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Successful targeting of the NRG1 fusion reveals durable response to afatinib in lung adenocarcinoma: a case report.

ABSTRACT: The treatments for advanced non-small cell lung cancer (NSCLC) patients have been improved by developing tyrosine kinase inhibitors (TKIs) as targeted therapies. Oncogenic gene fusions resulting from structural DNA rearrangements have been proposed as a unique class of oncogenic drivers and therapeutic targets. Currently approved TKIs mainly focused on a few well-known fusion genes such as anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1 (ROS1). Fusions involving neuregulin 1 gene (NRG1) have been recently described in a small portion of solid tumors as actionable oncogenic drivers, leading to the activation of the erythroblastic leukemia viral oncogene homolog (ErbB)-mediated pathway. Therefore, gene fusions containing NRG1 could serve as a therapeutic candidate for ErbB-targeted treatment. In the present study, we report a lung adenocarcinoma patient harboring the CD74-NRG1 fusion, which was identified by next-generation sequencing (NGS). The patient received the irreversible pan-ErbB inhibitor, afatinib, as first-line treatment and showed a significant treatment response with a progression-free survival of 8 months. After progressive disease (PD), the second NGS did not identify novel genetic alterations that emerged after afatinib resistance. Our case supports the use of ErbB-targeted treatment for NRG1 fusion-positive NSCLC. Further studies are warranted to understand treatment effects and acquired resistance of afatinib in NGR1 fusion-positive patients.

SUBMITTER: Wu X

PROVIDER: S-EPMC8573434 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Successful targeting of the NRG1 fusion reveals durable response to afatinib in lung adenocarcinoma: a case report.

Wu Xiaokang X Zhang Dongqing D Shi Mengru M Wang Fang F Li Yuping Y Lin Quan Q

Annals of translational medicine 20211001 19

The treatments for advanced non-small cell lung cancer (NSCLC) patients have been improved by developing tyrosine kinase inhibitors (TKIs) as targeted therapies. Oncogenic gene fusions resulting from structural DNA rearrangements have been proposed as a unique class of oncogenic drivers and therapeutic targets. Currently approved TKIs mainly focused on a few well-known fusion genes such as anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1 (ROS1). Fusions involving neureguli ...[more]

PMID: 34805369

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Project description:BackgroundNeuregulin 1 (NRG1) fusions, which activate ErbB signaling, are rare oncogenic drivers in multiple tumor types. Afatinib is a pan-ErbB family inhibitor that may be an effective treatment for NRG1 fusion-driven tumors.Patients and methodsThis report summarizes pertinent details, including best tumor response to treatment, for six patients with metastatic NRG1 fusion-positive tumors treated with afatinib.ResultsThe six cases include four female and two male patients who ranged in age from 34 to 69 years. Five of the cases are patients with lung cancer, including two patients with invasive mucinous adenocarcinoma and three patients with nonmucinous adenocarcinoma. The sixth case is a patient with colorectal cancer. NRG1 fusion partners for the patients with lung cancer were either CD74 or SDC4. The patient with colorectal cancer harbored a novel POMK-NRG1 fusion and a KRAS mutation. Two patients received afatinib as first- or second-line therapy, three patients received the drug as third- to fifth-line therapy, and one patient received afatinib as fifteenth-line therapy. Best response with afatinib was stable disease in two patients (duration up to 16 months when combined with local therapies) and partial response (PR) of >18 months in three patients, including one with ongoing PR after 27 months. The remaining patient had a PR of 5 months with afatinib 40 mg/day, then another 6 months after an increase to 50 mg/day.ConclusionThis report reviews previously published metastatic NRG1 fusion-positive tumors treated with afatinib and summarizes six previously unpublished cases. The latter include several with a prolonged response to treatment (>18 months), as well as the first report of efficacy in NRG1 fusion-positive colorectal cancer. This adds to the growing body of evidence suggesting that afatinib can be effective in patients with NRG1 fusion-positive tumors.Key pointsNRG1 fusions activate ErbB signaling and have been identified as oncogenic drivers in multiple solid tumor types. Afatinib is a pan-ErbB family inhibitor authorized for the treatment of advanced non-small cell lung cancer that may be effective in NRG1 fusion-driven tumors. This report summarizes six previously unpublished cases of NRG1 fusion-driven cancers treated with afatinib, including five with metastatic lung cancer and one with metastatic colorectal cancer. Several patients showed a prolonged response of >18 months with afatinib treatment. This case series adds to the evidence suggesting a potential role for afatinib in this area of unmet medical need.

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Successful targeting of the NRG1 fusion reveals durable response to afatinib in lung adenocarcinoma: a case report.

Publications

Successful targeting of the <i>NRG1</i> fusion reveals durable response to afatinib in lung adenocarcinoma: a case report.

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