1905 - NTRK1-3 Genomic Fusions in Non-Small Cell Lung Cancer (NSCLC) Determined by Comprehensive Genomic Profiling

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:

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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.