Analysis of Biological Characteristics of Advanced ALK-rearranged NSCLC

Study Overview
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Brief Summary
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BioEXALK is a prospective study evaluating the biological characteristics of advanced ALK-rearranged NSCLC treated with next generation TKIs in first line, included in the national EXPLORE ALK cohort (GFPC 03-2019), a non-interventional, national, multi-center cohort of ALK-rearranged NSCLC patients. BioExALK study will be proposed to every patient included in the Explore ALK GFPC 03-2019 study. Biological analysis will be performed on tumor tissue at diagnosis and at the time of disease progression when available and on circulating tumor DNA (ctDNA). For plasma testing, after obtained patient consent, blood samples will be taken and analyzed at the Léon Bérard Center (Lyon). Biological analysis on tissue obtained at diagnosis and at disease progression will be collected and be sent for centralized analysis to the Rouen University Hospital.

Detailed Description
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BioEXALK is a prospective study evaluating the biological characteristics of advanced ALK-rearranged NSCLC treated with new generation TKIs in first line, included in the national EXPLORE ALK cohort (GFPC 03-2019). Explore ALK GFPC 03-2019 is a non-interventional, national, multi-center cohort of ALK-rearranged NSCLC patients, whose RCB reference is 2020-A00771-38 and which obtained an approval from the IDF II Ethic Committee on 25/05/2020. Biological analysis will be performed on tissue at diagnosis and at the time of disease progression when available and on circulating tumor DNA (ctDNA) on three timepoints (diagnosis, at first tumor evaluation and at the time of disease progression). Tissue : RNAseq will be performed on tumor biopsy (10 slides of 5 microns) to identify the ALK fusion partner and its variant and associated co-mutations.. ctDNA : NGS panel on DNA including a large panel of fusions and mutations will be performed on blood samples (30mL on EDTA or STRECKs tubes) at diagnosis, at the time of the first evaluation and at the time of progression). For plasma testing, after obtained patient consent, blood samples (35mL on EDTA or STRECKs tubes) at diagnosis, at the first evaluation and at disease progression will be taken. The ALKis include alectinib and brigatinib as first-line therapy or other drugs with marketing authorizations (lorlatinib, entrectinib) or in early access programs (EAPs). Liquid biopsies will be analyzed with a NGS panel allowing the identification of ALK fusion partners and resistance mechanisms (mutations, fusions, copy number variations). Samples will be sent for centralized analysis to the Léon Bérard Center (Lyon). For biological analysis on tissue obtained at diagnosis, the ALK fusion partner and its variant will be identified by RNAseq. Whenever a tissue re-biopsy is performed at the time of disease progression as part of the standard of care management of the patient, the remaining tissue sample will be collected as part of the BioExALK study, so that RNAseq analysis will be performed to look for resistance mechanisms. Tissue samples (10 slides of 5 microns) will be sent for centralized analysis to the Rouen University Hospital.

Official Title
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Biological Characterization of Advanced ALK-rearranged Non-small Cell Lung (NSCLC) Cancer Included in EXPLOREALK Study

Conditions
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Non-small Cell Lung Cancer, ALK Gene Rearrangement Positive

Intervention / Treatment
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* Genetic: RNAseq


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Stage IIIB/IV NSCLC non eligible to locoregional treatment with curative intent ALK rearrangement confirmed by IHC and/or FISH or NGS according to local methods Patient included in the EXPLORE ALK study Age > or = 18 years Patient treated with first-line new generation ALKi Patient agrees to sign an informed consent form and to collect blood samples at inclusion, first tumor evaluation and progression and for whom tumor biopsy at diagnosis is available Patient enrolled in the french National Health Insurance program or with a third- party payer Exclusion Criteria: Patients who do not wish to participate in Bioexalk Patients under guardianship

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Bioexalk cohort<br>All patients included in Explore ALK GFPC 03-2019 study who agree to participate in Bioexalk. | Genetic: RNAseq<br>* Tissue : RNAseq will be performed on tumor biopsy (10 slides of 5 microns) to identify the ALK fusion partner and its variant and associated co-mutations. ctDNA : NGS panel on DNA including a large panel of fusions and mutations will be performed on blood samples<br>* Other names: DNA NGS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS assessed by local review using RECIST v1.1, defined as time from treatment initiation to the first clinical or radiological progression or death from any cause | From date of treatment initiation up to 72 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS defined as time from treatment initiation to death from any cause. | From date of treatment initiation up to 72 months | 
| Duration of Response (DoR) | DoR assessed by local review using RECIST v1.1, defined as time from treatment initiation to the first clinical or radiological progression, death, consent withdrawn, adverse event, protocol deviations, lost to follow-up, or initiation of a new line of anticancer therapy. | From date of treatment initiation up to 72 months | 
| Overall Response Rate (ORR) | ORR defined as objective response rate of complete response or partial response measured by local review RECIST v1.1. | From date of treatment initiation up to 72 months | 
| Circulating tumoral DNA (ctDNA) clearance on Progression Free Survival (PFS) of stage IV ALK-rearranged NSCLC patients | ctDNA clearance will be determine as clearance of the fusion when detectable and/or clearance of relevant mutations when fusion not detected | From date of treatment initiation up to 72 months | 
| Circulating tumoral DNA (ctDNA) clearance on Overall Survival (OS) of stage IV ALK-rearranged NSCLC patients | ctDNA clearance will be determine as clearance of the fusion when detectable and/or clearance of relevant mutations when fusion not detected | From date of treatment initiation up to 72 months | 
| Circulating tumoral DNA (ctDNA) clearance on Duration of Response (DoR) of stage IV ALK-rearranged NSCLC patients | ctDNA clearance will be determine as clearance of the fusion when detectable and/or clearance of relevant mutations when fusion not detected | From date of treatment initiation up to 72 months | 
| Circulating tumoral DNA (ctDNA) clearance on Overall Response Rate (ORR) of stage IV ALK-rearranged NSCLC patients | ctDNA clearance will be determine as clearance of the fusion when detectable and/or clearance of relevant mutations when fusion not detected | From date of treatment initiation up to 72 months | 
| Description of mechanisms of resistance associated with first-line tyrosine kinase inhibitors | The following mechanisms of resistance will be assessed: secondary mutations on ALK, mutations or translocations on other genes of interest, histological transformations | From date of treatment initiation up to 72 months | 
| Description of mechanism of resistance associated with each ALK-fusion partner | The following mechanisms of resistance will be assessed: secondary mutations on ALK, mutations or translocations on other genes of interest, histological transformations | From date of treatment initiation up to 72 months | 
| Concordance between ALK fusion partner and co-mutations | ALK fusion partner and co-mutation identifications based on liquid and tissue biopsies at Baseline | From date of treatment initiation up to 72 months | 
| Impact of presence or absence of serum Anti-ALK antibodies at diagnosis on OS |  | From date of treatment initiation up to 72 months |