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Primary Resistance to Brigatinib in a Patient with Lung Adenocarcinoma Harboring ALK G1202R Mutation and LIPI-NTRK1
Zhiwei Xiao1, Xuewu Huang1, Biyuan Xie2
1Oncology Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, People's Republic of China.
Purpose:
Anaplastic lymphoma kinase (ALK) inhibitors have transformed the management of non-small-cell lung cancer (NSCLC) patients with ALK gene rearrangement. This paper reports a new resistance mechanism to a second-generation ALK inhibitor, brigatinib.
Case Report:
A 43-year-old woman who had no history of smoking was diagnosed with stage IVa (T2bN2M1b) lung adenocarcinoma. After the first-line chemotherapy failed, the patient received crizotinib due to the presence of EML4-ALK fusion by next-generation sequencing (NGS). The patient had disease progression after 8 months on crizotinib, and a second NGS identified the ALK G1202R resistance mutation. Therefore, she was switched to brigatinib. After only 53 days of treatment with brigatinib, the patient developed a new 1.6×1.2 cm lesion in the mediastinal lymph node. A third NGS testing revealed a new form of NTRK rearrangement (LIPI-NTRK1). The patient died 16 months after diagnosis.
Conclusion:
This paper provides new insights into the primary resistance to brigatinib in NSCLC patients carrying ALK G1202R mutation. The new fusion form of NTRK rearrangement was detected, which may provide potential treatment options after brigatinib resistance.
Insights
A new resistance mechanism to brigatinib, an anaplastic lymphoma kinase (ALK) inhibitor, was identified in non-small cell lung cancer (NSCLC). A novel NTRK rearrangement emerged after brigatinib treatment, suggesting new therapeutic avenues.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Anaplastic lymphoma kinase (ALK) inhibitors, such as brigatinib, are crucial for treating ALK-rearranged non-small cell lung cancer (NSCLC).
- Resistance to ALK inhibitors necessitates understanding novel resistance mechanisms to guide subsequent treatment strategies.
Observation:
- A patient with ALK-rearranged NSCLC developed resistance to crizotinib, acquiring the ALK G1202R mutation.
- Following treatment with brigatinib, the patient exhibited disease progression and developed a new mediastinal lymph node lesion.
- Next-generation sequencing (NGS) identified a novel NTRK rearrangement (LIPI-NTRK1) as the cause of brigatinib resistance.
Findings:
- This case highlights a previously undocumented resistance mechanism to brigatinib in ALK-mutated NSCLC.
- The emergence of LIPI-NTRK1 fusion represents a new pathway for therapeutic failure under ALK inhibition.
- The patient's rapid progression and subsequent molecular findings underscore the complexity of treatment resistance.
Implications:
- The identification of LIPI-NTRK1 rearrangement offers potential therapeutic targets for patients resistant to brigatinib.
- This finding expands the understanding of resistance mechanisms in ALK-NSCLC, informing future treatment algorithms.
- Further research into NTRK rearrangements as a resistance mechanism may lead to the development of novel therapeutic strategies.
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