Reply to the Letter to the Editor From Zhou et al
Authors: Ibiayi Dagogo-Jack, Mari Mino-Kenudson
Journal: Journal of Thoracic Oncology (2020)

We appreciate the interest generated by our study on the clinicopathologic characteristics of BRG1-deficient NSCLC.1Dagogo-Jack I. Schrock A.B. Kem M. et al.Clinicopathologic characteristics of BRG1-deficient NSCLC.J Thorac Oncol. 2020; 15: 766-776Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar In our analysis, we had observed that BRG1-deficient NSCLCs harbored molecular features that have been associated with both response and refractoriness to immunotherapy. Specifically, BRG1 loss most often occurred in the context of truncating SMARCA4 mutations. This category of SMARCA4 alteration is enriched for higher tumor mutation burden (12.2 mutations per megabase).1Dagogo-Jack I. Schrock A.B. Kem M. et al.Clinicopathologic characteristics of BRG1-deficient NSCLC.J Thorac Oncol. 2020; 15: 766-776Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar In contrast to the favorable effects of high tumor mutation burden,2Ready N. Hellmann M.D. Awad M.M. et al.First-line nivolumab plus ipilimumab in advanced non-small-cell lung cancer (CheckMate 568): outcomes by programmed death ligand 1 and tumor mutational burden as biomarkers.J Clin Oncol. 2019; 37: 992-1000Crossref PubMed Scopus (330) Google Scholar,3Rizvi H. Sanchez-Vega F. La K. et al.Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing.J Clin Oncol. 2018; 36: 633-641Crossref PubMed Scopus (823) Google Scholar BRG1 loss frequently overlapped with KEAP1 and STK11 mutations, both of which have been associated with resistance to checkpoint inhibitors.4Skoulidis F. Goldberg M.E. Greenawalt D.M. et al.STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma.Cancer Discov. 2018; 8: 822-835Crossref PubMed Scopus (774) Google Scholar,5Arbour K.C. Jordan E. Kim H.R. et al.Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer.Clin Cancer Res. 2018; 24: 334-340Crossref PubMed Scopus (207) Google Scholar As 41% and 52% of BRG1-deficient NSCLCs in our data set had comutation of KEAP1 or STK11, respectively, isolating the unique impact of BRG1 loss on treatment outcomes was challenging. Our analysis of immunotherapy outcomes was also limited by the small number of patients who received the treatment. Thus, although we reported a median progression-free survival on carboplatin and pemetrexed combined with pembrolizumab of 35 days and noted that all the three patients who received checkpoint inhibitor monotherapy experienced primary progression, we emphasized that larger follow-up studies that included patients with SMARCA4 mutations without confounding comutations would be necessary to truly evaluate the independent impact of BRG1 inactivation on immunotherapy efficacy. In the absence of these larger studies, Zhou et al.6Zhou H. Shen J. Liu J. Fang W. Zhang L. Efficacy of immune checkpoint inhibitors in SMARCA4-mutant NSCLC.J Thorac Oncol. 2020; Abstract Full Text Full Text PDF Scopus (8) Google Scholar used two publicly available data sets to attempt to tease out the effect of the SMARCA4 mutation status (and the interplay between SMARCA4 and KEAP1/STK11 mutations) on the response to immunotherapy. Through this approach, the authors identified 26 patients with truncating SMARCA4 mutations treated with checkpoint inhibitor monotherapy, half of whom had concurrent KEAP1 or STK11 mutations. In this heterogeneous cohort of patients, most of whom received immunotherapy in the second-line setting, patients with SMARCA4 mutations were more likely to achieve an objective response than patients with SMARCA4 wild-type NSCLC. Importantly, survival outcomes were most favorable for patients who had tumors with truncating SMARCA4 mutations without KEAP1 or STK11 comutations. Although the results presented in the letter by Zhou et al.6Zhou H. Shen J. Liu J. Fang W. Zhang L. Efficacy of immune checkpoint inhibitors in SMARCA4-mutant NSCLC.J Thorac Oncol. 2020; Abstract Full Text Full Text PDF Scopus (8) Google Scholar suffer from some of the same limitations as our original analysis (including small sample size), the ability to detect a favorable effect of the SMARCA4 mutations despite these constraints is intriguing. As checkpoint inhibitors are the backbone of initial treatment for most patients with metastatic NSCLC and there is ongoing need to identify predictive biomarkers of immunotherapy efficacy, the noteworthy findings by Zhou et al.6Zhou H. Shen J. Liu J. Fang W. Zhang L. Efficacy of immune checkpoint inhibitors in SMARCA4-mutant NSCLC.J Thorac Oncol. 2020; Abstract Full Text Full Text PDF Scopus (8) Google Scholar lend additional support to our call for larger studies evaluating the relationship between BRG1 inactivation and immunotherapy outcomes. Efficacy of Immune Checkpoint Inhibitors in SMARCA4-Mutant NSCLCJournal of Thoracic OncologyVol. 15Issue 8PreviewSMARCA4 mutation occurs in about 10% of patients with NSCLC.1 Moreover, NSCLC with SMARCA4 mutation often harbored comutations in STK11 and KEAP1. It was reported that patients with SMARCA4 mutations usually had a high tumor mutation burden (TMB). However, little is known about the efficacy of immune checkpoint inhibitors (ICIs) for SMARCA4-mutant NSCLC. Recently, Dagogo-Jack et al.2 described the clinicopathologic characteristics of patients with BRG1-deficient NSCLC with truncating SMARCA4 mutations in this journal. Full-Text PDF Open Archive