Abstract A046: Real world adoption of off-label combination treatment to treat non-small cell lung cancer resistance

Abstract Purpose No targeted therapy combinations have achieved regulatory approval for the treatment of biomarker positive resistance in non-small cell lung cancer (NSCLC), though there is more than a decade of investigation into these combinations. Given the widespread availability of next-generation sequencing (NGS) to detect such resistance in routine clinical practice, we reviewed the real-world experience of using off-label targeted therapy combinations to treat advanced NSCLC at our academic safety-net hospital. Methods Pharmacy records from the Hematology/Oncology Department at Boston Medical Center during the years 2017 to 2024 were reviewed. We identified 111 patients treated by three thoracic oncologists who received an oral, targeted therapy at some point during this time. Eligible patients received an off-label combination of targeted therapy for advanced NSCLC. Ineligible patients included those who received combinations of targeted therapy for other conditions, an approved targeted therapy in combination with chemotherapy, and approved combinations of targeted therapy. Finally, we reviewed the available published evidence to support the combination dosing. Results Eight eligible patients were identified who were treated with 9 combination regimens. The median age of the patients was 72 years (age 29-89 years). 6 patients had EGFR exon 19 deletions and 2 had EML4-ALK fusions. The median number of treatment lines preceding off-label targeted combination therapy was 2.5 (range: 1-9); the median number of targeted therapies preceding off-label combination therapy was 1.5 (range: 1-3), with a median treatment duration of 10.5 months (range: 1-48 months). The 9 combination regimens included addition of a MET inhibitor (n=3), a RET inhibitor (n=2), a MEK inhibitor (n=2), an ALK inhibitor (n=1) and an EGFR antibody (n=1). The median duration of treatment with off-label combination therapy was 7 months (range: 1-35 months), and was longest for alectinib and capmatinib (15 months ongoing & 25 months, ongoing) and gefitinib and selpercatinib (35 months, ongoing). Seven patients required dose reductions for toxicity and two patients had toxicities requiring discontinuation of therapy. Evidence to support combination regimens included retrospective cohort studies (n=3), published case reports/series (n=3), and a prospective cohort study (n=1). Conclusion Off-label combination therapy to treat targeted therapy resistance in advanced NSCLC is feasible in an academic health-safety net setting. Additional real-world evidence is needed to clarify best practices with this emerging approach. Citation Format: Justin A. Battaglini, Maha AlDoughaim, Katie Li, Jasmine Patel, Sita Bhatt, Peter Everett, Geoffrey Oxnard, Umit Tapan. Real world adoption of off-label combination treatment to treat non-small cell lung cancer resistance [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A046.