KEAP1-NFE2L2 Mutations in NSCLC: Increased Awareness Needed. Reply to “KEAP1-NFE2L2–Mutant NSCLC and Immune Checkpoint Inhibitors: A Large Database Analysis”
Authors: Marco Mazzotta, Daniele Marinelli, Marcello Maugeri-Saccà
Journal: Journal of Thoracic Oncology (2020)

In the letter entitled “KEAP1-NFE2L2–mutant NSCLC and immune checkpoint inhibitors: a large database analysis,” Zhang et al.1Zhang C, Zhang C, Li J, Wang H. KEAP1-NFE2L2 mutant NSCLC and immune checkpoint inhibitors: a large database analysis. J Thorac Oncol. 2020.Google Scholar evaluated the impact of KEAP1-NFE2L2 mutations among patients with advanced NSCLC treated with immune checkpoint inhibitors (ICIs). Using the ICI-treated Memorial Sloan Kettering Cancer Center clinical sequencing cohort (available at http://www.cbioportal.org), the authors noticed that patients whose tumors harbored mutations in the KEAP1-NFE2L2 pathway had a shorter survival. Surprisingly, KEAP1-mutant tumors were also characterized by a higher tumor mutation burden as compared with wild-type NSCLC. KEAP1 and NFE2L2 encode two interacting proteins that mediate a cytoprotective response against xenobiotics and oxidative stress.2Jaramillo M.C. Zhang D.D. The emerging role of the Nrf2-Keap1 signaling pathway in cancer.Genes Dev. 2013; 27: 2179-2191Crossref PubMed Scopus (887) Google Scholar The transcriptional output of the NFE2L2-mediated gene transcription ranges from detoxifying enzymes and antioxidant proteins to multidrug resistance proteins.2Jaramillo M.C. Zhang D.D. The emerging role of the Nrf2-Keap1 signaling pathway in cancer.Genes Dev. 2013; 27: 2179-2191Crossref PubMed Scopus (887) Google Scholar The KEAP1-NFE2L2 pathway is frequently mutated in lung adenocarcinoma (LAC) and lung squamous cell carcinoma, with a mutational frequency that is approximately 20% to 30% (available at http://www.cbioportal.org). Accumulating evidence has linked genomic alterations in the KEAP1-NFE2L2 pathway to survival outcomes in NSCLC. For instance, we reported inferior survival outcomes in the presence of KEAP1-NFE2L2 mutations among patients with advanced LAC treated with chemotherapy in the first-line setting.3Goeman F. De Nicola F. Scalera S. et al.Mutations in the KEAP1-NFE2L2 pathway define a molecular subset of rapidly progressing lung adenocarcinoma.J Thorac Oncol. 2019; 14: 1924-1934Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar Moreover, mutations in the KEAP1-NFE2L2 pathway were accompanied by increased expression levels of central components of the DNA damage repair network.3Goeman F. De Nicola F. Scalera S. et al.Mutations in the KEAP1-NFE2L2 pathway define a molecular subset of rapidly progressing lung adenocarcinoma.J Thorac Oncol. 2019; 14: 1924-1934Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar At that time, we also hypothesized a possible increased efficacy of ICIs in the KEAP1-NFE2L2–mutant background. This claim was exclusively based on data from independent investigators, in particular preclinical evidence indicating tumor regression with ICI upon Keap1 and Pten deletion in murine models,4Best S.A. De Souza D.P. Kersbergen A. et al.Synergy between the KEAP1/NRF2 and PI3K pathways drives non-small-cell lung cancer with an altered immune microenvironment.Cell Metab. 2018; 27: 935-943.e4Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar and the presence of KEAP1 mutations among patients with NSCLC obtaining durable clinical benefit from ICI reported by Rizvi et al.5Rizvi N.A. Hellmann M.D. Snyder A. et al.Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.Science. 2015; 348: 124-128Crossref PubMed Scopus (5526) Google Scholar A more focused analysis carried out by Zhang et al.1Zhang C, Zhang C, Li J, Wang H. KEAP1-NFE2L2 mutant NSCLC and immune checkpoint inhibitors: a large database analysis. J Thorac Oncol. 2020.Google Scholar conveyed the opposite message. Although the hypothesis is intriguing and deserves further study, the data available so far do not allow us to draw any definitive conclusions. Indeed, it is unclear whether this proposed relationship may be, to some extent, modified when taking into account some underlying factors (annotated in the Memorial Sloan Kettering Cancer Center database), such as histology, sex, type of treatment, or tumor mutation burden. Moreover, given the number of patients analyzed, we supposed that only LAC were included in survival analysis. However, considering the increasingly greater use of next-generation sequencing–based diagnostic pathology, increased attention is needed in reporting and interpreting KEAP1-NFE2L2 alterations in routine clinical practice. Consistently, our still unpublished data from a pilot prospective study envisioning clinical sequencing with an approved assay partially align with the observations of Zhang et al.1Zhang C, Zhang C, Li J, Wang H. KEAP1-NFE2L2 mutant NSCLC and immune checkpoint inhibitors: a large database analysis. J Thorac Oncol. 2020.Google Scholar However, it seems that a more granular level of classification of KEAP1-NFE2L2 alterations is necessary to achieve a full reproducibility of the results across different cohorts. In conclusion, the data presented by Zhang et al.1Zhang C, Zhang C, Li J, Wang H. KEAP1-NFE2L2 mutant NSCLC and immune checkpoint inhibitors: a large database analysis. J Thorac Oncol. 2020.Google Scholar provided some interesting clues on a possible association between KEAP1-NFE2L2 mutations and reduced efficacy of ICIs in NSCLC. Whether the connection between KEAP1-NFE2L2 mutations and unresponsiveness to ICIs will gain a more concrete shape, urgent actions are needed to tackle this therapeutically “orphan” molecular subtype. The authors thank Tania Merlino for editorial assistance.