Target Specific Therapy for Actionable and Approved Tumor-agnostic Biomarkers Associated with Improved Survival in Rare Cancers

Background
Rare cancers – defined as an incidence rate of less than 6 per 100,000 diagnoses per year – collectively account for close to 25% of cancer burden and represent a critical unmet clinical need. The emergence of regulatory approvals for tumor-agnostic therapies based on genomic biomarkers has expanded treatment options for these patients (pts) but clinical sequencing is not yet broadly adopted for rare cancers. Here, we assess the incidence and clinical utility of FDA-approved tumor-agnostic biomarkers in a large real-world rare cancers cohort.

Methods
The Tempus Lens Platform used to query the de-identified Tempus multimodal database to analyze a cohort of 45,085 real-world pts with 615 rare cancer diagnoses. All pts had DNA (Tempus xT) and/or RNA sequencing (Tempus xR). Pts were screened for FDA- approved tumor-agnostic biomarkers, including high tumor mutational burden (TMB-H, ≥ 10 mut/Mb), high microsatellite instability (MSI-H), NTRK and/or RET fusions, BRAFV600E mutations and HER2 overexpression (IHC-3+). Pts were classified based on their reported biomarker status and treatment start of the approved targeted therapy relative to the FDA- approval date. Real-world overall survival (rwOS) was defined as the time from sample collection to death or loss to follow-up. Hazard ratios (HR) from Cox-proportional hazards models were adjusted for age, sex, race, ethnicity, and stage at p < 0.05 (Wald test).

Results
The median age of pts was 64 years old, 59% were female, 50% of those with documented race were white and 36% had metastatic disease. The most common diagnoses were within the genital system (25%), digestive system (23%), soft tissue (12%), brain (11%) and lung (6.5%). Of the total cohort, 13% (5,881) were positive for at least one tumor-agnostic biomarker. TMB-H was the most prevalent (10.3%), followed by HER2+ (5.5%), BRAFV600E (2.6%), MSI-H (1.9%), NTRK (0.5%) and RET (0.2%) fusions. Of 59% (3,480) of pts with recorded treatments, 33% (1,138) received the approved treatment following the approval date (tumor-agnostic biomarker-positive matched) while 64% (2,227) received other treatments (tumor-agnostic biomarker-positive unmatched). Pts with tumor-agnostic biomarker-positive matched treatments had significantly improved rwOS compared to tumor-agnostic biomarker- positive unmatched pts (HR = 0.8, p = 0.024) and to tumor-agnostic biomarker-negative individuals (HR = 0.68, p < 0.001).

Conclusions
A large percent (13%) of pts with rare cancer diagnoses were found to harbor an actionable biomarker associated with an FDA-approved tumor-agnostic therapy. Pts who received therapies for approved tumor-agnostic biomarkers versus those pts with the biomarker who did not receive the matched treatment demonstrated a significant survival benefit, underscoring the importance of NGS testing to optimize treatment selection for rare cancer pts.