Genomic Therapy Matching in Rare and Refractory Cancers.
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Lin Frank P, Thavaneswaran Subotheni, Grady John P, Napier Christine E, Kansara Maya, Sebastian Lucille, Kee Damien, Desai Jayesh, Zaheed Milita, Chinchen Sarah, Oakes Samantha R, Blackburn James, Scott Hamish S, Glover Anthony, Fox Stephen B, Goldstein David, Leo Paul, Amanuel Benhur, Mersiades Antony, Millward Michael, Brown Michael P, Charakidis Michail, Pokorny Adrian M J, Craft Paul, Espinoza David, Grimison Peter, Harrup Rosemary, Joshua Anthony M, O'Byrne Ken, Lee Chee Khoon, Cowley Mark J, Ballinger Mandy L, Simes John, Thomas David M, Australian Molecular Screening and Therapeutic program investigators and contributors
Аннотация
OBJECTIVE: To assess whether a tiered, evidence-based framework for matching genomic biomarkers to therapies is associated with differential overall survival in patients with advanced solid tumors.
DESIGN, SETTING, AND PARTICIPANTS: This multicenter cohort study was conducted within the Molecular Screening and Therapeutic program, a nationwide precision oncology program in Australia. Patients aged 18 years and older with advanced, refractory solid tumors and adequate Eastern Cooperative Oncology Group Performance Status were enrolled from June 2016 to December 2021, with follow-up through July 2022. Data were analyzed from July 2022 to July 2024.
EXPOSURES: Systemic therapy following comprehensive genomic profiling. Therapies were classified as matched or unmatched using the TOPOGRAPH (Therapy-Oriented Precision Oncology Guidelines for Recommending Anticancer Pharmaceuticals) knowledge base, which stratifies biomarker-drug pairs by level of evidence (tiers 1-3A, prospective trial evidence; tiers 3B/4, investigational/repurposed).
MAIN OUTCOME AND MEASURES: The primary outcome was overall survival from date of molecular profiling results. The hypothesis was tested using a time-dependent multivariable Cox proportional hazards model, adjusted for age, Eastern Cooperative Oncology Group Performance Status, cancer type, prior therapy, and prior receipt of matched therapy.
RESULTS: Of 3383 patients (mean [SD] age 57.1 [14.3] years; 1792 [53.0%] female), 1270 (37.5%) had a clinically active (tiers 1-3A) biomarker. Among patients with a tier 1 to 3A biomarker receiving treatment, those receiving matched therapy had a longer median overall survival than those receiving unmatched therapy (21.2 months [95% CI, 17.1-26.8 months] vs 12.8 months [95% CI, 11.7-13.9 months]; adjusted hazard ratio [aHR], 0.60; 95% CI, 0.44-0.82; P = .001). In contrast, among patients receiving therapy matched to investigational evidence (tiers 3B/4), there was not an associated survival benefit compared with unmatched therapy (14.5 months [95% CI, 12.6-18.4 months] vs 12.8 months [95% CI, 12.0-14.7 months]; aHR, 1.04; 95% CI, 0.84-1.29; P = .71). Patients who received therapies repurposed from other cancer types based solely on a biomarker and lacking direct evidence (tier 3B) did not experience longer survival compared with those receiving unmatched therapy (13.6 months [95% CI, 8.0-16.8 months] vs 12.5 months [95% CI, 11.3-13.5 months]; aHR, 1.40; 95% CI, 1.00-1.96; P = .047).
CONCLUSIONS AND RELEVANCE: In this cohort study of patients with advanced solid tumors, matching therapies to genomic biomarkers was associated with improved survival only when supported by prospective clinical trial evidence. These findings support using an evidence-based framework to prioritize genomically guided therapies.