The French multicentric molecular analysis platforms and personalized medicine trials MOST, MOST Plus and MEGAMOST

Background and purpose In this manuscript we describe the academic French multicentric molecular analysis platforms including PROFILER, promoted by Centre Léon Berard, and the multicentric personalized medicine trials MOST, MOST Plus and MEGAMOST. Patients/material and methods MOST, MOST Plus and MEGAMOST comprise 14 cohorts with different targeted agents and immunotherapies. Results and interpretation PROFILER has recruited 5,991 patients in 10 years, MOST and MOST Plus 875 patients since 2014 and MEGAMOST 172 patients since 2020, and are still ongoing. We provide a description of the local, national and international implications of these initiatives, and we review the results of the sorafenib and olaparib cohorts.


Introduction
The first generation of personalized medicine umbrella or basket trials in France allowed 10-20% of patients to receive a targeted treatment based on molecular analysis (mainly targeted sequencing and comparative genomic hybridization (CGH)) [1][2][3].It is estimated that 40-50% of patients would benefit from theoretical orientation if more treatments were available and accessible [4,5].Drug Rediscovery Protocol (DRUP)-like trials have the potential to increase the number of compounds and molecular markers to orient patients to targeted treatments.Centre Léon Bérard (CLB) and partnering sites have developed an environment combining multiple types of molecular analysis and orientation to academic DRUP-like trials called MOST and MEGAMOST for patients with advanced or metastatic cancers.

Molecular analysis and sequencing programs
Several molecular analysis programs are currently running in our hospital resulting in multiple levels of molecular information (Table 1).Most of the platforms are multicentric, either regional in Rhône Alpes and centralised at CLB as for ProfiLER01, or national and centralised in dedicated sites (including CLB), as for FMG2025.

ProfiLER screening programs
The ProfiLER01 (NCT01774409) is a multicentric, prospective and non-randomised ongoing program.ProfiLER is dedicated to adult patients with advanced/metastatic cancer who progressed after at least one line of standard treatment.The current molecular analysis includes the identification of single nucleotide variants (which evolved across three different panels over time), copy number alterations (using CGH array), tumour mutational burden, microsatellite status (both implemented since 2023) and oncogenic fusion using in-house genomic workflows.ProfilER02 (NCT03163732) included FoundationOne® CDX panel of 324 genes (under review).This is a multidisciplinary effort including the molecular biology platform, the Gilles Thomas Bioinformatics Platform, the biosamples management platform, the clinical staff and the molecular tumour board.The molecular tumour board is made up of medical oncologist, pathologist, molecular biologists, bioinformaticians and data scientists meeting every week to recommend matched molecular-targeted agents including immunotherapies and including those accessible in clinical trials [6].
The ProfiLER01 program enrolled 5,991 patients between February 2013 and November 2023 and were ongoing at this time.On the basis of these data, our team has previously described the molecular characteristics of several population sample sizes.The main selection criteria include adult patients with metastatic or unresectable solid tumours of any type, not amenable to curative treatment, and those who previously received at least one prior systemic treatment regimen.

MOST
The MOST program (NCT02029001) started in 2014 with a multiarm, genomic-driven Phase II trial, conducted using a randomised discontinuation design.This is a way to evaluate the efficacy of molecular targeted agent oriented towards a matched molecular alteration in a randomized fashion.After an induction period of treatment of 12 weeks, patients with stable disease are randomly assigned (1:1) to continuation or interruption of matched therapy defining the maintenance period (Figure 1).Between 2014 and November 2023, we enrolled 427 patients in five cohorts with the molecular targeted agents lapatinib, sorafenib, everolimus, pazopanib, or nilotinib oriented by predefined somatic alterations (Table 2).The trial is running in six French sites (Centre Léon Bérard, Hospices Civil de Lyon, Institut Curie, Institut Paoli Calmettes, Oncopole Toulouse, Institut Bergonié).The primary endpoint is progression-free rate at 16 weeks after randomisation.
The nilotinib cohort continues only for advanced pigmented villonodular synovitis (TGCT/PVNS), a group of locally aggressive tumours with activation of the CSF1R pathway [16].The everolimus, pazopanib and lapatinib cohorts are closed to enrolment and under analysis.Although there is a randomisation for comparative analysis, a potential limitation in the including patients with gastro-oesophageal cancers [7], patients with alterations in homologous recombination-related genes and distinct platinum response in metastatic triple-negative breast cancers [8], patients with primary brain tumours [9], refractory gynaecological cancers [10], metastatic sarcomas [11] and paediatric tumours [12].

