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 NSCLC | SMARCA4 Intact NSCLC | Significance | |
|---|---|---|---|
| Cases | 2,840 | 37,479 | |
| % Male/female | 57/43 | 49/51 | P < 0.0001 |
| Median age | 64 | 67 | NS |
| GA/tumor | 3.2 | 5.6 | P < 0.0001 |
| TP53 | 70% | 64% | NS |
| KRAS | 28% | 30% | NS |
| EGFR | 7% | 18% | P < 0.0001 |
| STK11 | 34% | 13% | P < 0.0001 |
| PIK3CA | 5% | 10% | P < 0.0001 |
| RB1 | 6% | 8% | NS |
| MET | 4% | 5% | NS |
| BRAF | 4% | 5% | NS |
| ERBB2 | 6% | 4% | NS |
| CDK4 | 2% | 4% | P < 0.0001 |
| CDK 6 | 2% | 2% | NS |
| ALK ROS1 NTRK1/3 | 2% | 5% | P < 0.0001 |
| PD-L1 (CD274) amp | 1% | 1% | NS |
| PD-L1 Low | 26% | 27% | NS |
| PD-L1 High | 18% | 29% | P < 0.0001 |
| Median TMB (mut/Mb) | 12.2 | 6.1 | P < 0.0001 |
| TMB > 10 mut/Mb | 60% | 35% | P < 0.0001 |
| TMB > 20 mut/Mb | 27% | 10% | P < 0.0001 |
| MSI High | 0.8% | 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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