Clinical trial NCT05996263: 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)
Official 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.
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Lung Cancer Stage III
Lung Cancer Stage IV
Keywords: PDL1
PET/CT
Pembrolizumab
KEAP1/NFE2L2
Lead sponsor: University Hospital, Brest
Sponsor class: OTHER
First posted: 2023-08-18
Enrollment: 75
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients treated or being treated with immunotherapy alone with pembrolizumab in 1st-line metastatic NSCLC.

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.

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.

Eligibility 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.)

Primary outcomes:
measure: Progression-Free survival (PFS)
timeFrame: through study completion, an average of 1 year
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: through study completion, an average of 1 year
Other outcomes:
measure: Robustness of the prediction model
timeFrame: through study completion, an average of 1 year
Locations:
city: Brest
country: France
facility: Chu Brest
Study officials:
affiliation: Radiation Oncology Department, Brest University Hospital
name: Vincent BOURBONNE, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: