OBJECTIVES: Significant uncertainty in precision medicines, driven by small benefitting populations and heterogeneity in tumor-agnostic indications, challenge reimbursement deliberations in health technology assessments (HTA). Life-cycle HTA aims to generate real-world evidence to manage this uncertainty, and requires an index economic model to establish how estimated cost effectiveness evolves as new evidence emerges. We developed an open-source index economic evaluation of entrectinib, a tumor-agnostic therapy with conditional market authorization. We aimed to replicate the HTA revisions to a sponsor-submitted economic evaluation, from publicly available information, to support life-cycle decision making.

METHODS: We used partitioned survival analysis to determine tumor-agnostic and tumor-specific cost effectiveness, adhering to best-practice recommendations. We utilized publicly-available HTA reviews for parameterization and estimated incremental costs from a healthcare payer perspective (2021 Canadian dollars), quality-adjusted life years (QALYs), incremental cost-effectiveness ratios (ICER) and incremental net monetary benefit (INMB). We assessed the impact of diagnostic tests, and derived a decision algorithm for identifying the most cost-effective tumor indications.

RESULTS: One third of parameters (n=30) were unavailable in the Canadian reimbursement review and were sourced from international reviews. Tumor-agnostic incremental costs $69,723 (95% CI: $37,741, $94,125) and QALYs 0.13 (-0.39, 0.41) yielded INMB -$56,501 at a willingness to pay of $100,000/QALY. Inclusion of companion diagnostic testing costs diminished expected value (INMB CAD -2,364,520 at 100,000/QALY). Heterogeneity was considerable across tumor indications with treatment for advanced lung cancer providing the greatest value (INMB: -$24,772 at $100,000/QALY).

CONCLUSIONS: Our open-source tumor-agnostic analysis found the value of entrectinib varied substantially across tumor indications. Opaque reporting in HTA reimbursement reviews impeded our ability to establish a trustworthy index economic model to operationalize life-cycle HTA. Open science models and refinement of best practice guidelines for tumor-agnostic evaluations are urgently needed to address precision medicine uncertainty and support continued patient access decisions for conditionally approved therapies.