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Poster Display session 1

1893 - SMARCA4 Deficient Non-Small Cell Lung Cancer (NSCLC): A Comprehensive Genomic Profiling (CGP) Study

Date

28 Sep 2019

Session

Poster Display session 1

Topics

Tumour Site

Non-Small Cell Lung Cancer

Presenters

Stephen Graziano

Citation

Annals of Oncology (2019) 30 (suppl_5): v602-v660. 10.1093/annonc/mdz260

Authors

S.L. Graziano1, D. Lin2, J.A. Elvin2, J. Vergilio2, J..K. Killian2, N. Ngo2, S. Ramkissoon2, E. Severson2, A. Hemmerich2, D. Duncan2, C. Edgerly2, S.M. Ali3, A.B. Schrock3, J. Chung3, E.S. Sokol3, P. Reddy4, K. McGregor4, V.A. Miller3, B.M. Alexander3, J.S. Ross5

Author affiliations

  • 1 Medical Oncology, Upstate Medical University, 13210 - Syracuse/US
  • 2 Pathology, Foundation Medicine, 02141 - Cambridge/US
  • 3 Clinical Development, Foundation Medicine, 02141 - Cambridge/US
  • 4 Medical Affairs, Foundation Medicine, 02141 - Cambridge/US
  • 5 Pathology And Urology, Upstate Medical University, 13210 - Syracuse/US

Resources

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Abstract 1893

Background

The 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.

Methods

From 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).

Results

SMARCA4d 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.Table:

1583P

SMARCA4 Deficient NSCLCSMARCA4 Intact NSCLCSignificance
Cases2,84037,479
% Male/female57/4349/51P < 0.0001
Median age6467NS
GA/tumor3.25.6P < 0.0001
TP5370%64%NS
KRAS28%30%NS
EGFR7%18%P < 0.0001
STK1134%13%P < 0.0001
PIK3CA5%10%P < 0.0001
RB16%8%NS
MET4%5%NS
BRAF4%5%NS
ERBB26%4%NS
CDK42%4%P < 0.0001
CDK 62%2%NS
ALK ROS1 NTRK1/32%5%P < 0.0001
PD-L1 (CD274) amp1%1%NS
PD-L1 Low26%27%NS
PD-L1 High18%29%P < 0.0001
Median TMB (mut/Mb)12.26.1P < 0.0001
TMB > 10 mut/Mb60%35%P < 0.0001
TMB > 20 mut/Mb27%10%P < 0.0001
MSI High0.8%0.2%NS

Conclusions

SMARCA4d 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.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Foundation Medicine.

Funding

Foundation Medicine.

Disclosure

D. 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.

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