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)

Lung Cancer Stage IV Clinical Trial

— 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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05996263
• Other study ID #: 29BRC23.0142 - PEMBROMIC
• Status: Recruiting
• Start date: August 1, 2023
• Est. completion date: August 31, 2023

Study information

• Verified date: August 2023
• Source: University Hospital, Brest
• Contact: Vincent BOURBONNE, MD, PhD
• Phone: +33298223398
• Email: vincent.bourbonne[@]chu-brest.fr
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 75
• Est. completion date: August 31, 2023
• Est. primary completion date: August 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.)

Related Conditions & MeSH terms

• Lung Cancer Stage III
• Lung Cancer Stage IV
• Lung Neoplasms

Locations

Country	Name	City	State
France	Chu Brest	Brest

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Brest

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Robustness of the prediction model	Robustness will be assessed by comparing predictions obtained from 2 different blind reviewers	through study completion, an average of 1 year
Primary	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	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