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)

Trial Title: 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)

NCT ID: NCT05996263

Condition: Lung Cancer Stage III
Lung Cancer Stage IV

Conditions: Official terms:
Lung Neoplasms

Conditions: Keywords:
PDL1
PET/CT
Pembrolizumab
KEAP1/NFE2L2

Study type: Observational

Overall status: Recruiting

Study design:

Time perspective: Retrospective

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.

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.

Criteria for eligibility:

Study pop:
Patients treated or being treated with immunotherapy alone with pembrolizumab in 1st-line metastatic NSCLC.

Sampling method: Non-Probability Sample
Criteria:
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.)

Gender: All

Minimum age: 18 Years

Maximum age: N/A

Healthy volunteers: No

Locations:

Facility:
Name: Chu Brest

Address:
City: Brest
Zip: 29609
Country: France

Status: Recruiting

Contact:
Last name: Vincent BOURBONNE, MD, PhD

Phone: +33298223398
Email: vincent.bourbonne@chu-brest.fr

Start date: August 1, 2023

Completion date: August 31, 2024

Lead sponsor:
Agency: University Hospital, Brest
Agency class: Other

Source: University Hospital, Brest

Record processing date: ClinicalTrials.gov processed this data on November 12, 2024

Source: ClinicalTrials.gov page: https://clinicaltrials.gov/ct2/show/NCT05996263