Response to Standard Therapies and Comprehensive Genomic Analysis for Patients with Lung Adenocarcinoma with <i>EGFR</i> Exon 20 Insertions

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Purpose:</jats:title> <jats:p>EGFR exon 20 insertions (ex20ins) are an uncommon genotype in non–small cell lung cancer (NSCLC) for which targeted therapies are under development. We sought to describe treatment outcomes and genomic and immunophenotypic characteristics of these tumors.</jats:p> </jats:sec> <jats:sec> <jats:title>Experimental Design:</jats:title> <jats:p>We identified sequential patients with NSCLC with EGFR ex20ins and compared their clinical outcomes and pathologic features with other patients with NSCLC.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>Among 6,290 patients with NSCLC, 106 (2%) had EGFR ex20ins. Patients with EGFR ex20ins were more likely to be Black (14% vs. 6%; P &lt; 0.001) or Asian (22% vs. 10%; P &lt; 0.001) compared with all other patients with NSCLC. Median tumor mutational burden (TMB; 3.5 vs. 5.9; P &lt; 0.001) and proportion of tumors with PD-L1 expression ≥1% (22% vs. 60%; P &lt; 0.001) were lower in EGFR ex20ins compared with other NSCLCs (TMB, n = 5,851 and PD-L1 expression, n = 282) and EGFR del 19/L858R (median TMB, 3.5; P = 0.001 and 39% PD-L1 ≥ 1%; P = 0.02). Compared with a 2:1 cohort of patients with metastatic NSCLC without targetable alterations (n = 192), EGFR ex20ins patients had longer overall survival (median 20 vs. 12 months; HR, 0.56; P = 0.007) and longer time to treatment discontinuation (TTD) for platinum chemotherapy (median, 7 vs. 4 months; HR, 0.6; P = 0.02) and no improvement in TTD for immune checkpoint inhibitors (ICI; HR, 1.75; P = 0.05).</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>With better outcomes on platinum chemotherapy, patients with EGFR ex20ins NSCLC have improved prognosis, lower PD-L1 expression and TMB, and derive less benefit from ICIs compared with patients with NSCLC without targetable oncogenes. Improving molecularly targeted therapies could provide greater benefit for patients with EGFR ex20ins.</jats:p> </jats:sec>