Abstract 4120: Acquired TPM3-NTRK1 fusion resistant to larotrectinib in a non-small cell lung cancer with EML4-ALK fusion progressed on lorlatinib
Authors: Choi Horyun , Kim Jinah , Lee Yeun Ho , Kim Leeseul , Kim Na Hyun , Chae Young Kwang 
Published: June 2022

Abstract
Background: As oncogenic driver genes have been detected, targeted therapy plays a crucial role in non-small cell lung cancer (NSCLC) with targeted mutation. Lorlatinib, a selective third-generation inhibitor of anaplastic lymphoma kinase (ALK), is a treatment option for ALK-positive NSCLC patients who previously failed on ALK tyrosine kinase inhibitors (TKIs). Larotrectinib, a highly selective tropomyosin receptor kinase (TRK) inhibitor, is a treatment option for NSCLC with neurotrophic tyrosine receptor kinase (NTRK) mutation. Herein, we present an acquired TPM3-NTRK1 fusion resistant to larotrectinib in lung adenocarcinoma with EML4-ALK fusion progressed on lorlatinib.
Case Presentation: A 48-year-old male with stage IV adenocarcinoma of lung with metastatic disease of bone was initially treated with carboplatin, pemetrexed, and pembrolizumab. Follow up CT in 4 months showed numerous hepatic lesions and liver biopsy demonstrated large cell neuroendocrine carcinoma. Upon progression of disease (PD), systemic therapy regimen was switched to combination of carboplatin, paclitaxel, and bevacizumab. After two months since starting the new regimen, a second PD was observed. Follow-up MRI brain demonstrated multiple small metastatic lesions. Subsequently, he was started on alectinib 600 mg twice a day given EML 4-ALK fusion mutation [4.8% of variant allele frequency (VAF)] in circulating tumor DNA (ctDNA) NGS assay. Follow-up CT chest in 5 months showed 5 mm left lower lobe nodule which remained unchanged in size. He maintained SD for 9 months before repeat MRI brain demonstrated PD with new leptomeningeal carcinomatosis. Subsequently, he received whole brain radiotherapy and the treatment regimen was switched to lorlatinib 100 mg daily. In 7-week follow-up CT, the 5 mm nodule in the left lower lobe was stable. Follow-up MRI brain in 16 weeks showed decrease in size and number of numerous enhancing parenchymal and leptomeningeal lesions. Overall SD was maintained for 8 months before follow-up MRI brain showed new punctate lesions. Repeat ctDNA NGS assay revealed new TPM3-NTRK1 fusion (VAF 0.2%) and ALK L1196M (VAF 2.8%), and a decision was made to add larotrectinib 100 mg daily. The 6-week follow-up MRI brain showed new parenchymal brain metastases.
Discussion: It has been reported that the development of ALK resistance mutations may be associated with specific EML4-ALK variants. However, the influence of the specific EML4-ALK variants in NSCLC was not fully investigated. We report the case of acquired TPM3-NTRK1 fusion resistant to larotrectinib and acquired ALK L1196M in lung adenocarcinoma with EML4-ALK fusion progressed on lorlatinib. Further investigations are warranted to explore the mechanism of resistance to ALK TKIs.
Citation Format: Horyun Choi, Jinah Kim, Yeun Ho Lee, Leeseul Kim, Na Hyun Kim, Young Kwang Chae. Acquired TPM3-NTRK1 fusion resistant to larotrectinib in a non-small cell lung cancer with EML4-ALK fusion progressed on lorlatinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4120.