1583P - SMARCA4 deficient non-small cell lung cancer (NSCLC): A comprehensive genomic profiling (CGP) study

Abstract

BackgroundThe SMARCA4 catalytic ATPase, can be inactivated by several types of genomic alterations (GA) in NSCLC. SMARCA4 deficient (d) NSCLC is an aggressive subtype of primary lung adenocarcinoma that is often confused with metastatic disease to the lung. MethodsFrom a series of 40,319 clinically advanced NSCLC, 2,840 (7%) SMARCA4d and 37,479 (93%) SMARCA4i cases underwent hybrid capture-based CGP using FFPE material. Microsatellite instability (MSI) was determined on 114 loci and tumor mutational burden (TMB) and (mutations (mut) per/ Mb) was determined on 1.1 Mbp of sequenced DNA. PD-L1 expression was measured by IHC (Dako 22C3). ResultsSMARCA4d was inactivated by short variant base substitutions and truncations (88%), deletions (9%), duplications (1%), rearrangement/fusions (1%). SMARCA4d patients were slightly younger and featured significantly fewer females (Table). At 3.2 vs 5.6 GA/tumor, SMARCA4d tumors had significantly fewer driver-type GA than SMARCAi tumors. Although non-targetable GA in TP53 and KRAS were similar, SMARCA4d cases features significantly lower frequencies of the EGFR and PIK3CA SV targets and fusions in ALK, ROS1 and NTRK1-3 genes. In contrast, SMARCA4d tumors had a significantly higher frequency of STK11 mutations while also having a higher median TMB and greater proportion of cases with > 10 and > 20 mut/Mb. CDK4/6 GA were more frequent in the SMARCA4i cases.Table1583PTableSMARCA4 Deficient NSCLCSMARCA4 Intact NSCLCSignificanceCases2,84037,479% Male/female57/4349/51P<0.0001Median age6467NSGA/tumor3.25.6P<0.0001TP5370%64%NSKRAS28%30%NSEGFR7%18%P<0.0001STK1134%13%P<0.0001PIK3CA5%10%P<0.0001RB16%8%NSMET4%5%NSBRAF4%5%NSERBB26%4%NSCDK42%4%P<0.0001CDK 62%2%NSALK ROS1 NTRK1/32%5%P<0.0001PD-L1 (CD274) amp1%1%NSPD-L1 Low26%27%NSPD-L1 High18%29%P<0.0001Median TMB (mut/Mb)12.26.1P<0.0001TMB > 10 mut/Mb60%35%P<0.0001TMB > 20 mut/Mb27%10%P<0.0001MSI High0.8%0.2%NS ConclusionsSMARCA4d NSCLC is characterized by pleomorphic histology, TTF1- IHC and significant reduction in targetable driver mutations in genes such as EGFR, ALK, ROS1 and NTRK1-3. Despite new evidence that SMARCA4d tumors can respond to cell cycle inhibitors such as palbociclib, the CDK4/6 mutation frequencies is not increased in this tumor subset. Higher TMB levels in SMARCA4d NSCLC suggests strong potential for immunotherapy benefit, but the significantly enriched STK11 GA frequency may reduce overall response rates to checkpoint inhibitors. Legal entity responsible for the studyFoundation Medicine. FundingFoundation Medicine. DisclosureD. Lin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. J.A. Elvin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. J. Vergilio: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. J.K. Killian: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. N. Ngo: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. S. Ramkissoon: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. E. Severson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. A. Hemmerich: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. D. Duncan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. C. Edgerly: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. S.M. Ali: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. A.B. Schrock: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. J. Chung: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. E.S. Sokol: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. P. Reddy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. K. McGregor: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. V.A. Miller: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. B.M. Alexander: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. J.S. Ross: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. All other authors have declared no conflicts of interest.