Acquired resistance to third-generation epidermal growth factor receptor (EGFR) inhibitors (eg, osimertinib) may result in MET gene amplification and/or c-MET protein overexpression. Telisotuzumab vedotin (ABBV-399; teliso-v), an anti–c-MET antibody-drug conjugate that can both disrupt c-MET signaling and deliver a cytotoxic payload into tumor cells, has shown antitumor activity in a phase 1/1b trial (NCT02099058) in patients (pts) with non-small cell lung cancer (NSCLC) with c-MET overexpression. Here we describe the teliso-v plus osimertinib cohort (arm E) of this trial. Arm E of this phase 1/1b open-label study evaluates safety, pharmacokinetics, and preliminary efficacy of teliso-v, administered intravenously once every 2 weeks, in combination with oral osimertinib (80 mg once a day) in pts with metastatic NSCLC whose disease progressed on osimertinib. Pts must have documented osimertinib-sensitive EGFR mutations, and c-MET overexpression (defined by central immunohistochemistry test) in tumor tissue obtained post-osimertinib progression. Arm E consists of safety lead-in (SLP; n=3–6), safety evaluation (SEP; n=3–12), and expansion (n=3–12) phases. Teliso-v will first be evaluated at 1.6 mg/kg and escalated to 1.9 mg/kg on the basis of safety signals in SLP and SEP phases. Radiographic tumor assessments will continue until disease progression, start of a new anticancer therapy, death, or consent withdrawal. Response evaluation will be based on Response Evaluation Criteria in Solid Tumors version 1.1. Planned enrollment is 3–24 pts; to date, 3 pts are enrolled. NCT02099058. Medical writing support was provided by Mary L. Smith, PhD, CMPP, from Aptitude Health, Atlanta, GA, and funded by AbbVie. AbbVie.