Optimising primary molecular profiling in non-small cell lung cancer.

Molecular profiling of NSCLC is essential for optimising treatment decisions, but often incomplete. We assessed the efficacy of protocolised molecular profiling in the current standard-of-care (SoC) in a prospective observational study in the Netherlands and measured the effect of providing standardised diagnostic procedures. We also explored the potential of plasma-based molecular profiling in the primary diagnostic setting. This multi-centre prospective study was designed to explore the performance of current clinical practice during the run-in phase using local SoC tissue profiling procedures. The subsequent phase was designed to investigate the extent to which comprehensive molecular profiling (CMP) can be maximized by protocolising tumour profiling. Successful molecular profiling was defined as completion of at least EGFR and ALK testing. Additionally, PD-L1 tumour proportions scores were explored. Lastly, the additional value of centralised plasma-based testing for EGFR and KRAS mutations using droplet digital PCR was evaluated. Total accrual was 878 patients, 22.0% had squamous cell carcinoma and 78.0% had non-squamous NSCLC. Stage I-III was seen in 54.0%, stage IV in 46.0%. Profiling of EGFR and ALK was performed in 69.9% of 136 patients included in the run-in phase, significantly more than real-world data estimates of 55% (p<0.001). Protocolised molecular profiling increased the rate to 77.0% (p = 0.049). EGFR and ALK profiling rates increased from 77.9% to 82.1% in non-squamous NSCLC and from 43.8% to 57.5% in squamous NSCLC. Plasma-based testing was feasible in 98.4% and identified oncogenic driver mutations in 7.1% of patients for whom tissue profiling was unfeasible. This study shows a high success rate of tissue-based molecular profiling that was significantly improved by a protocolised approach. Tissue-based profiling remains unfeasible for a substantial proportion of patients. Combined analysis of tumour tissue and circulating tumour DNA is a promising approach to allow adequate molecular profiling of more patients.

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Copyright: © 2024 Schouten et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Déclaration de conflit d'intérêts

This study was an investigator-initiated trial, designed by the authors and financially supported by unrestricted grants from Merck Sharp & Dohme, AstraZeneca, Novartis, Pfizer, and Roche. These sponsors approved the manuscript but had no role in the study’s design, conduct, data collection, management, analysis, interpretation, manuscript preparation, or the decision to submit the manuscript for publication. The authors have declared the following potential conflicts of interest: Robert D. Schouten received research funding from AstraZeneca, Roche Pharma AG, Roche Diagnostics, MSD, Novartis, and Pfizer. J.A. Burgers received support for another investigator-initiated study from MSD and consulting fees from Roche. Ed Schuuring gave lectures for multiple companies, consulted in advisory boards for multiple companies, and received research grants from multiple companies. S.M. Willems received research funding from Lilly, Roche, Amgen, Pfizer, MSD, and Bayer. K. Monkhorst held a consulting or advisory role for multiple companies, was part of a speakers’ bureau for Quadia, received research funding from multiple companies, and had travel, accommodations, and expenses covered by Takeda. D. van den Broek held a consulting or advisory role for Roche Molecular Diagnostics. M.M. van den Heuvel held a consulting or advisory role for multiple companies, received research funding from multiple companies, and has patents, royalties, and other intellectual property from research funding by multiple companies. All other authors declared no conflicts of interest. None of the funding, support, or sponsoring described alters our adherence to PLOS ONE policies on sharing data and materials, and there are no restrictions on the sharing of data and/or materials.