Prognostic Value of Combined Approach Based on KEAP1/NFE2L2 Mutations and Pre-therapeutic FDG-PET/CT Radiomic Analysis in Advanced Non-small-cell Lung Cancer PDL1 ≥ 50% Treated With Pembrolizumab (PEMBROMIC)

Study Overview
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Brief Summary
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Pembrolizumab has been approved for first-line locally advanced or metastatic NSCLC with a tumor proportion score (TPS) ≥50% for PDL1, based on the results of KEYNOTE-024. However, even with a positive PDL1 status, only a fraction of patients respond to immunotherapy. In the KEYNOTE-024 study evaluating pembrolizumab versus chemotherapy in first-line advanced NSCLC with PDL1 TPS ≥50%, the response rate in the pembrolizumab arm alone was 45%. NFE2L2 is a transcription factor that directs the expression of free radical defense genes that may interfere with radiation-induced DNA damage. KEAP1 is an adaptor protein that targets NFE2L2 for ubiquitination and proteasomal destruction as part of normal homeostasis. These new biomarkers are of clinical interest, as KEAP1/NFE2L2 mutations predict radiation resistance in patients with localized NSCLC treated with radiotherapy but not surgery. Some data also suggest a role for the KEAP1/NFE2L2 axis in response to immunotherapy. Establishing a predictive model for the presence of the KEAP1/NFE2L2 mutation would provide a tool for predicting survival (progression-free and overall), even before the patient starts immunotherapy.

Detailed Description
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Pembrolizumab has been approved for first-line locally advanced or metastatic NSCLC with a tumor proportion score (TPS) ≥50% for PDL1, based on the results of KEYNOTE-024. However, even with a positive PDL1 status, only a fraction of patients respond to immunotherapy. In the KEYNOTE-024 study evaluating pembrolizumab versus chemotherapy in first-line advanced NSCLC with PDL1 TPS ≥50%, the response rate in the pembrolizumab arm alone was 45%. This result led to the approval of pembrolizumab for first-line advanced NSCLC with PDL1 TPS ≥ 50%, which nevertheless represents only 22% of patients with stage IIIB/IV NSCLC. Early identification of biomarkers for patients unlikely to benefit from first-line pembrolizumab is therefore a crucial step in selecting suitable candidates. Furthermore, in cancer, genomic alterations in NFE2L2, KEAP1 and CUL3 result in constitutive activation of NRF2-dependent gene transcription, which promotes cellular resistance to oxidative stress, xenobiotic efflux, proliferation and metabolic reprogramming. Somatic mutations in NFE2L2 and KEAP1 are found in 3.5-15% and 12-17% of NSCLC patients respectively. NFE2L2 is a transcription factor that directs the expression of free radical defense genes that may interfere with radiation-induced DNA damage. KEAP1 is an adaptor protein that targets NFE2L2 for ubiquitination and proteasomal destruction as part of normal homeostasis. These new biomarkers are of clinical interest, as KEAP1/NFE2L2 mutations predict radiation resistance in patients with localized NSCLC treated with radiotherapy but not surgery. Some data also suggest a role for the KEAP1/NFE2L2 axis in response to immunotherapy. Establishing a predictive model for the presence of the KEAP1/NFE2L2 mutation would provide a tool for predicting survival (progression-free and overall), even before the patient starts immunotherapy.

Official Title
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Prognostic Value of Combined Approach Based on KEAP1/NFE2L2 Mutations and Pre-therapeutic FDG-PET/CT Radiomic Analysis in Advanced Non-small-cell Lung Cancer PDL1 ≥ 50% Treated With Pembrolizumab.

Conditions
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Lung Cancer Stage III, Lung Cancer Stage IV

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Histologically or cytologically proven non-small-cell lung cancer (NSCLC) Stage IV NSCLC. Stage III NSCLC unresectable and not amenable to radiotherapy PD-L1 expression ≥ 50%. No previous systemic treatment for NSCLC. Patients treated for 1st-line metastatic disease with immunotherapy alone (pembrolizumab) No opposition expressed Patient affiliated to a social security scheme Exclusion Criteria: PD-L1 expression <50 Neuroendocrine tumors Secondarily metastatic patients Previous treatments Opposition formulated Patient under legal protection (guardianship, curatorship, etc.)

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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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free survival (PFS) | PFS is defined as the time elapsed between initiation of treatment and tumor progression or death from any cause. | through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time elapsed between initiation of treatment and death, whatever the cause. | through study completion, an average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PDL1, PET/CT, Pembrolizumab, KEAP1/NFE2L2