Other molecular analysis programs
The 'France Génomique plan 2025' (FMG2025) provides whole genome sequencing (WES) and RNAseq for patients with refractory diseases.Analyses are performed on two platforms: Auvergne Rhônes Alpes Genomique (AURAGEN) in Lyon covering the analysis of Southern France and Sequencing Omics Information Analysis (SeqOIA) in Paris covering the analysis of Northern France [13].It proposes extensive molecular testing with WES and RNA sequencing for multiple diseases including 60 types of rare diseases, uncharacterized suspected genetic predispositions and eight indications in oncology: refractory cancers, rare cancers, cancer of unknown primary and haematology.The first patients were included in October 2019 and up to early 2023, 8,447 reports were generated including 1,969 patients with cancer.
Another program, PRISM-Portal, evaluates the impact of ctDNA at the start of metastatic disease, during treatment and/ or at progression.The proportion of patients with ctDNA sequencing has helped guide therapy.
The PLANET program (NCT05099068) aims to generate sequential molecular analysis for patients treated with standard therapies, including detection of mutations, amplifications, insertions/deletions, microsatellite instability, mutational burden and expression alteration using RNA Sequencing either on tumor and/or liquid biopsies.

MOST-MOST Plus and MEGAMOST
MOST-MOST Plus and MegaMOST trials are composed of multiple treatment cohorts defined by the combination of a targeted treatment and a biomarker derived from molecular profiling.New cohorts are opened on a regular basis through the integration of new study treatments, generally in indications unexplored by pivotal pharma-initiated trials.Both have adaptive Bayesian approach, futility interim analysis and a target of 50 patients analysed for the primary endpoint for each cohort [14].A Bayesian approach allows updating knowledge gradually rather than restricting revisions in a trial design with fixed interpretation of the results of the MOST trial is that it does not include a control group of patients not driven on prespecified genomic alterations.

MOST Plus
MOST Plus is an amended version of MOST (NCT02029001) with the addition of 2 cohorts of patients treated with olaparib or the combination of durvalumab and tremelimumab (Table 2).The induction period of treatment is 12 weeks for olaparib and 52 weeks for immunotherapy before randomisation of patients with stable disease (for olaparib) or stable disease and objective response (for D+T cohort).The MOST Plus durvalumab and tremelimumab is ongoing and recruited 189 patients up to November 2023.The MOST Plus olaparib cohort, presented at ESMO2023, included 213 patients with somatic or germline

Conclusion and perspectives
The high failure rate of clinical development in oncology is mainly due to the erroneous hypothesis that all patients affected by a similar tumour type would be biologically identical (this is represented by selection criteria of clinical trials oriented on tumour types).The MOST trials are clearly aiming at repositioning molecular targeted agents with a personalized medicine strategy (Figure 2).The success of repurposing molecular targeted agents in oncology is supported by the recent analysis of the main factors leading to the best Likelihood of FDA Approval (LoA) for pharmaceutical compounds together with their companion diagnostic tools, namely (1) rare disease therapy (LoA = 17%), (2) development of a treatment with biomarkers (i.e.companion diagnostic tools, LoA = 16%), and (3) prior approval (i.e.repositioning, LoA +3.6%) [18,19].When a cohort meets the efficacy endpoint in a cohort of a DRUP-like trial, it can support drug approval and reimbursement in the participating country.For example, nivolumab, an immune-checkpoint inhibitor targeting anti-PD1, obtained approval and reimbursement in the Netherlands on July 1st, 2022, based on a cohort of the DRUP trial evaluating the treatment of dMMR/ MSI solid tumours of any origin [5,20,21].Nevertheless, two teams in the PCM4EU consortium showed that up to 40-50% of patients with rare cancers could have a genomic-driven orientation if treatments were available and accessible in the country of the patients [4,5].To this end, DRUP-like trials such as MOST trials include a process of public, open, and shared evaluation of the treatment efficacy.The collaboration of several DRUP-like trials on data sharing will support an efficient process to approve compounds repurposing in rare cancers.

Figure 1 .
Figure 1. A. the MOST plus study scheme and B. Inclusions in MOST, MOST Plus and MEGAMOST In blue (MOST and MOST-Plus) or green (MegaMOST): ongoing cohorts, in grey: cohorts closed.Of note, avapritinib cohort was opened in October 2023.C. Inclusion number PROFILER 2013-2023.MTT: Molecular Target Therapy; CR: complete response; PR: partial response; SD: stable disease; PD: progression disease; R: randomisation.

Figure 2 .
Figure 2. The molecular diagnostic programs are used to orient patients to the MOST Plus and MEGAMOST clinical trials.

Table 2 .
Cohorts of the MOST+ and MEGAMOST trial.
MEGAMOSTMEGAMOST (NCT04116541) is an ongoing phase II, genomic-driven adaptive Master protocol.Patients are assigned to a treatment cohort based on molecular alterations/characteristics detected on tumour samples (from primary tumour or