AUY922 may be an effective therapy for pts with EGFR ins20 mutations with med PFS 6.1 mo and is generally well-tolerated, though reversible low-grade ocular toxicity is common. To our knowledge, this is the first trial designed specifically for pts with this rare genotype. Further study of AUY922 in this population is warranted. Clinical trial information: NCT01854034 Clinical trial information: NCT01854034

+ Treatment is ongoing