Abstract 1905
Background
The Neurotrophic Tyrosine Kinase genes, NTRK1-3 are extremely rare drivers of a wide variety of malignancies. The recent pan-cancer approval of kinase inhibitor drugs targeting NTRK has sparked interest in the frequency of NTRK rearrangements found in NSCLC.
Methods
Comprehensive genomic profiling (CGP) was performed on FFPE samples from 42,791 NSCLC cases. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 loci.
Results
58 (0.1%) of the NSCLC featured genomic fusions or rearrangements in the NTRK1-3 genes (Table). The ages and genders of NTRK1-3 fusion+ cases were similar to NSCLC in general and did not enrich for younger patients. NTRK fusions were highest in adenocarcinomas (67%) and squamous cell carcinomas (SCC; 9%). The average genomic alterations (GA) per NTRK1-3 altered tumor ranged from 6.1 – 8.2 GA and was higher than that reported for EGFR, ALK and ROS1 driven NSCLC. The NTRK1-3 fusions involved a wide variety of fusion partners with NTRK1- IRF2BP2 (6) and NTRK1-TPM3 (9) most frequent. The levels of TMB and frequencies of PD-L1 expression were higher than EGFR, ALK and ROS1 altered cases. The STK11 GA frequencies were similar to NSCLC in general but lower than the frequency in lung adenocarcinoma only.Table:
1549P
NTRK1 | NTRK2 | NTRK3 | |
---|---|---|---|
Cases | 47 | 5 | 6 |
Median age/Range | 64 (22-88) | 68 (65-76) | 71 (63-74) |
Gender m/f | 23/24 | 3/2 | 5/1 |
NSCLC Types Adenocarcinoma NSCLC NOS Large Cell Neuroendocrine SCC Sarcomatoid Large Cell | 31 10 2 2 1 1 | 4 1 | 4 2 |
GA/tumor | 6.1 | 8.2 | 6.2 |
TP53 | 55% | 80% | 67% |
KRAS | 15% | 0% | 17% |
STK11 | 11% | 20% | 0% |
MSI High | 0% | 0% | 0% |
Median TMB mut/Mb | 3.5 | 11.3 | 14.4 |
TMB >10/20 mut/Mb | 22%/7% | 60%/20% | 67%/33% |
PD-L1 Expression low/high | 32%/16% (n = 19) | 50%/50% (n = 2) | 0%/33% (n = 3) |
Conclusions
Although the addition of RNA sequencing may marginally increase their detection, based on this DNA-only CGP sequencing study, NTRK1-3 fusions are extremely rare in NSCLC. These NTRK1-3 fusion-driven NSCLC differ from other well-known driver associated NSCLC such as EGFR, ALK and ROS1 in their having higher GA/tumor, TMB and PD-L1 expression frequencies suggesting that immunotherapies may also be available for the care of these patients, possibly as a combination therapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Foundation Medicine.
Funding
Foundation Medicine.
Disclosure
E.S. Sokol: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. S.E. Trabucco: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. D.X. Jin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. G.M. Frampton: 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. D. Lin: 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. 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. P. Reddy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. K. McGregor: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. B.M. Alexander: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: 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
5152 - Comprehensive Geriatric Assessment (CGA) can categorize elderly glioblastoma (GBM) patients into three groups predicting survival: a monoinstitutional study
Presenter: Eleonora Bergo
Session: Poster Display session 1
Resources:
Abstract
4079 - Triggering anti-GBM immune response with EGFR-mediated photoimmunotherapy
Presenter: Gabriela Kramer-marek
Session: Poster Display session 1
Resources:
Abstract
4364 - Upregulation of sFRP3 circulating expression levels correlates survival outcomes in glioblastoma
Presenter: Gema Bruixola
Session: Poster Display session 1
Resources:
Abstract
2327 - Characterization and pre-clinical modeling of genetic aberrations in pediatric gliomas
Presenter: Itai Moshe
Session: Poster Display session 1
Resources:
Abstract
3154 - Preclinical Study of Novel Tetracyclic Small Molecule, CC12, for Brain Cancer
Presenter: Liyun Fann
Session: Poster Display session 1
Resources:
Abstract
5759 - CHLOROBRAIN phase IB trial: The addition of chloroquine, an autophagy inhibitor, to concurrent radiation and temozolomide for newly diagnosed glioblastoma
Presenter: Inge Compter
Session: Poster Display session 1
Resources:
Abstract
1382 - A Phase II Clinical Trial Evaluating the Efficacy and Safety of Apatinib Combined with dose-dense Temozolomide in Recurrent Glioblastoma
Presenter: Yong Wang
Session: Poster Display session 1
Resources:
Abstract
4407 - Phase 0 Trial of Ceritinib in Brain Metastases and Recurrent Glioblastoma
Presenter: Shwetal Mehta
Session: Poster Display session 1
Resources:
Abstract
1469 - Pembrolizumab (Pem) in recurrent high-grade glioma (HGG) patients with mismatch repair deficiency (MMRd): an observational study
Presenter: Mario Caccese
Session: Poster Display session 1
Resources:
Abstract
4217 - Outcome of high-grade gliomas (HGGs) treated into immunotherapeutic early-phase clinical trials (ieCTs): a single-center experience
Presenter: Matteo Simonelli
Session: Poster Display session 1
Resources:
Abstract