Primary endpoint was met in a multicentre, prospective ProfiLER-02 study with a more than 10% increase in treatment recommendations using the commercially available Foundation OneCDX (F1CDX) panel compared to limited hospital homemade control gene panel (CTL). The F1CDX panel increased the total number of molecular-based recommended therapies in this specific population of patients who did not present approved predictive biomarkers to guide molecular-based recommended therapies routinely used in specific cancer types.
The study also showed an increased number of patients in whom molecular-based recommended therapies were effectively initiated using the F1CDX panel compared to CTL panel according to Dr. Olivier Trédan of the Centre Léon Bérard and Cancer Research Center of Lyon in Lyon, France and colleagues, who published the findings on 7 April 2025 in the Nature Medicine.
The authors wrote in the background that they previously reported the use of next-generation sequencing (NGS) with panels of 59-69 genes and microarray-based comparative genomic hybridisation in the ProfiLER-01 study. Molecular profiling in enrolled patients with metastatic cancer allowed proposing molecular-based recommended therapies in 27% of the patients, including 6% in whom molecular-based recommended therapy was initiated. SHIVA, MPACT and MATCH, also reported that the rates of molecular-based recommended therapies initiation have been disappointing (below 9.5%) with a short duration of clinical benefits.
Several large genomic programmes aimed to establish standardised high-throughput whole-genome sequencing (WGS) in patients with cancer. The 100,000 Genomes Project study conducted within the National Health Service in England, aimed to link genomic and real-world clinical data. Patients with cancer showed a high prevalence of genetic variants, and a multidisciplinary molecular tumour board (MTB) intensively discussed the cases to determine clinical actionability and provide molecular-based recommended therapies. The correlation between WGS and patient outcomes allowed confirming prognostic signatures and/or predictive genomic biomarkers.
However, to date, the clinical impact of a large NGS panel, such as WGS, on molecular-based recommended therapy initiations through clinical trial inclusions or off-label prescription of targeted agents and outcomes remains unclear. In an attempt to assess this impact, the multicentre prospective randomised ProfiLER-02 study aimed to evaluate the added value of a larger number of screened genomic biomarkers from the F1CDX panel of 324 cancer-related genes compared to academic hospital molecular profiling panel with limited biomarker detection, CTL panel of 87 single-nucleotide/indel genes and genome-wide copy number variations, reviewed by MTB to identify molecular-based recommended therapies for patients with advanced and/or metastatic solid cancers.
Using paired data from both panels for each patient, the primary endpoint was the proportion of patients with molecular-based recommended therapies identified. Main secondary endpoints included the number of patients with at least one actionable alteration leading to molecular-based recommended therapies identification, the number of patients with and without molecular-based recommended therapies initiated, progression-free survival, best overall response, duration of response and safety.
Among the 741 patients screened, 45.7% had quality-checked tumour samples. Molecular-based recommended therapies were identified with F1CDX in 175 patients (51.6%) and with CTL in 125 patients (36.9%), translating to a significant increase of 14.8% (p < 0.001) with the more comprehensive gene panel versus the limited panel, meeting the primary endpoint. However, no differences in clinical outcomes were observed in these patients with advanced and/or metastatic cancer in need of treatment beyond standard genomic alterations.
The authors concluded that their findings illustrate the potential for larger gene panels to increase the number of molecularly matched therapies. Larger studies are needed to assess the clinical benefit of expanded molecular-based recommended therapies. Further developments in DNA- and RNA-sequencing technology, including combined advances in chemistry, bioinformatics and artificial intelligence, associated with other -omics technologies, are required to overcome the current challenges, promote the use of functional genomics and contribute to translating such approaches into efficient routine clinical applications.
This work received partial funding from Roche Pharma AG. The F1CDX panel was provided for free by Foundation Medicine. This work was supported by the Integrated Cancer Research Site LYriCAN, the Institut National du Cancer, Agence Nationale de la Recherche LabEx DEvweCAN, PIA Institut Convergence Francois Rabelais PLAsCAN, Fondation ARC contre le Cancer, La Ligue contre le Cancer and the European Community (EURACAN). The Centre Léon Bérard, as the sponsor, was responsible for trial conception and coordination, data analysis and publication writing.
Reference
Trédan O, Pouessel D, Penel N, et al. Broad versus limited gene panels to guide treatment in patients with advanced solid tumors: a randomized controlled trial. Nature Medicine; Published online 7 April 2025. DOI: https://doi.org/10.1038/s41591-025-03613-x