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.
Resources from the same session
5054 - Inhibition of Rspo-Wnt pathway Facilitates Checkpoint Blockade Therapy by anti-RSPO3 antibody (DBPR117)
Presenter: John Hsu
Session: Poster Display session 1
Resources:
Abstract
3305 - A phase I dose-escalation and expansion trial of intratumorally administered CV8102, alone and in combination with anti-PD-1 in patients with advanced solid tumors
Presenter: Jürgen Krauss
Session: Poster Display session 1
Resources:
Abstract
5353 - Phase 1/2 Study of 9-ING-41, a small molecule selective Glycogen Synthase Kinase-3 Beta (GSK-3β) Inhibitor, as a Single Agent and Combined with Chemotherapy, in Patients with Refractory Hematological Malignancies or Solid Tumors
Presenter: Benedito Carneiro
Session: Poster Display session 1
Resources:
Abstract
3946 - Trial in progress: a Phase I, open-label study of GSK1795091 administered in combination with immunotherapies in participants with advanced solid tumors (NCT03447314).
Presenter: Aaron Hansen
Session: Poster Display session 1
Resources:
Abstract
3449 - Radiographic Phenotyping to Identify Intracranial Disseminated Recurrence in Brain metastases Treated With Radiosurgery Using Contrast-enhanced MR Imaging
Presenter: CheYu Hsu
Session: Poster Display session 1
Resources:
Abstract
4553 - Association between TP53 mutations and efficacy of Osimertinib for brain metastasis from EGFR-mutant lung cancer
Presenter: Lijuan Chen
Session: Poster Display session 1
Resources:
Abstract
4942 - Response assessment of melanoma brain metastases treated by stereotactic radiotherapy or immunotherapy or both: a comparison of RECIST 1.1, RANO and iRANO criteria
Presenter: Emilie Le Rhun
Session: Poster Display session 1
Resources:
Abstract
3529 - Management of multiple brain metastases by Staged SRS focusing on utmost risk lesions
Presenter: shaoqun Li
Session: Poster Display session 1
Resources:
Abstract
5315 - Whole brain radiotherapy plus simultaneous in-field boost versus whole brain radiotherapy plus fractionated stereotactic radiotherapy for multiple brain metastases of non-small cell lung cancer
Presenter: Lu Li
Session: Poster Display session 1
Resources:
Abstract
1116 - 3D based texture analysis serving as potential diagnostic factor in discriminating primary central nervous system lymphoma from metastatic brain tumors: A preliminary study
Presenter: Wen Guo
Session: Poster Display session 1
Resources:
Abstract