Molecular-Guided Off-Label Targeted Therapy in a Large-Scale Precision Oncology Program

Area of Science:

• Oncology
• Genomics
• Pharmacology

Background:

• Comprehensive genomic profiling (CGP) identifies actionable mutations in cancer.
• Targeted agents (TAs) improve outcomes for patients with specific mutations.
• Real-world data on off-label TA use in Veterans is limited.

Purpose of the Study:

• To evaluate the real-world experience of off-label TA use in Veterans who underwent CGP.
• To assess the efficacy and toxicity of off-label TAs based on CGP results.
• To compare outcomes based on OncoKB annotation levels for off-label TA use.

Main Methods:

• Retrospective analysis of the National Precision Oncology Program database and VA Corporate Data Warehouse (Feb 2019-Dec 2021).
• Identified patients who received one of 73 TAs for malignancy post-CGP.
• Used OncoKB annotations to define off-label TA use; chart abstraction for response, toxicities, and progression.

Main Results:

• 169 Veterans (0.9%) received 183 off-label TA regimens for variants in 31 genes.
• Off-label TA use was highest in thyroid (8.6%) and breast (7.6%) cancers.
• 27% of regimens (n=160) prescribed >4 weeks led to response; median progression-free survival (PFS) was 5.3 months.
• Patients receiving TAs with higher OncoKB evidence levels (2/3A/3B) had longer median PFS (5.8 months) vs. level 4 (3.7 months).

Conclusions:

• Off-label TA administration post-CGP is infrequent but can yield responses in a significant proportion of Veterans.
• Targeted agents with lower OncoKB evidence levels (level 4) are associated with worse outcomes compared to those with higher evidence levels.