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)

Conditions: Lung Cancer Stage III; Lung Cancer Stage IV

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.

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.)

Keywords: pdl1 pet/ct pembrolizumab keap1/nfe2l2