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Clinicopathological features and resistance mechanisms in HIP1-ALK-rearranged lung cancer: A multicenter study
Jin Kang1,2, Qiu-Mei Deng1,3, Kai-Cheng Peng1
1Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
Abstract:
Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) respond well to ALK tyrosine kinase inhibitors (TKIs), and echinoderm microtubule-associated protein-like 4 (EML4)-ALK-rearranged NSCLC accounts for the majority of those patients. However, few studies have evaluated ALK-TKIs treatment for patients with huntingtin-interacting protein 1 (HIP1)-ALK fusions. This retrospective study evaluated the clinicopathological characteristics, genomic features, response to ALK-TKIs, and resistance mechanisms in 11 cases with HIP1-ALK fusions from five Chinese centers. Patients who received crizotinib at the Chinese centers had an objective response rate of 90% [9/10 cases, 95% confident index (CI): 54.1%-99.5%], median progression-free survival of 17.9 months (95% CI: 5.8-NA months), and median overall survival of 58.8 months (95% CI: 24.7-NA months). One patient who received first-line lorlatinib treatment achieved partial response for > 26.5 months. Despite the small sample size, HIP1-ALK (H21:A20) variant was the most common variant (four of 11 cases, 36.4%) and associated with better outcomes. Among the 11 cases, there were eight patients having available specimens for genetic testing before ALK-TKIs treatment and four patients undergoing biopsy after ALK-TKIs failure. The most common coexisting gene was TP53 among 11 patients and two of four patients after crizotinib failure harbored acquired ALK mutations (e.g., L1152V/Q1146K and L1196M). Brigatinib treatment appeared to be effective for a patient who failed crizotinib treatment because of the L1152V/Q1146K mutations, which might be related to increased binding affinity to these mutants. Although HIP1-ALK-rearranged NSCLC appears to initially respond well to ALK-TKIs, crizotinib resistance may be correlated with the AKAP9-BRAF fusion, ALK compound mutations (L1152V/Q1146K), and the ALK L1196M mutation. Larger studies are needed to evaluate the significance of HIP1-ALK-rearranged NSCLC.
Insights
Huntingtin-interacting protein 1 (HIP1)-ALK fusions in non-small cell lung cancer (NSCLC) show a high response rate to ALK tyrosine kinase inhibitors (TKIs). Crizotinib resistance mechanisms include acquired ALK mutations and fusions.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) is effectively treated with ALK tyrosine kinase inhibitors (TKIs).
- Echinoderm microtubule-associated protein-like 4 (EML4)-ALK rearrangements are the most common driver in ALK-positive NSCLC.
- Limited data exists on the efficacy and resistance of ALK-TKIs in patients with huntingtin-interacting protein 1 (HIP1)-ALK fusions.
Purpose of the Study:
- To evaluate the clinicopathological characteristics and genomic features of HIP1-ALK fusions in NSCLC.
- To assess the response to ALK-TKIs, including crizotinib and lorlatinib, in patients with HIP1-ALK fusions.
- To investigate the mechanisms of resistance to ALK-TKIs in this patient cohort.
Main Methods:
- Retrospective analysis of 11 patients with HIP1-ALK fusions from five Chinese centers.
- Review of clinicopathological data, genomic profiles, and treatment responses to ALK-TKIs.
- Genetic testing of tumor specimens before and after TKI treatment to identify resistance mutations.
Main Results:
- Patients receiving crizotinib achieved a 90% objective response rate, with a median progression-free survival of 17.9 months.
- The HIP1-ALK (H21:A20) variant was the most common, associated with better outcomes.
- Resistance mechanisms included acquired ALK mutations (e.g., L1152V/Q1146K, L1196M) and AKAP9-BRAF fusion.
Conclusions:
- HIP1-ALK-rearranged NSCLC shows a significant initial response to ALK-TKIs.
- Acquired ALK mutations and fusions are key mechanisms of crizotinib resistance.
- Brigatinib demonstrated potential efficacy in a patient with specific crizotinib-resistant mutations.
