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Clinical Outcomes of Patients With Advanced ALK-Rearranged Lung Squamous Cell Carcinoma Treated With ALK Tyrosine
Yuanze Sun1, Dan Yang1, Zhe Huang2
1Guizhou Medical University, Guiyang, Guizhou, China; Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
Background:
DNA-based next-generation sequencing (NGS) has identified ALK rearrangements in lung squamous cell carcinoma (LUSC), a subset of nonsmall cell lung cancer traditionally lacking effective targeted therapies. While ALK tyrosine kinase inhibitors (TKIs) like crizotinib and alectinib are effective in ALK-rearranged lung adenocarcinoma, their efficacy in LUSC remains poorly defined due to limited subtype-specific data.
Methods:
We presented a case of ALK-rearranged LUSC and established a patient-derived xenograft (PDX) model to validate the tumor-inhibitory effects of various ALK-TKIs on ALK-positive LUSC. Additionally, we conducted a retrospective study that included 28 patients diagnosed with stage IIIC-IV LUSC who received treatment at Hunan Cancer Hospital between June 2014 and May 2024 to evaluate the clinical characteristics and therapeutic outcomes of ALK-rearranged LUSC in a real-world cohort.
Results:
We report a patient with LUSC harboring a novel CSNK1G3-ALK fusion, who demonstrated treatment response and durable disease control with first-line alectinib for over 30 months. PDX-based in vivo studies demonstrated significant tumor shrinkage with crizotinib, alectinib, and lorlatinib compared to vehicle control. In the retrospective cohort (n = 28), first-line ALK-TKI treatment was associated with improved progression-free survival (median PFS: 16.0 months vs. 3.0 months, P < .01), overall survival (median OS: 30.0 months vs. 18.5 months, P = .039), and objective response rates (ORR: 75% vs. 25%, P = .021), compared to first-line chemotherapy.
Conclusions:
This study provides real-world evidence supporting the therapeutic benefit of ALK-TKIs in ALK-rearranged LUSC, highlighting their potential as a viable therapeutic strategy for this rare nonsmall cell lung cancer subtype.
Insights
This study shows ALK tyrosine kinase inhibitors (TKIs) are effective for ALK-rearranged lung squamous cell carcinoma (LUSC). Real-world data confirms ALK-TKIs improve survival and response rates compared to chemotherapy in LUSC patients.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Next-generation sequencing (NGS) identifies anaplastic lymphoma kinase (ALK) rearrangements in a subset of lung squamous cell carcinoma (LUSC).
- ALK-rearranged lung adenocarcinoma shows efficacy with ALK tyrosine kinase inhibitors (TKIs), but data for LUSC is limited.
- LUSC traditionally lacks effective targeted therapies, highlighting an unmet clinical need.
Purpose of the Study:
- To evaluate the efficacy of ALK-TKIs in ALK-rearranged LUSC.
- To establish and utilize a patient-derived xenograft (PDX) model for preclinical assessment of ALK-TKI activity in LUSC.
- To analyze clinical characteristics and treatment outcomes in a real-world cohort of ALK-rearranged LUSC patients.
Main Methods:
- Case presentation of a patient with a novel CSNK1G3-ALK fusion in LUSC treated with alectinib.
- Establishment of a PDX model to test in vivo efficacy of crizotinib, alectinib, and lorlatinib.
- Retrospective analysis of 28 stage IIIC-IV LUSC patients treated with ALK-TKIs or chemotherapy.
Main Results:
- A patient with a novel CSNK1G3-ALK fusion achieved durable response (>30 months) with first-line alectinib.
- PDX models showed significant tumor inhibition with crizotinib, alectinib, and lorlatinib.
- In the retrospective cohort, first-line ALK-TKI treatment improved median progression-free survival (16.0 vs. 3.0 months), median overall survival (30.0 vs. 18.5 months), and objective response rates (75% vs. 25%) compared to chemotherapy.
Conclusions:
- ALK-TKIs demonstrate significant therapeutic benefit in ALK-rearranged LUSC.
- This study provides real-world evidence supporting ALK-TKIs as a viable treatment strategy for this rare NSCLC subtype.
- Targeted therapy with ALK-TKIs represents a promising approach for patients with ALK-rearranged LUSC.
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