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Clinical Impact of Next-Generation Sequencing-Guided Targeted Therapies in Advanced Cancer: A Systematic Review and
F Kazmi1, R Katyal1, T F D Liu1
1Department of Oncology, Norfolk and Norwich University Hospital, Norwich, NR4 7UY, UK.
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.
Insights
Next-generation sequencing (NGS)-guided matched targeted therapies (MTTs) improve progression-free survival in advanced cancers, particularly when combined with standard of care (SOC). Overall survival benefits are tumor-specific, and increased toxicity necessitates careful patient selection.
Area of Science:
- Oncology
- Genomics
- Clinical Trials
Background:
- Precision oncology utilizes next-generation sequencing (NGS) for targeted therapies in cancer.
- The efficacy of matched targeted therapies (MTTs) in relapsed or metastatic cancer is not well-established.
- This review focuses on advanced solid and hematological tumors.
Purpose of the Study:
- To evaluate the efficacy and safety of NGS-guided MTTs in advanced cancers.
- To compare MTTs (alone or with SOC) against SOC alone.
- To analyze progression-free survival (PFS), overall survival (OS), and adverse events.
Main Methods:
- Systematic review and meta-analysis of 30 randomized controlled trials (RCTs) including 7393 patients.
- Searches included CENTRAL, MEDLINE, EMBASE, reference lists, and conference proceedings up to October 2024.
- Random-effects meta-analysis using the DerSimonian-Laird method.
Main Results:
- MTTs reduced disease progression risk by 30-40%.
- No consistent OS benefit with MTT monotherapy; combination with SOC improved OS in prostate and urothelial cancers.
- MTTs increased toxicity, especially in combination regimens; most studies had high risk of bias.
Conclusions:
- NGS-guided MTTs significantly improve PFS, especially with SOC.
- OS benefits are tumor-specific; increased toxicity requires careful patient selection.
- Routine genomic profiling is recommended for advanced or recurrent cancers.
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