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AACR 2022: Case of Acquired TPM3-NTRK1 Fusion Resistant to Therapy in Lung Cancer

By: Celeste L. Dixon
Posted: Thursday, April 14, 2022

A case report of stage IV lung adenocarcinoma accompanied by bone metastases, which eventually progressed on the third-generation ALK inhibitor lorlatinib and then the TRK inhibitor larotrectinib, was presented during the American Association for Cancer Research (AACR) Annual Meeting 2022 (Abstract 4120/4). The report adds to the knowledge about acquired fusions—in this case, a TPM3-NTRK1 fusion—that may prove resistant to therapy, said Young Kwang Chae, MD, MPH, MBA, of Northwestern University Feinberg School of Medicine, Chicago, and colleagues. Targeted therapy currently plays a crucial role in addressing non–small cell lung cancer (NSCLC), and the mechanisms of resistance to ALK tyrosine kinase inhibitors should continue to be investigated, the investigators noted.

The male patient was aged 48 and had initially been treated with carboplatin, pemetrexed, and pembrolizumab; 4 months later, after disease progression, he began receiving carboplatin, paclitaxel, and bevacizumab instead. Disease progression to the brain 2 months later was treated with alectinib because of the presence, the team said, of EML 4-ALK fusion mutation (variant allele frequency of 4.8%) in a circulating tumor DNA (ctDNA) next-generation sequencing (NGS) assay.

Disease progression again occurred about a year later. At this point, the patient received whole-brain radiotherapy, and his treatment regimen was switched to lorlatinib. After about another year of improvements and then stable disease, wrote Dr. Chae and co-investigators, “a repeat ctDNA NGS assay revealed a new TPM3-NTRK1 fusion (variant allele frequency of 0.2%) and ALK L1196M (variant allele frequency of 2.8%), and a decision was made to add larotrectinib at 100 mg daily.” However, a 6-week follow-up MRI showed new parenchymal brain metastases.

Disclosure: The study authors reported no conflicts of interest.


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