Letter to the Editor Concerning Diminished Efficacy of Programmed Death-(Ligand) 1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma Is Affected by KRAS Mutation Status

We thank and appreciate the detailed analysis performed by Ricciuti et al.1Ricciuti B. Arbour K.C. Lin J.J. et al.Diminished efficacy of programmed death-(ligand)1 inhibition in STK11- and KEAP1-mutant lung adenocarcinoma is affected by KRAS mutation status.J Thorac Oncol. 2022; 17: 399-410Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar to predict the immunotherapy response in STK11- and KEAP1-mutant lung adenocarcinoma, and we like to draw attention to some important points. In addition to common actionable mutations, tumor suppressor gene abnormalities, such as TP53, STK11, CDKN2A8, and KEAP1, are also common but are currently not clinically actionable; therefore, they are still treated with conventional chemotherapy with or without immunotherapy. KRAS is the most often identified oncogenic driver in lung adenocarcinoma, and KRAS G12C mutation is now targetable by sotorasib as was revealed in phase 2 CodeBreaK100 trial.2Spira A.I. Wilson F.H. Shapiro G. et al.Patient-reported outcomes (PRO) from the phase 2 CodeBreaK 100 trial evaluating sotorasib in KRASp.G12C mutated non-small cell lung cancer (NSCLC).J Clin Oncol. 2021; 39 (9057–9057)Google Scholar Although promising results have been obtained, it is not satisfactory compared with other actionable driver mutations. In addition, there is a gap for first-line treatment of patients with KRAS mutation for both KRAS G12C mutation and other KRAS mutations. The phase 3 KEYNOTE-042 study was reanalyzed to clarify the effect of KRAS mutation status on the efficacy of first-line pembrolizumab in patients with at least 1% of programmed death-ligand 1 (PD-L1) expression.3Herbst R.S. Lopes G. Kowalski D.M. et al.LBA4 Association of KRAS mutational status with response to pembrolizumab monotherapy given as first-line therapy for PD-L1-positive advanced nonsquamous NSCLC in Keynote-042.Ann Oncol. 2019; 30: XI63-XI64Abstract Full Text PDF Google Scholar Accordingly, although extremely high benefits of progression-free survival and overall survival were revealed in patients harboring KRAS mutation by pembrolizumab compared with chemotherapy, the advantage of pembrolizumab was disappeared in patients without KRAS mutation even with PD-L1 expression. Although this study is a posthoc analysis and needs to be confirmed by phase 3 studies, monoimmunotherapy in patients with PD-L1 expression in the first-line treatment of patients harboring KRAS mutation yielded non-negligible results. Moreover, the presence of PD-L1 expression was a considerable predictive biomarker for response to immunotherapy in patients with KRAS mutation, not only in the first line but also in subsequent treatment lines.4Mazieres J. Drilon A. Lusque A. et al.Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the immunotarget registry.Ann Oncol. 2019; 1: 1321-1328Abstract Full Text Full Text PDF Scopus (622) Google Scholar It is known that comutation of KRAS mutation and STK11 or KEAP mutation is a negative predictor for immunotherapy efficacy. Nevertheless, efficacy analysis according to the presence of PD-L1 expression has been found in this study, and this article revealed that the presence of this comutation was a negative predictor biomarker despite the presence of PD-L1 expression. But, most importantly, it turned out that although PD-L1 expression was over 50%, the response to immunotherapy was quite low. In light of these data, it is understood that a monoimmunotherapy treatment decision cannot be made by looking only at PD-L1 expression, and detailed genomic analyses are needed. In addition, although monoimmunotherapy does not work in the presence of these comutations, this is also responsible for chemotherapy-resistant disease. Although the median survival rates were 11 to 12 months with conventional chemotherapies in NSCLC, the median survival rate decreased to 4 months in the presence of this comutation according to this study. In this regard, the presence of this comutation is a prognostic biomarker rather than a predictor for immunotherapy. Nevertheless, the author claims that comutation is a predictive biomarker for response to immunotherapy throughout the article except for the limitation section. Thus, we think that this expression may lead to scientific bias. Tulay Kus, Gokmen Aktas: Design, Execution, Analysis of the paper, Approved the final version. Diminished Efficacy of Programmed Death-(Ligand)1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma Is Affected by KRAS Mutation StatusJournal of Thoracic OncologyVol. 17Issue 3PreviewSTK11 and KEAP1 mutations (STK11 mutant [STK11MUT] and KEAP1MUT) are among the most often mutated genes in lung adenocarcinoma (LUAD). Although STK11MUT has been associated with resistance to programmed death-(ligand)1 (PD-[L]1) inhibition in KRASMUT LUAD, its impact on immunotherapy efficacy in KRAS wild-type (KRASWT) LUAD is currently unknown. Whether KEAP1MUT differentially affects outcomes to PD-(L)1 inhibition in KRASMUT and KRASWT LUAD is also unknown. Full-Text PDF Open ArchiveReply to Kus and AktasJournal of Thoracic OncologyVol. 17Issue 6PreviewWe thank Drs. Kus and Aktas for their interest in our article entitled “Diminished Efficacy of Programmed Death-(Ligand)1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma Is Affected by KRAS Mutation Status,” in which we identified that STK11 and KEAP1 mutations are associated with diminished programmed death-(ligand)1 (PD-[L]1) blockade efficacy among KRAS mutant but not KRAS wild-type nonsquamous NSCLC.1 Full-Text PDF