Lung cancer is diagnosed at metastatic stage in 60% of the cases. For these patients, first-line treatment is based on histology and molecular characterization of non-squamous non-small cell lung cancer (NSCLC). Thus, quality and quantity of tumor tissue are crucial to determine the appropriate treatment (targeted therapies, chemotherapy and immunotherapy). However, in routine practice, tissue quality and quantity can be limited (25%), resulting in the need for tumor rebiopsy for molecular analysis. Therefore, lung cancer patients often experience substantial delays before treatment initiation that may be associated with worse patient experience of subsequent cancer care and poorer clinical outcomes. "Liquid biopsies" (LB) are used to detect genomic alterations in cell-free circulating DNA (cfDNA). Since very recently, they are routinely used in reference centers for the detection of EGFR-mutations when tissue is not sufficient for molecular characterization. Importantly, the feasibility and clinical relevance of systematic liquid biopsies in routine practice has never been evaluated in patients with suspicious advanced lung cancer. Investigators hypothesize that using systematic LB in patients with clinical suspicion of metastatic lung cancer may reduce time-to-treatment initiation and avoid tissue rebiopsy. Investigators performed a retrospective study including 250 NSCLC patients treated in a tertiary Cancer Center and in the University Hospital of Lyon, France. The mean time-to-appropriate frontline treatment initiation (TTI) was 42+/-22.5 days. With the use of LB at the time of first consultation, the investigators believe it is possible to reduce the mean TTI down to 33 days (21% reduction in TTI) in the overall population with suspicious metastatic lung cancer, including a 50% and 40% reduction in TTI for EGFR/ALK/ROS1/BRAF V600E subgroups and KRAS/LKB1/ERBB2/c-MET/BRAF non V600E subgroups, respectively. Investigators therefore designed a "real-life" randomized study to evaluate the feasibility and clinical relevance of LB to decrease the TTI, which may in turn improve patients' outcome. Genomic analyses of circulating cfDNA will be performed using a robust and highly sensitive technology (InVision®), that profiles the presence of genomic aberrations in a panel of 35 genes including mutations, insertion/deletions and rearrangements, including all actionable alterations required to initiate the appropriate first-line therapy (EGFR-, ALK-, ROS1 and BRAF V600E).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
DIAGNOSTIC
Masking
NONE
Enrollment
319
During the first visit, liquid biopsy will be performed using the InVisionFirst® panel. Cytological or histological sampling will be planned. According to InVisionFirst® results, treatment will be initiated: * regardless of cytological/histological and tissue molecular analysis in case of EGFR, BRAF V600E-mutation, ALK- or ROS1-rearrangement identified on InvisionFirst® panel. * regardless of molecular characterization performed on tissue sample in case of ERBB2-, BRAF non V600E-, c-MET-, KRAS-,LKB1-, NTRK and/or RET mutation on InVisionFirst® panel. Treatment will be based on pathology results and if appropriate on PD-L1 level of expression. * for patients with none of the previous alterations, treatment will be initiated after obtaining pathology results and genomic characterization from the tumor tissue analysis.
Centre Hospitalier de Bayeux
Bayeux, France
Hopital Louis Pradel
Bron, France
Centre François Baclesse
Caen, France
Centre Maurice Tubiana
Caen, France
Infirmerie Protestante
Caluire-et-Cuire, France
Centre Hospitalier Public du Cotentin
Cherbourg, France
CH Les Oudairies
La Roche-sur-Yon, France
Hôpital Privé Jean Mermoz
Lyon, France
Centre Leon Berard
Lyon, France
Groupe Hospitalier de la région de Mulhouse et Sud-Alsace
Mulhouse, France
...and 6 more locations
Time-to-appropriate Treatment Initiation (TTI)
It is defined as the time between the date of randomization and the date of appropriate-treatment initiation (whatever the start date occurs before or after the biopsy results). As all the patients will receive an appropriate-treatment, no censored data are expected, thus the TTI will be analyzed as a continuous outcome. Appropriate treatment is defined as follow: * Based on contributive results on tissue OR liquid biopsy: * EGFR- or BRAF V600E-mutations, ALK- or ROS1- rearrangements: specific targeted therapies * None of the four previous alterations: investigator's choice (chemotherapy and/or immunotherapy or targeted therapies based on pathology results, PD-L1 expression and access to therapies in the context of Temporary Used Authorization or clinical trials) * In case of non-contributive results on tissue AND liquid biopsy: any treatment initiated by investigator (chemotherapy or immunotherapy based on pathology results and PD-L1 level of expression).
Time frame: From date of randomisation to start date of appropriate treatment , assessed up to 12 months
Rate of treatment initiated before molecular results
Defined as the proportion of patients with a treatment initiated without any available molecular results (tissue and liquid biopsy)
Time frame: From date of randomisation to 12 months
Time to availability of informative molecular pathology results
Defined as the time from randomization to date of availability of informative molecular pathology results (positive or negative).
