KRAS and ERBB-family genetic alterations affect response to PD-1 inhibitors in metastatic nonsquamous NSCLC

Published on 2019-11-16T13:06:45Z (GMT) by
<div>Background:<p>Programmed cell death 1 (PD-1) and PD-ligand 1 (PD-L1) inhibitors represent novel therapeutic options for advanced non-small cell lung cancer (NSCLC). However, approximately 50% of patients do not benefit from therapy and experience rapid disease progression. PD-L1 expression is the only approved biomarker of benefit to anti-PD-1/PD-L1 therapy. However, its weakness has been evidenced in many studies. More recently, tumor mutational burden (TMB) has proved to be a suitable biomarker, but its calculation is difficult to obtain for all patients.</p>Methods:<p>We tested specific NSCLC genetic alterations as potential immunotherapy biomarkers. Tumor DNA was obtained from advanced NSCLC patients treated with anti-PD-1 monoclonal antibody nivolumab (<i>n =</i> 44) or pembrolizumab (<i>n =</i> 3). The mutational status of 22 genes was assessed by targeted next-generation sequencing and the association with survival was tested in uni- and multivariate models. The association between gene mutations and clinical benefit was also investigated.</p>Results:<p>The most frequently mutated genes were <i>TP53</i> (49%), <i>KRAS</i> (43%), <i>ERBB2</i> (13%), <i>SMAD4</i> (13%), <i>DDR2</i> (13%), <i>STK11</i> (9%), <i>ERBB4</i> (6%), <i>EGFR</i> (6%), <i>BRAF</i> (6%), and <i>MET</i> (6%). We confirmed that <i>KRAS</i><sub>mut</sub> patients have a better response to PD-1 inhibitors, showing a longer progression-free survival (PFS) and overall survival (OS) than <i>KRAS</i><sub>wt</sub> patients. In addition, we observed that patients with <i>ERBB</i>-family mutations, including <i>EGFR, ERBB2</i>, and <i>ERBB4</i> all failed to respond to PD-1 antibodies, independently of <i>KRAS</i> status.</p>Conclusions:<p>This study suggests that the analysis of <i>KRAS</i> and <i>ERBB</i>-family gene mutational status is valuable when assessing the clinical practice for the selection of NSCLC patients to treat with PD-1 inhibitors.</p></div>

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Cinausero, Marika; Laprovitera, Noemi; Maglio, Giovanna De; Gerratana, Lorenzo; Riefolo, Mattia; Macerelli, Marianna; et al. (2019): KRAS and ERBB-family genetic alterations affect response to PD-1 inhibitors in metastatic nonsquamous NSCLC. SAGE Journals. Collection. https://doi.org/10.25384/SAGE.c.4742126.v1