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Chemotherapy and Immunotherapy for KEAP1/NFE2L2-Mutant Lung Cancer

By: Gavin Calabretta, BS
Posted: Friday, September 10, 2021

A recent study published in Frontiers in Oncology suggests that Kelch-like ECH-associated protein 1/nuclear factor (erythroid-derived 2)-like 2 (KEAP1/NFEL2) mutations in non–small cell lung cancer (NSCLC) appear to be linked with poor response to chemotherapy and immunotherapy. According to Haiyu Zhou, MD, of Guangdong Provincial People’s Hospital, China, and colleagues, the research investigated treatment methods for patients with these mutations.

The study used an in-house cohort (n = 733) and two previously completed phase II/III trials—POPLAR (n = 211) and OAK (n = 642)—from which blood-based next-generation sequencing data were available. For further reference, mRNA expression data from a Cancer Genome Atlas cohort (n = 998) were also used for gene set enrichment analysis. In both the in-house cohort and POPLAR/OAK trials, patients were given either chemotherapy (docetaxel) or anti–PD-L1 immunotherapy (atezolizumab).

Excluding EGFR and ALK mutations, atezolizumab treatment in patients with KEAP1/NFE2L2 wild-type disease resulted in longer overall survival compared with docetaxel treatment (OAK/POPLAR, hazard ratio = 0.6, 95% confidence interval [CI] = 0.5–0.73; P < .001). However, in patients with KEAP1/NFE2L2-mutant disease, the median overall survival did not significantly differ between the two treatments (OAK/POPLAR, hazard ratio = 0.74, 95% CI = 0.52–1.05; P = 0.095). KEAP1/NFE2L2 mutations were also found to be associated with worse overall survival in both atezolizumab (OAK/POPLAR, HR = 1.97, 95% CI = 1.48–2.63, P < .001) and docetaxel cohorts (OAK/POPLAR, HR = 1.68, 95% CI = 1.27–2.22, P < .001). These mutations were significantly correlated with higher tumor mutational burden in both the OAK/POPLAR and in-house studies. Lastly, gene set enrichment analysis revealed downregulation of DNA repair functions and deficient T-cell infiltration in patients with KEAP1/NFE2L2-mutant disease.

“The KEAP1/NFE2L2 mutation, as a poor prognostic factor for NSCLC, is associated with poor prognosis with immunotherapy or chemotherapy,” the authors concluded.

Disclosure: For full disclosures of the study authors, visit frontiersin.org.



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