Marsh, Sydney

9090 Background: The clinicopathologic characteristics and optimal treatment strategies for non-sensitizing EGFR ( ns- EGFR) and HER2 activating mutations in NSCLC remain unclear. Methods: Single-center retrospective study of patients seen at University of Colorado from 2008 – 2018 with stage IV NSCLC was performed. Clinicopathologic features and treatment outcomes of patients with ns-EGFR (Exon 18, Exon 20, L861Q) and HER2 mutations were collected. Best response to TKI was determined (RECIST v1.1). PFS was calculated using Kaplan-Meier method. Results: Among 359 patients, we identified 49 ns-EGFR (36 Exon 20, 10 Exon 18, 3 L861Q) and 28 HER2 mutations (27 Exon 20, 1 gene amplification) detected via NGS (65/77), real-time PCR (9/77), FISH (1/77) and undocumented (2/77). PDL1 > 50% was seen in 44% ns- EGFR and 57% HER2. Adenocarcinoma was the most common histology (97%). Most patients were female (62%), never smokers (63%), and presented with metastatic disease (stage: I 5%, II 4%, III 6%, IV 85%). HER2+ NSCLC demonstrated a tropism for lung metastases (64%) that was significant when compared to EGFR Exon 19, EGFR L858R, ALK, ROS1, and KRAS cohorts (p < 0.001). No differences were found when other metastatic sites were compared. Among evaluable patients, response rates to TKI therapy is shown. Aggregate median PFS on TKI for ns-EGFR and HER2+ NSCLC was 6 months compared to EGFR Exon 19 (15 months; p < 0.01; HR 0.4; CI 0.24 – 0.67) and EGFR L858R (22 months; p < 0.01; HR 0.27 and 0.8; CI 0.14 – 0.54). Aggregate median OS for ns-EGFR and HER2+ NSCLC was 28 months with no differences when compared to EGFR Exon 19 and L858R subgroups. Conclusions: HER2+ NSCLC appears to have a predisposition for lung metastases. Higher DCR was observed with newer generation TKIs, but novel targeted therapeutic approaches are needed as overall outcomes remain poor. [Table: see text]