Clinical outcomes and characterization of HER2 alterations in non-small cell lung cancer (NSCLC).

Abstract

8538 Background: Subsets of NSCLC carry alterations in the human epidermal growth factor receptor 2 (HER2) gene such as mutations (mt), amplification (amp), and protein overexpression. These alterations reflect distinct patient (pt) populations and disease biology, translating to variable outcomes with immunotherapy +/- chemotherapy. HER2-directed therapies have shown significant efficacy for HER2 mt and to a lesser extent HER2 3+ NSCLC. We describe the genomic landscape of HER2-altered NSCLC in a large cohort of tumors from the Caris database and explore pt outcomes. Methods: Next-generation sequencing of DNA (592-gene or WES) and RNA (WTS) was performed on NSCLC samples (n=52,690, Caris Life Sciences, Phoenix, AZ). IHC was performed on FFPE sections (HER2 staining intensity of 2+, >5%). HER2 amp was defined as copy number > 6. Tumor microenvironment studies were calculated by QuantiSeq. Significance was calculated using chi-square, Fisher’s exact, or Mann-Whitney U test, with p-values adjusted for multiple comparisons (q<0.05). Overall survival (OS) was estimated from insurance claims data using Cox proportional hazards model to calculate hazard ratio (HR) and log-rank tests to calculate P values. Results: 670 tumors were HER2 mt (N=492 within the kinase domain, 133 extracellular domain, 47 transmembrane domain, 16 other, 400 HER2 amp, and 272 HER2 IHC 2+. Treatment (tx) received prior to tumor sample collection is not reported in 64.2% HER2 mt, 68.8% HER2 2+, 56.5% HER2 amp (may reflect tx naive pts). Among female pts, HER2 mt was more common than amp or overexpressed 3+ (59.7% vs. 39.8% vs 36.2% p<0.01). HER2 mt correlated with improved OS compared to HER2 amp and a cohort of NSCLC driverless tumors (wild type EGFR, ALK, ROS1, RET, KRAS, and HER2). When compared to ROS1+, ALK+ and EGFR mt, HER2 mt had shorter OS (Table). Higher frequency of co-mts are noted in HER2 amp vs mt, including TP53 (90% vs 57%), EGFR (10% vs 6%), SMARCA4 (12% vs 5%), CDKN2A (16% vs 5%), NKX2-1 (2% vs 0.5%) and TMB-H (47% vs 21%), all p<0.001. No differences in PD-L1 expression were observed. Higher frequency of co-mts for HER2 IHC 2+ vs HER2 mt, including KRAS (33% vs 3%), KEAP1 (21% vs 7%), BRAF (5% vs 0.8%), EGFR (13% vs 6%) and SMARCA4 (11% vs 5%), all p<0.001. HER2 mt tumors had greater infiltration of NK cells, B cells, M2 macrophages, neutrophils and Tregs (FC 1.2-1.3) vs. HER2 IHC 2+. Conclusions: This study highlights the significant differences in OS and co-alterations for HER2 mt vs other HER2 altered and NSCLC driverless tumors. This data confirms the unmet need to further explore these differences to optimize tx and improve OS. NSCLC cohorts compared to HER2 mt cohort (22.0 months). NSCLC Cohort Survival (months) HR, 95% CI p-value HER2 amp 12.3 0.67 (0.57-0.79) <0.001 HER2 2+ 14.1 0.92 (0.77-1.09) 0.33 Driverless 16.2 0.85 (0.77-0.94) <0.01 ROS1 fusion 35.3 1.3 (1.0-1.7) 0.02 ALK fusion 47.4 1.9 (1.6-2.3) <0.001 EGFR mt 30.7 1.3 (1.2-1.5) <0.001