Off-Label Use of Precision Oncology Therapeutics in Advanced Solid Cancers Following Identification of Associated Variants via Multicancer Next-Generation Sequencing Panel: A Real-World Evidence Pilot Study

Background: Off-label use of pharmaceuticals, including in precision oncology, is common but not necessarily lacking in evidence of efficacy and safety. Concerns about payer coverage hindering comprehensive genomic profiling (CGP) in preci­sion oncology are raised, yet studies show that CGP rarely leads to prescribing of off-label therapies (2%-7%). We investigated off-label therapy utilization post- CGP via liquid biopsy using a clinicogenomic database. Variants associated with US Food and Drug Administration (FDA)-approved therapies were identified in patients. Methods: We reviewed clinical reports for FDA-approved therapy-asso­ciated variants, focusing on five genes (EGFR, PIK3CA, ATM, BRCA1, BRCA2) with >1% frequency. We then used the GuardantINFORM database (137 000+ patients) to assess off-label use impact, including variants of uncertain significance (VUSs) influence. Results: Among variants with an associated FDA-approved therapy in another indication (n = 18 660), only 0.8% had subsequent off-label therapy claims unrelated to on-label cancer types. Clinical trial enrollment post-CGP in the group receiving off-label therapy was 19%. For VUSs in five genes, 1.2% received off-label therapies (n = 21 606). Conclusions: CGP via validated liquid biopsy seems to result in minimal inappropriate use of off-label therapies. These findings can in­form payer coverage policies regarding CGP’s impact on advanced solid cancers.