With the widespread application of Next generation sequencing(NGS) in accurate tumor diagnosis and treatment, MET fusion mutation has been found in many solid tumors. Compared with the exon 14 skipping mutation of MET and the amplification of MET, the fusion mutation is rarer (the mutation frequency is about 0.29%), and no definite dosing plan for MET fusion is recommended in the current guidelines.

The case shared today describes an advanced patient with a clinical diagnosis of squamous cell carcinoma of the lung who was found to carry TFG-MET gene fusion after NGS testing and was comprehensively evaluated for a first-line regimen of crizotinib, which had a sustained partial response of more than 17 months.

01. Case Introduction

In May 2022, a 70-year-old woman was admitted for examination for a cough and a chest CT showed a 2.6 cm primary mass in the lower lobe of the left lung and a whole-body scan showed multiple metastases, including pleural, lymph node and muscle metastases. A final diagnosis of stage IV squamous cell lung cancer was made based on the findings of subsequent immunohistochemistry (IHC) including TTF1 (−), NAPSIN A (−) and other findings.

02. Detection results of molecular markers

DNA based NGS testing of the right cervical lymph node revealed a rare TFG-MET fusion (E6:E15), TMB-L: 1 Muts/Mb, and low-grade microsatellite instability (MSI-L) with a PD-L1 immunohistochemical stain showing 90% of TPS (Dako 22C3). Protein activity verification of rare fusions revealed the activity of the MET protein (Figure 1).

 Figure 1.TFG-MET fusion diagram (1. A); Validation of MET protein activity (EPR19067 antibody) (1.b)

03. Clinical option 

NCCN guidelines recommend immune checkpoint inhibitors (ICIs) as a first-line treatment for operable molecular biomarker-negative non-small cell lung cancer. Although MET fusion is not included in the general list of operable gene mutations in NSCLC, previous studies have also shown that the use of MET inhibitors can improve the efficacy of subsequent chemotherapy or immunotherapy. Following discussions in a multidisciplinary consultation (MDT), it was finally decided to treat this patient with first-line crizotinib (started in June 2022 with a 250mg bid regimen).

04. Patient Follow-up

After about two months of treatment with crizotinib, a chest CT scan showed complete resolution of the left lower primary lung tumor, together with resolution of the pleural effusion and partial resolution of the cervical lymph nodes (Figure 2). By the end of the reporting period, the patient had been on crizotinib for 17 months and sustained remission.

Figure 2.CT scan showing changes over time in primary and metastatic lymph nodes in the left lung.

(a) Primary degeneration of the left lung.  (b) The right supraclavicular lymph nodes:

20220518: 3.2 × 2.7 cm, 20220727: 2.5 × 2.1 cm, 20230404: 2.3 × 1.9 cm.

05. Case Summary

(1) The median progression-free survival (PFS) was 7.3 months (95% CI: 1.2-7.6) in patients with advanced NSCLC with MET 14 skipping mutation treated with crizotinib first-line, and previous cases suggest that PFS of primary MET-fused lung adenocarcinoma (4.0-14 months) is comparable to that of this case (17 months). The efficacy of crizotinib for MET fusion has once again been demonstrated and the clinical response is presumed to be no worse than in patients with the MET 14 skipping mutation.

(2) The rare fusion, exon break fusion or inter-gene fusion detected at DNA level shall be further verified at RNA or protein level. RNA-based NGS can further verify that the fusion detected at the DNA level is transcriptionally expressed, thereby reducing the risk that DNA-based NGS may detect genetic fusion variants without benefiting from targeted therapy.

Reference

Cheng W, Xu T, Yang L, Yan N, Yang J,  Fang S. Dramatic response to crizotinib through MET phosphorylation inhibition in rare TFG-MET fusion advanced squamous cell lung cancer. Oncologist.  2024 Jul 2:oyae166. doi: 10.1093/oncolo/oyae166. Epub ahead of print. PMID: 38954846.

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