Time frame: From date of randomisation to date of molecular results, assessed up to 12 months
Progression Free Survival (PFS)
Defined as the time from randomization to the date of the first documented clinical or radiological progression (as per RECIST version 1.1.) or death due to any cause.Patients who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment.
Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 30 months
Incidence of diagnostic test-emergent adverse events
Safety assessed according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version5
Time frame: From date of randomization to follow-up visit month 12 or death due to any cause, whichever came first, assessed up to 30 months
The impact of cancer on the patient's quality of life using the European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life core questionnaire (QLQ-C30)
64 questions related to cancer impact on health and daily activities composed this questionnaire. Each item has to be graded from 1 to 4 (1 = not at all, 4= very much). More the score is high, worst the quality of life is.
Time frame: At baseline, at Day 21 post-baseline, at the time of treatment initiation (within 6 weeks after baseline), at 8 weeks post treatment initiation and every 3 months post initiation of treatment until 12 months
Evaluation of lung cancer symptoms impact on health and daily activities using the Lung Cancer Symptoms Scale (LCSS) questionnaire
10 questions related to lung cancer symptoms impact on health and daily activities composed this questionnaire. Each item has to be graded from 1 to 10. More the score is high, worst the quality of life is.
Time frame: At baseline, at Day 21 post-baseline, at the time of treatment initiation (within 6 weeks after baseline), at 8 weeks post treatment initiation and every 3 months post initiation of treatment until 12 months
Evaluation of anxiety and depression level using Hospital Anxiety and Depression (HAD)Scale
6 questions related to anxiety and 6 questions related to depression composed this questionnaire. Each item has to be graded from 0 to 3. More the score of anxiety or depression is high, worst the quality of life is.
Time frame: At baseline, at Day 21 post-baseline, at the time of treatment initiation (within 6 weeks after baseline), and at 8 weeks post treatment initiation
Concordance between molecular status on tissue and liquid biopsies in the experimental arm
Evaluated by the proportion of discordances (error rates) between tissue and liquid biopsies for the mutational status.
Time frame: From date of randomization to follow-up visit month 12 or death due to any cause, whichever came first, assessed up to 30 months
Biopsy avoidance rate in the experimental arm
Be defined as the proportion of patients with an initial non-informative tissue biopsy and an informative liquid biopsy allowing appropriate treatment initiation without need for tissue rebiopsy.
Time frame: From date of randomization to follow-up visit month 12 or death due to any cause, whichever came first, assessed up to 30 months
The cost analysis
All costs items related to the stratégies and supported by the payers will be collected prospectively for each patient. Mean total costs will be calculated for the 2 stratégies and be compared between the arms.
Time frame: From date of randomization to follow-up visit month 12 or death due to any cause, whichever came first, assessed up to 30 months
The effectiveness analysis using the EuroQoL 5 Dimensions 5 Levels (EQ-5D-5L)
Preferences will be measured using EuroQoL 5 Dimensions 5 Levels questionnaire. Five attributes will therefore be investigated: mobility, self-care, usual activity, pain/discomfort, and anxiety/depression. Each attributes having five levels (from "able to \[…\]"/"no pain/discomfort/anxiety/depression" to "unable to \[…\]"/ "extremely pain/discomfort/anxiety/depression"). More the patient is unable to doing daily activities and painful/anxious, worst the quality-adjusted life-year (QALYs) is.
Time frame: At baseline, at Day 21 post-baseline, at the time of treatment initiation (within 6 weeks after baseline), at 8 weeks post treatment initiation and every 3 months post initiation of treatment until 12 months
QALYS comparaison between 2 arms
Mean QALYs (based on EQ-5D-5L score) will be calculated for each arm and will be compared between the 2 arms.
Time frame: At baseline, at Day 21 post-baseline, at the time of treatment initiation (within 6 weeks after baseline), at 8 weeks post treatment initiation and every 3 months post initiation of treatment until 12 months
The budget impact analysis in experimental arm
The Liquid biopsy using the InVisionFirst® cost, the evolution of market shares, the data pertaining to the target population, and the costs involved with treating the pathologies will be analysed to to estimate the budget impact on the French National Health Insurance of the generalization of innovative Liquid biopsy using the InVisionFirst® panel strategy.
Time frame: From date of randomization to follow-up visit month 12 or death due to any cause, whichever came first, assessed up to 30 months
Exploratory objectives : Whole-exome sequencing
Additional mandatory 10 ml DNA STRECK tubes will be collected for patients signing study consent.
Time frame: At baseline, at the time of treatment initiation (within 6 weeks after baseline), at 8 weeks after the treatment initiation, and at the progression if occured within 12 month post-baseline.
Exploratory objectives : miRNA profiling
Additional mandatory 10 ml RNA STRECK tubes will be collected for patients signing study consent.
Time frame: At baseline, at the time of treatment initiation (within 6 weeks after baseline), at 8 weeks after the treatment initiation, and at the progression if occured within 12 month post-baseline.
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