PMC7446323_01
Pathologic and molecular features of a TRK fusion-positive lung cancer. Photomicrographs of (A) cytology from the patient's lung adenocarcinoma and (B) positive immunohistochemistry results remarkable for cytoplasmic and membranous staining using a pan-TRK antibody are shown. (C) A map of the EPS15-NTRK1 fusion protein that resulted from an in-frame fusion between EPS15 exon 21 and NTRK1 exon 10. (D) A schematic that shows the domains of the fusion protein depicted as possibly dimerizing at the coiled-coil region of EPS15 where that protein is known to form homodimers.
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An endobronchial biopsy showed an adenocarcinoma consistent with a lung primary (thyroid transcription factor 1 positive, napsin A positive, and cytokeratin 7 positive by immunohistochemistry; Figs 1A and 1B). To further evaluate this apparent mitogenic driver-negative lung adenocarcinoma, targeted multiplex RNA sequencing (MSK Solid Fusion Panel) was performed. This identified a novel activating TRK fusion (in-frame fusion between EPS15 exon 21 and NTRK1 exon 10; Figs 1C and 1D).
Extracranial response to larotrectinib in a patient with TRK fusion-positive lung cancer. (A) Baseline computed tomography imaging of the chest revealed innumerable bilateral pulmonary metastases that resulted in substantial dyspnea. Treatment with larotrectinib achieved a brisk clinical response within the first 2 weeks as evidenced by decreased shortness of breath. This was accompanied by a radiologic partial response to therapy that (B) was observed at 8 weeks and (C) was confirmed at 16 weeks. Previously solid and semisolid confluent nodules regressed substantially.
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Tumors [RECIST] version 1.1; Fig 2), with regression of all areas of disease. This included near total resolution of all brain metastases at 8 weeks (95% reduction in aggregate tumor volume) and subsequently, a complete intracranial response by 16 weeks (Fig 3).
Intracranial response to larotrectinib in a patient with TRK fusion-positive lung cancer. Axial contrast-enhanced T1-weighted images at (A) baseline (brain metastases highlighted by circles), (B) 8 weeks, and (C) 16 weeks after treatment with larotrectinib was initiated demonstrate decreased and then resolved metastases in the right-side insula and left-side occipital lobe. Three-dimensional models at (D) baseline and (E) post-treatment at 8 weeks and (F) post-treatment at 16 weeks confirmed decreased burden of metastatic intracranial disease (segmented in green voxels and quantified at bottom). No residual disease was detectable at 16 weeks.
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Tumors [RECIST] version 1.1; Fig 2), with regression of all areas of disease. This included near total resolution of all brain metastases at 8 weeks (95% reduction in aggregate tumor volume) and subsequently, a complete intracranial response by 16 weeks (Fig 3).
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Response to larotrectinib in a patient with a TRK fusion-positive metastatic breast cancer. Baseline axial computed tomography imaging of the brain was performed with the addition of iodinated contrast that showed (A) metastatic brain disease (circles) and after 8 weeks of treatment with larotrectinib, (B) complete response. Radiologic partial response was also evident in the patient's liver metastases at (C) 8 weeks, which continue at (D) 16 weeks. This partial response was visualized throughout her liver, adrenal, and bone metastases.
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Brain imaging obtained in the absence of symptoms showed at least three subcentimeter brain metastases (Fig 4). Of note, her CNS metastases likewise regressed at the first follow-up assessment at 4 weeks, with a complete response in the CNS at 8 weeks (Fig 4).