Clinical Impact of Next-Generation Sequencing-Guided Targeted Therapies in Advanced Cancer: A Systematic Review and Meta-Analysis.

AIMS: Precision oncology, driven by next-generation sequencing (NGS), enables the use of matched targeted therapies (MTTs) tailored to tumour-specific genomic alterations. While benefits in early-stage cancer are well-established, the impact of MTTs in relapsed or metastatic settings remains unclear. This systematic review and meta-analysis (PROSPERO ID: CRD42023471466) evaluates the efficacy and safety of NGS-guided MTTs in patients with advanced solid and haematological tumours. MATERIALS AND METHODS: Searches of CENTRAL, MEDLINE, EMBASE (to 30 October 2024), reference lists, and conference proceedings identified randomized controlled trials (RCTs) comparing NGS-guided MTTs (alone or combined with standard of care systemic treatment [SOC]) versus SOC alone in patients with advanced cancers that had progressed after at least one prior systemic therapy. Primary outcomes were progression-free survival (PFS), overall survival (OS), and grade ≥3 adverse events. Data extraction and bias assessment were conducted independently by two reviewers. Random-effects meta-analysis was performed using the DerSimonian-Laird method. RESULTS: Thirty RCTs (7393 patients) were included that collectively enrolled patients with eight different cancer types. With a median follow-up ranging from 12 months to 62.3 months, MTTs were associated with a 30-40% reduction in the risk of disease progression. No consistent OS benefit was observed with MTT monotherapy. However, combining MTTs with SOC resulted in improved OS, particularly in patients with prostate and urothelial cancer, but conferred PFS gain without OS improvement in those with breast and ovarian cancer. In terms of adverse events, we observed MTTs increased toxicity risk compared to SOC, specifically, in combination regimens. Most studies were at high risk of bias, with performance and detection bias being common limitations. CONCLUSION: NGS-guided MTTs significantly enhance PFS, especially when combined with SOC, with OS benefits being more tumour-specific. Increased toxicity rates with MTTs underscore the need for careful in patient selection. Furthermore, genomic profiling should be routinely integrated into the management of patients with advanced or recurrent cancers.