Purpose <p>No targeted therapy combinations have achieved regulatory approval for the treatment of biomarker-positive resistance in non-small cell lung cancer (NSCLC). Given the widespread availability of next-generation sequencing (NGS) to detect resistance, we reviewed the real-world experience of using off-label targeted therapy combinations to treat advanced NSCLC at our academic safety-net hospital.</p> Methods <p>Pharmacy records from the Hematology/Oncology Department at Boston Medical Center during the years 2017 to 2024 were reviewed. One hundred eleven patients received oral, targeted therapy during this time. Our study focused on those patients who received an off-label combination of targeted therapies for advanced NSCLC. We reviewed their demographics, treatment history, molecular data, and published evidence to support the combination.</p> Results <p>Eight patients were treated with nine combination regimens. The median age was 69&#xa0;years (age 29–89&#xa0;years). Six patients had EGFR exon 19 deletions and two had EML4-ALK fusions. The nine combination regimens included addition of a MET inhibitor (<i>n</i> = 3), a RET inhibitor (<i>n</i> = 2), a MEK inhibitor (<i>n</i> = 2), an ALK inhibitor (<i>n</i> = 1), and an EGFR antibody (<i>n</i> = 1). The median duration of treatment was 7&#xa0;months (range: 1–35&#xa0;months), and was longest for alectinib and capmatinib (15&#xa0;months ongoing and 25&#xa0;months, ongoing) and gefitinib and selpercatinib (35&#xa0;months, ongoing). Available supporting evidence included retrospective cohort studies (<i>n</i> = 5), published case reports/series (<i>n</i> = 2), and a prospective cohort study (<i>n</i> = 1).</p> Conclusion <p>Off-label combination therapy to treat targeted therapy resistance in advanced NSCLC is feasible in routine clinical practice. Additional real-world evidence is needed to clarify best practices with this emerging approach.</p>