Efficacy of Immune Checkpoint Inhibitors in SMARCA4-Mutant NSCLC

SMARCA4 mutation occurs in about 10% of patients with NSCLC.1Graziano S.L. Lin D. Elvin J.A. et al.SMARCA4 deficient non-small cell lung cancer (NSCLC): a comprehensive genomic profiling (CGP) study.Ann Oncol. 2019; 30: v652-v653Abstract Full Text PDF Google Scholar 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.2Dagogo-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 Scopus (41) Google Scholar described the clinicopathologic characteristics of patients with BRG1-deficient NSCLC with truncating SMARCA4 mutations in this journal. In the study of Dagogo-Jack et al.,2Dagogo-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 Scopus (41) Google Scholar among the four patients receiving ICI monotherapy, three patients experienced disease progression, and one patient was lost to follow-up. The median progression-free survival (PFS) for five patients receiving chemotherapy combined with ICIs was about 1.17 months. These data seemed to suggest that patients with BRG1-deficient NSCLC did not benefit from immunotherapy. But the results may have been influenced by the small sample size and comutations of STK11/KEAP1. Therefore, we aimed to further assess the role of truncating SMARCA4 mutation in a larger, ICIs-treated NSCLC cohort. A publicly available cohort of 441 patients with NSCLC treated with ICIs (385 from Memorial Sloan Kettering Cancer Center, 56 from Dana Farber Cancer Institute) was used to evaluate the association between truncating SMARCA4 mutation and response to ICIs therapy.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 (831) Google Scholar,4Samstein R.M. Lee C.H. Shoushtari A.N. et al.Tumor mutational load predicts survival after immunotherapy across multiple cancer types.Nat Genet. 2019; 51: 202-206Crossref PubMed Scopus (1817) Google Scholar SMARCA4 mutation was defined as any putative truncating mutation (nonsense mutation, frameshift mutation, insertion and deletion, and splice-site mutation). The overall survival (OS), PFS (calculated from the ICIs therapy start date), and clinical response to ICIs (objective response rate [ORR], disease control rate [DCR], and durable clinical benefit [DCB]) were evaluated. We also performed a subgroup analysis according to the comutation status of STK11/KEAP1 to independently assess the impact of pure SMARCA4 mutations (without STK11/KEAP1 comutations). Institutional review board approval and informed consent were waived because all data were deidentified and publicly available from the website (cBioPortal for Cancer Genomics) (https://www.cbioportal.org/). There was no significant difference in the distribution of age, sex, smoking status, and pathologic findings between the two groups (p > 0.05, Table 1). A total of 30 patients treated with ICIs (30 of 441, 6.80%) had truncating SMARCA4 mutation. Comutations of STK11/KEAP1 were found in 16 patients with SMARCA4 mutation (16 of 30, 53.33%). The median TMB of patients with SMARCA4 mutation was 8.85 mut/Mb. A total of 26 patients (26 of 30, 86.67%) received anti–programmed cell death protein 1/programmed death-ligand 1 monotherapy, and the mean lines of treatment was about 2.17. In the cohort of patients treated with ICIs with OS data (N = 412), the OS of 26 patients with SMARCA4 mutation was similar to that of those without the mutation (median OS: 13 mo versus 12 mo, p = 0.96; Fig. 1A). A total of 296 patients had available data for the evaluation of response to ICIs (PFS, ORR, DCR, and DCB), of whom 19 patients were detected with SMARCA4 mutation. The median PFS was similar between two groups (median PFS, 6.57 mo for mutant subgroup versus 4.37 mo for wild-type subgroup, p = 0.26; Fig. 1B). Patients with SMARCA4 mutation had significantly higher ORR (52.63% versus 20.22%, p = 0.001) and DCB (55.56% versus 32.45%, p = 0.045) and numerically higher DCR (68.42% versus 56.68%, p = 0.32) (Fig. 1C). When considering the comutation status of STK11/KEAP1, we found that patients with pure SMARCA4 mutation were found to have a numerically better OS (p = 0.15) and significantly longer PFS (p = 0.04) than those with SMARCA4 mutation and STK11/KEAP1 comutation, those with STK11/KEAP1 mutation, and those without SMARCA4/STK11/KEAP1 mutation (Fig. 1D and E). Seven of the 10 patients with pure SMARCA4 mutation responded to ICIs (one complete response and six partial responses, Fig. 1F). Moreover, patients with pure SMARCA4 mutation had better OS and PFS than patients who had SMARCA4 mutation with STK11/KEAP1 comutations (median OS, > 17 mo [not reached] versus 5 mo, p = 0.06; median PFS, > 6.57 mo [not reached] versus 1.80 mo, p = 0.01).Table 1The Baseline Characteristics of 441 Patients With NSCLC Treated With ICIsCharacteristicsSMARCA4 Wild-Type (N = 411)SMARCA4-Mutant (N = 30)p valueSex (%)0.224 Male192 (46.7)18 (60.0) Female219 (53.3)12 (40.0)Age (%)0.778 <311(0.3)0 31–5035 (9.8)2 (6.9) 50–6077 (21.6)5 (17.2) 61–70118 (33.1)13 (44.8) >71125 (35.1)9 (31.0) NA551Smoke (%)0.253 Never58 (20.9)2 (10.5) Ever206 (74.4)16 (84.2) Current13 (4.7)1 (5.3) NA13411Pathologic finding (%)0.234 LUAD319 (77.6)25 (83.3) LUSC55 (13.4)1 (3.3) Other37 (9.0)4 (13.3)Therapy (%)0.537 Mono377 (91.7)26 (86.7) Combo38 (8.3)4 (13.3)Lines of treatment (mean [SD])2.25 (1.16)2.17 (0.79)0.772ICI, immune checkpoint inhibitor; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; NA, not available. Open table in a new tab ICI, immune checkpoint inhibitor; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; NA, not available. Our results revealed that there was no significant difference in the efficacy of ICI treatment for NSCLC between SMARCA4-mutant and wild-type subgroups. A previous study reported a successful case regarding nivolumab in a patient with SMARCA4-deficient NSCLC with high TMB,5Naito T. Umemura S. Nakamura H. et al.Successful treatment with nivolumab for SMARCA4-deficient non-small cell lung carcinoma with a high tumor mutation burden: a case report.Thorac Cancer. 2019; 10: 1285-1288Crossref PubMed Scopus (34) Google Scholar which was contrary to our results and also the results of Dagogo-Jack et al.2Dagogo-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 Scopus (41) Google Scholar In our study, SMARCA4 mutation was correlated with high TMB but not associated with the efficacy of immunotherapy. Comutations of STK11/KEAP1 is common among patients with SMARCA4 mutation, which may be associated with resistance to immunotherapy. Therefore, we considered the comutation status of STK11/KEAP1 for the first time. Notably, patients with pure SMARCA4 mutations were found to benefit more from ICIs treatment. This may improve our precise management of these patients with SMARCA4 mutation according to the STK11/KEAP1 comutation status. However, our conclusion should be interpreted with caution, considering the limited sample size and the fact that not all patients had available data regarding treatment response. Further research is warranted to verify the predictive role of pure SMARCA4 mutations and explore the potential mechanisms. The authors acknowledge the efforts of Memorial Sloan Kettering Cancer Center and Dana Farber Cancer Institute in providing high-quality data resources for the researchers. This work was supported by the National Key Research and Development Program of People’s Republic of China (grant no. 2016YFC0905500, 2016YFC0905503), the Chinese National Natural Science Foundation project (grant no. 81872499, 81772476), the Science and Technology Program of Guangdong (grant no. 2017B020227001), and Science and Technology Program of Guangzhou (grant no. 201607020031, 201704020072). Drs. Zhou, Shen, and Zhang designed the study. Drs. Zhou, Shen, and Liu analyzed the data and interpreted the results with the help of Prof. Fang. Drs. Zhou and Shen drafted the article. Prof. Fang and Prof. Zhang critically revised the article. All authors read and approved the final manuscript. Clinicopathologic Characteristics of BRG1-Deficient NSCLCJournal of Thoracic OncologyVol. 15Issue 5PreviewTen percent of NSCLCs harbor mutations in SMARCA4, the gene encoding the SWItch/Sucrose Non-Fermentable ATPase BRG1. In preclinical models, BRG1 inactivation increases tumor aggressiveness but enhances sensitivity to drugs that target oxidative phosphorylation and inhibit SMARCA2, EZH2, CDK4, or CDK6. To facilitate translation of preclinical findings into clinical studies exploiting these therapeutic vulnerabilities, we assessed the clinical features of patients with tumors harboring BRG1-inactivating mutations. Full-Text PDF Open ArchiveReply to the Letter to the Editor From Zhou et alJournal of Thoracic OncologyVol. 15Issue 8PreviewWe appreciate the interest generated by our study on the clinicopathologic characteristics of BRG1-deficient NSCLC.1 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).1 In contrast to the favorable effects of high tumor mutation burden,2,3 BRG1 loss frequently overlapped with KEAP1 and STK11 mutations, both of which have been associated with resistance to checkpoint inhibitors. Full-Text PDF Open Archive