Testing Osimertinib as a Treatment for Lung Cancers With an EGFR Exon 20 Change

This phase II trial studies how well osimertinib works in treating patients with non-small cell lung cancer with EGFR exon 20 insertion mutation that is stage IIIB-IV or has come back after a period of improvement (recurrent). Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVE: I. To evaluate the best objective response rate of osimertinib (AZD9291) among patients with EGFR exon 20 insertions. SECONDARY OBJECTIVES: I. To determine the safety profile of 160 mg once daily (QD) dose of osimertinib (AZD9291) in patients with EGFR Exon 20 insertion mutations. II. To determine the progression-free survival. III. To determine the overall survival. TERTIARY OBJECTIVES: I. To characterize molecular markers of response to treatment in circulating tumor deoxyribonucleic acid (DNA). II. To evaluate biomarkers of response to treatment through retrospective analyses of pre-treatment tumor tissue. III. To identify resistance mechanisms to osimertinib (AZD9291) through post-progression tumor biopsies and circulating tumor (ct)DNA. OUTLINE: Patients receive osimertinib orally (PO) once daily (QD) on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA), magnetic resonance imaging (MRI) or computed tomography (CT) with contrast, and collection of blood samples throughout the trial. After completion of study treatment, patients are followed up at 30 days and every 3 months for up to 5 years.