Background: Immune checkpoint blockade has led to unprecedented durable clinical benefit in metastatic non-small cell lung cancer (NSCLC), but response rates are low for patients with targetable driver mutations. EGFR and HER-2 exon 20 mutations account for ~4% of NSCLC, but outcomes for these patients when treated with immune checkpoint blockade have not been previously reported. Methods: We queried GEMINI, a MD Anderson Lung Cancer Moon Shot funded database for prospective collection of clinical information for patients with NSCLC, for patients with driver mutations in EGFR exon 19, 20, 21 and HER-2 exon 20 and treated with immune checkpoint inhibitors. We assessed overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Results: From 2014 to 2018, 90 patients with classic EGFR mutations (exon 19 del + exon 21 L858R, n = 38), EGFR exon 20 mutations (n = 36; no T790M included) and HER-2 exon 20 mutations (n = 16) had been treated with checkpoint inhibitors. Compared to classic EGFR mutants, EGFR exon 20 mutants demonstrated a higher disease control rate at 6 and 12 months as well as higher ORR. Also, EGFR exon 20 mutants demonstrated significantly higher PFS (HR 0.45, p = 0.002) and OS (HR 0.2, p < 0.001) (Table). These differences remained significant in multivariate analysis after adjusting for age, smoking status, radiation prior to treatment initiation and treatment with concurrent agents such as chemotherapy and/or radiation. HER-2 exon 20 mutants had similar ORR and PFS compared to classic EGFR mutants (HR 1.1, p = 0.8) (Table). Conclusions: EGFR exon 20 mutations are associated with superior outcome from immune checkpoint inhibitors compared to classic EGFR and HER-2 exon 20 mutations. Further studies on PD-L1 status and tumor mutation burden in these molecularly-defined groups are ongoing to address potential underlying mechanisms associated with these findings.