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) (PEMBROMIC)

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.

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.

Study Overview

• Status: Recruiting
• Conditions: Lung Cancer Stage III; Lung Cancer Stage IV

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 Type: Observational
• Enrollment (Estimated): 75

Contacts and Locations

• Study Contact: Name: Vincent BOURBONNE, MD, PhD; Phone Number: +33298223398; Email: vincent.bourbonne@chu-brest.fr

Study Locations

• France
  • Brest, France, 29609
    • Recruiting
    • CHU Brest
    • Contact: Vincent BOURBONNE, MD, PhD; Phone Number: +33298223398; Email: vincent.bourbonne@chu-brest.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

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

Description

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.)

Study Plan

How is the study designed?

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: University Hospital, Brest
• Investigators: Principal Investigator: Vincent BOURBONNE, MD, PhD, Radiation Oncology Department, Brest University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2023
• Primary Completion (Actual): August 31, 2023
• Study Completion (Estimated): August 31, 2024

Study Registration Dates

• First Submitted: August 1, 2023
• First Submitted That Met QC Criteria: August 16, 2023
• First Posted (Actual): August 18, 2023

Study Record Updates

• Last Update Posted (Actual): August 9, 2024
• Last Update Submitted That Met QC Criteria: August 8, 2024
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: PET/CT; Pembrolizumab; PDL1; KEAP1/NFE2L2
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms
• Other Study ID Numbers: 29BRC23.0142 - PEMBROMIC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All collected data that underlie results in a publication
• IPD Sharing Time Frame: Data will be available beginning three years and ending fifteen years following the final study report completion
• IPD Sharing Access Criteria: Data access requests will be reviewed by the internal committee of Brest UH. Requestors will be required to sign and complete a data access agreement
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No