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Zhifang Liu
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P86 - Targeted Therapy - Clinically Focused - New Target (ID 263)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P86.20 - The Prevalence of NTRK1 Fusion in a Chinese Lung Cancer Cohort (ID 3601)
00:00 - 00:00 | Presenting Author(s): Zhifang Liu
- Abstract
Introduction
At present, several neurotrophin receptor kinase (NTRK) inhibitors have been marketed and achieved marked efficacy in TRK fusion positive cancers, including lung cancers. However, there are few investigations on the molecular characteristics of NTRK fusion in Chinese lung cancers. We herein retrospectively explore the prevalence of NTRK1 fusion in a large Chinese lung cancer population and estimate the proportion of patients with NTRK1 fusion who may benefit in clinic.
Methods
A total of 12,565 Chinese lung cancer patients, including 8,167 adenocarcinoma patients, was used for the investigation of NTRK1 fusion, especially NTRK1 fusions with critical kinase domains. From 2017 to 2019, these patients’ ctDNA or tumor specimens were performed with targeted sequencing that including NTRK1 fusion testing. Concomitant drive mutations were also analyzed.
Results
NTRK1 fusions were identified in a total of 11 patients (11/12565, 0.088%), including 7 adenocarcinoma patients (7/8167, 0.086%). The median age of these patients was 62 years old, ranging from 46 to 74. Eight fusion partners were identified, seven of which had critical kinase domains, exception NTRK1-CDH7. The partners TPM3, TPR, IRF2BP2 and LMNA have been reported in lung cancer. Here, we found three fusion forms of TPM3-NTRK1 (3 pts); One form of TPR-NTRK1 (2 pts), IRF2BP2-NTRK1 (1 pt) and LMNA-NTRK1 (1 pt), respectively. Interestingly, we here identified another three novel partners of NTRK1: DPP10, FRMPD1 and KMT2C, and all of these novel fusions harbored critical kinase domains of NTRK1. According to clinical results of LOXO-101, NTRK1 fusion with critical kinase domain had a good response to this inhibitor. Therefore, in our cohort, it is likely that 0.08% (10/12565) of lung cancer patients would benefit clinically from NTRK inhibitors. We then analyzed the concomitant driver mutations, seven of the ten NTRK functional fusion cases (70%) owned tumor suppressor gene TP53 co-mutations. Five of the ten (50%) patients had actionable EGFR co-mutations, EGFR L858R in 4 pts and G719C in 1 pt. Mis-match repair genes (MLH3, MSH2, MSH6), BRAF V600E and PIK3CA E545Q co-mutated with NTRK1 fusion in 3 patients, 2 patients and 1 patient respectively. EGFR sensitive mutations (L858R/G719C) and TP53 hotspot mutations easily co-mutated in the same NTRK1 functional fusions patients (4 pts) and all of these patients were previously treatment with EGFR TKIs. Meaningfully, one NTRK1 fusion patient, without the treatment of EGFR TKIs, was with co-mutations of EGFR L858R and BRAF V600E. Previous clinical investigations or experiments have confirmed that gene fusion could mediate the resistance of EGFR-TKI, and the combination of EGFR TKIs and gene fusion inhibitors may be an effective treatment for these patients.
Conclusion
Here, we identified 10 cases (in 12,565 cases, 0.08%) with functional NTRK1 fusions in a Chinese lung cancer cohort; these patients may be benefit from NTRK inhibitors in clinic. Three novel partners (DPP10-, FRMPD1- and KMT2C-) were found in our cohort. Half of the NTRK1 fusion patients were co-mutated with EGFR activating mutations, which meaning that understanding of gene fusion mediating EGFR-TKI resistance is helpful to the development of follow-up treatment strategies.
