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Detection of Targetable Alterations in Non-small Cell Lung Cancer using Next-generation Sequencing
Published on: October 10, 2025
Response to crizotinib in advanced ALK-rearranged non-small cell lung cancers with different ALK-fusion variants
Yan Li1, Tongtong Zhang2, Jing Zhang1
1Departments of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Introduction:
Anaplastic lymphoma kinase (ALK) rearrangements are present in approximately 5% of non-small-cell lung cancers (NSCLCs). NSCLCs with ALK-rearrangement can be effectively treated with crizotinib. However, magnitude and duration of responses are found to be heterogeneous. This study explored the clinical efficacy of crizotinib in different ALK variants.
Methods:
Among 96 ALK-rearrangement patients treated with crizotinib, 60 patients were identified with tumor specimens that could be evaluated by next-generation sequencing (NGS). We retrospectively evaluated the efficacy of crizotinib in different ALK variants.
Results:
The median Progression-free survival (PFS) of the 96 ALK-rearrangement patients was 14.17 months. Among the 60 patients with NGS results, the most frequent variants were variant 3a/b (33.33%), variant 1 (23.33%) and variant 2 (15.00%). The percentage of rare EML4-ALK variants and non EML4-ALK variants were 10.00% and 18.33%. Survival analysis showed that patients with variant 2 appeared to have longer PFS than others (P = .021); also, patients with TP53 mutation seemed to have an unfavorable PFS than those with TP53 wild-type with a borderline p value (P = .068). After adjusting for other baseline characteristics, EML4-ALK variant 2 was identified as an important factor for a better PFS of crizotinib. We also found that patients with variant 3a/b had shorter duration of response to crizotinib; however, no significant difference of PFS was observed between the PFS of variant3a/b and non-v3 EML4-ALK variants.
Conclusions:
Our results indicate prolonged PFS in patients with EML4-ALK variant 2.
Insights
Anaplastic lymphoma kinase (ALK) rearrangements in non-small-cell lung cancer (NSCLC) show varied responses to crizotinib. Patients with EML4-ALK variant 2 demonstrated significantly longer progression-free survival (PFS) when treated with crizotinib.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Anaplastic lymphoma kinase (ALK) rearrangements occur in about 5% of non-small-cell lung cancers (NSCLCs).
- Crizotinib is an effective treatment for ALK-rearranged NSCLCs, but response heterogeneity exists.
- Understanding ALK variants is crucial for optimizing treatment outcomes.
Purpose of the Study:
- To investigate the clinical efficacy of crizotinib in patients with different anaplastic lymphoma kinase (ALK) variants in non-small-cell lung cancer (NSCLC).
- To identify specific ALK variants associated with differential treatment responses to crizotinib.
Main Methods:
- Retrospective evaluation of 96 patients with ALK-rearrangement treated with crizotinib.
- Next-generation sequencing (NGS) was used to identify ALK variants in 60 patients.
- Survival analysis, including Progression-Free Survival (PFS), was performed.
Main Results:
- Median PFS for all 96 patients was 14.17 months.
- EML4-ALK variant 2 was associated with significantly longer PFS (P=.021).
- TP53 mutation showed a borderline trend towards unfavorable PFS (P=.068). Patients with variant 3a/b had shorter response durations.
Conclusions:
- EML4-ALK variant 2 is a significant factor for prolonged PFS in NSCLC patients treated with crizotinib.
- Further research into ALK variants can guide personalized NSCLC treatment strategies.
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