Prof. Andrés Cervantes, Dr. Desamparados Roda and colleagues of the Department of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of Valencia in Valencia, Spain published on 7 September 2021 in the British Journal of Cancer the results of a molecular-based approach using a customised next-generation sequencing (NGS) panel at a single academic institution. The molecular screening aimed to select the best potential therapeutic strategy for patients with advanced cancer to receive the treatment within the early clinical study programme. Despite the small number of patients who presented actionable mutations, gene fusions, and other genomic alterations, the study team demonstrated that molecular profiling is feasible and effective. The results confirm a substantial benefit in the molecularly matched cohort receiving experimental targeted therapies.
It was a single-centre, retrospective analysis, where the study team investigated the feasibility and efficacy of comprehensive molecular profiling in patients with advanced solid tumours. The first aim was to explore the benefit of a molecular profiling selection approach for candidates for early phase clinical studies in the context of targeted agents according to the evaluation of a molecular tumour board. Second, they investigated the impact of those targeted therapies compared to standard therapies of best investigators choice in subsequent treatment options for patients with advanced cancer. Third, by using a Bayesian model approach, they sought to define the primary predictive factors for potential treatment benefit.
All tumour samples were locally studied and analysed for individual genomic target alterations by NGS, evaluating DNA. In those cases, in which the transcriptomic analysis could have helped in treatment options, an RNA analysis was also implemented. Genomic analysis was performed by a customised panel that included the evaluation of hotspot mutations in 83 genes plus 4 full genes analysed. Transcriptomic protocol for fusion analysis was performed by RNA sequencing with ribosomic depletion. Data analysis was carried out by using an in-house-developed bioinformatics pipeline.
The primary endpoint was progression-free survival (PFS) assessed by the ratio of patients presenting 1.3-fold longer PFS on matched therapy (PFS2) than with prior therapy (PFS1).
The investigators molecularly screened 231 patients, of whom 87 were eligible for analysis. Each individual genomic report was reviewed and discussed weekly by a tumour board dedicated to precision medicine, attended by experts in medical oncology, molecular biology, pathology, clinical genetics and bioinformatics. Each result was discussed by taking into account the ESMO Scale for Clinical Actionability of molecular Targets. Additionally, they reviewed specific genomic results to debate common issues such as interpreting mutations with low allele frequency, the importance of tumour content or the potential role of other concomitant mutations. They stratified the patients into eligible or not for early phase clinical studies with targeted agents.
The most common tumour types were gynaecological, lung, breast, digestive and head and neck cancers. An actionable target was detected in 32 patients. An alteration of the DNA repair response pathway was detected in highest percentage of patients, followed by PIK3CA mutations, FGFR2 mutations and FGFR gene fusion, MET activations, ERBB family pathway alterations and PTEN mutations. Patients were mostly included in specific protocols developing novel PIK3CA, AKT, FGFR, Check-1, MET, HER2 and PARP inhibitors.
Patients who received matched therapy had 6.47 months median PFS2 (95% confidence interval [CI] 2.24–14.43) compared to 2.76 months in those who received standard therapy (95% CI, 2.14–3.91, Log-rank p = 0.022). The proportion of patients with a PFS2/PFS1 ratio over 1.3 was significantly higher in the experimental arm (0.33 vs 0.08; p = 0.008). The authors commented that the primary endpoint of increasing the PFS2/PFS1 ratio was reached and 33% of patients receiving molecular-matched therapies had a ratio ≥1.3, compared with only 7.9% of those who did not qualify for such therapies.
Moreover, disease control was seen in 68.7% of patients treated in the experimental arm, while it was only observed in 36.4% of those assigned to standard care. It is worth mentioning that 53% of patients treated in early phase clinical studies received post-progression treatment versus only 25% of those treated with standard therapies. Utilisation of the window of opportunity with experimental targeted agents early on does not preclude receiving further lines of standard therapies. Early treatment to block molecular drivers contributes towards better disease control and avoids rapid clinical deterioration, facilitating further therapeutic interventions.
The authors concluded that validation of true clinical relevance and actionability of each genomic alteration is critical and still far away from global standardisation. This highlights a need to incorporate a multidisciplinary molecular tumour board in academic institutions to expand the use of precision oncology. They demonstrated the pivotal role of the institutional molecular tumour board in evaluating the results of a customised NGS panel. This process optimises the selection of available therapies and improve disease control. However, prospective randomised trials are needed to confirm this approach and open the door to expanded drug access.
This study was supported by grants from the Instituto de Salud Carlos III and other. The authors acknowledged the support of the INCLIVA BioBank, as part of the Valencian Biobanking Network and the Spanish National Biobanks Network.
Gambardella V, Lombardi P, Carbonell-Asins JA, et al. Molecular profiling of advanced solid tumours. The impact of experimental molecular-matched therapies on cancer patient outcomes in early-phase trials: the MAST study. Br J Cancer; Published online 7 September 2021. DOI: https://doi.org/10.1038/s41416-021-01502-x