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 Details
Study Description
Brief Summary
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.
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Detailed Description
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.
Study Design
Outcome Measures
Primary Outcome Measures
- Progression-Free survival (PFS) [through study completion, an average of 1 year]
PFS is defined as the time elapsed between initiation of treatment and tumor progression or death from any cause.
Secondary Outcome Measures
- Overall Survival (OS) [through study completion, an average of 1 year]
OS is defined as the time elapsed between initiation of treatment and death, whatever the cause.
Other Outcome Measures
- Robustness of the prediction model [through study completion, an average of 1 year]
Robustness will be assessed by comparing predictions obtained from 2 different blind reviewers
Eligibility Criteria
Criteria
Inclusion Criteria:
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Age ≥ 18 years
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Histologically or cytologically proven non-small-cell lung cancer (NSCLC)
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Stage IV NSCLC. Stage III NSCLC unresectable and not amenable to radiotherapy
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PD-L1 expression ≥ 50%.
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No previous systemic treatment for NSCLC.
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Patients treated for 1st-line metastatic disease with immunotherapy alone (pembrolizumab)
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No opposition expressed
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Patient affiliated to a social security scheme
Exclusion Criteria:
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PD-L1 expression <50
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Neuroendocrine tumors
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Secondarily metastatic patients
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Previous treatments
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Opposition formulated
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Patient under legal protection (guardianship, curatorship, etc.)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Chu Brest | Brest | France | 29609 |
Sponsors and Collaborators
- University Hospital, Brest
Investigators
- Principal Investigator: Vincent BOURBONNE, MD, PhD, Radiation Oncology Department, Brest University Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 29BRC23.0142 - PEMBROMIC