Background: Poziotinib is a novel, oral, quinazoline-based pan-HER inhibitor that irreversibly blocks signaling through the EGFR family of tyrosine-kinase receptors, including human epidermal growth factor receptor (HER1/ErbB1/EGFR), HER2 (ErbB2), and HER4 (ErbB4), which leads to inhibition of the proliferation of tumor cells that overexpress these receptors or activated by EGFR or HER2 exon 20 mutations. There is no FDA approved targeted therapy for EGFR or HER2 exon 20 insertion mutant NSCLC. Chemotherapy remains the standard of care for metastatic disease with severe side effects and modest efficacy. Preclinical testing indicates that poziotinib is more active than currently approved tyrosine kinase inhibitors against cell lines with a range of EGFR exon 20 mutations in vitro when using the standard Ba/F3 model. An ongoing investigator-initiated study at MD Anderson is showing that poziotinib is effective at reducing tumor size in patients with EGFR or HER2 exon 20 mutations. The primary endpoint of this Phase 2 study is to evaluate the Objective Response Rate (ORR) to poziotinib in patients with EGFR or HER2 positive non-small cell lung cancer (NSCLC). Secondary endpoints are to evaluate the Disease Control Rate (DCR) and Duration of Response (DoR) in this group of patients. Methods: This is an open-label, multicenter study evaluating the efficacy and safety of poziotinib in patients with histologically or cytologically confirmed NSCLC with a documented EGFR or HER2 exon 20 insertion mutation. Patients with T790M point mutations will be excluded. Patients will be enrolled into one of two cohorts based on documented EGFR (Cohort 1; n = 87) or HER2 (Cohort 2; n = 87) exon 20 mutations. Both cohorts are enrolling simultaneously. Patients must be 18 years of age, have an ECOG score ≤2, and have adequate tumor tissue from biopsy or surgical procedure to enable molecular profiling. The starting dose of poziotinib is 16 mg PO daily with possible dose reductions to 14 mg and 12 mg for tolerability issues. Patients will be treated until either progression or intolerable adverse events. Response will be assessed by an Independent Image Review. Study enrollment began in October 2017. Clinical trial information: NCT 03318939.