Background: EGFR and HER2 (ERBB2) exon 20 insertion (ex20ins) mutations represent a subset of driver alterations in NSCLC, which historically have largely not responded to available targeted therapies. Recently, inhibitors specifically targeting ex20ins have shown efficacy in the clinic. Previous studies have described the landscape of EGFR ex20ins in NSCLC (PMID: 29981927), but similar descriptions of HER2 ex20ins are lacking. Methods: Hybrid capture-based comprehensive genomic profiling (CGP) was performed on 39,644 tissue and 4,062 blood-based circulating tumor DNA (ctDNA) samples from 43,706 unique patients with advanced NSCLC. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA for tissue samples and reported as mutations/Mb. Results:HER2 ex20ins were detected in 1.5% (648/43,706) of NSCLC cases (614 tissue and 34 ctDNA). HER2 ex20ins represented 35% (648/1,845) of HER2-altered NSCLCs overall, while 46% (843/1,845) of cases had HER2 amplification (≥5 copies), 17% (320/1,845) had a non-ex20ins HER2 short variant (SV; most commonly S310F in 84 cases and V659E in 29 cases), and 1.8% (34/1,845) had HER2 amplification + SV. There were 28 unique ex20ins including most commonly A775_G776insYVMA (69%, 450/648), G776 > VC (12%, 76/648) and P780_Y781insGSP (8.6%, 56/648). Cases with HER2 ex20ins were significantly enriched for adenocarcinoma histology (89% vs 66%), female gender (64% vs 51%) and low TMB (95% vs 65% TMB < 10 mut/Mb) compared to HER2 wild-type cases (all p < 0.0001). HER2 amplification (7 median copies, range 5-39) co-occurred in 16% (103/648) of HER2 ex20ins cases. Co-occurrence of other known NSCLC drivers in HER2 ex20ins cases was rare (0.8%, 5/648). In contrast, non-HER2ex20ins cases with HER2 amplification or other HER2 SVs each had co-occurring known driver alterations in ~30% of cases. There was no significant difference in histology, gender, age, HER2 co-amplification or TMB in cases with YVMA vs non-YVMA ex20ins. Conclusions:HER2 ex20ins are found in 1.5% of NSCLCs and are generally mutually exclusive of other known drivers. Detection of these alterations may be critical to identify matched targeted therapy options for this subset of patients.