# Genomic Therapy Matching in Rare and Refractory Cancers

## TL;DR

This study finds that matching cancer treatments to genomic biomarkers improves survival only when supported by strong clinical trial evidence.

## Contribution

The study introduces a tiered framework for genomic therapy matching and shows its survival benefits in advanced cancers.

## Key findings

- Patients with biomarker-matched therapies based on prospective trials had 21.2 months median survival vs 12.8 months for unmatched therapies.
- Therapies matched using preclinical or repurposed evidence did not show survival benefits.
- Repurposed therapies without direct evidence were associated with shorter survival.

## Abstract

This cohort study assesses whether a tiered, evidence-based framework for matching genomic biomarkers to therapies is associated with differential overall survival in patients with advanced solid tumors.

In patients with advanced, refractory cancers, is a tiered framework for matching genomic biomarkers to therapies associated with improved survival?

In this cohort study of 3383 patients with advanced solid tumors, those with biomarkers supported by prospective trial evidence who received matched therapy had a median overall survival of 21.2 months vs 12.8 months for those receiving unmatched therapy. No survival benefit was observed for therapies matched using preclinical evidence or repurposed from other cancer types.

These findings support prioritizing genomically guided therapies based on the strength of clinical evidence, as only matches supported by prospective trials were associated with a survival benefit.

The clinical utility of matching therapies to genomic biomarkers based on varying levels of evidence remains uncertain, particularly for patients with rare and refractory cancers.

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.

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.

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).

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.

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).

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.