Ensartinib Treatment for Rare Nonclassical ALK Fusion Lung Adenocarcinoma With Brain Metastasis

Introduction

ALK rearrangements constitute a clinically important molecular subtype of non–small cell lung cancer (NSCLC), particularly lung adenocarcinoma, occurring in approximately 3% to 7% of cases and more frequently in younger patients and nonsmokers.^1,2 These rearrangements generate oncogenic fusion proteins, most commonly EML4-ALK; however, an expanding spectrum of nonclassical fusion variants, including STRN-ALK, has been identified, many of which exhibit distinct biological behavior and therapeutic responses.^3,4 Patients with ALK-positive NSCLC often present with nonspecific respiratory or neurological symptoms, such as cough, dyspnea, weight loss, or brain metastases, which may complicate timely diagnosis.⁵

STRN-ALK is a nonclassical ALK fusion for which optimal detection strategies and treatment approaches remain incompletely defined. Emerging evidence indicates that such rare fusions may show variable sensitivity to ALK tyrosine kinase inhibitors compared with classical rearrangements.^4,6 Although most ALK inhibitors were developed for canonical fusions, the selective activity of newer agents, including ensartinib, has been reported in certain nonclassical ALK variants.⁷ Accordingly, comprehensive molecular profiling is essential to guide personalized therapy.

Here, we report a case of STRN-ALK–positive lung adenocarcinoma with brain metastasis in a 50-year-old woman. Compared with prior reports demonstrating central nervous system (CNS) response to ensartinib,⁸ this case further demonstrates the drug’s durable CNS control, sustained systemic response, and good long-term tolerability, highlighting the therapeutic potential of ensartinib in rare ALK-driven NSCLC.

Case Presentation

A 50-year-old woman presented with a 2-year history of cough and sputum production, and episodic wheezing, which had worsened over the past month, associated with increasing symptoms of dyspnea. Her cough was not associated with identifiable triggers or exacerbating factors; only occasional yellow, thick sputum was produced; she had no fevers or hemoptysis. She noted that her symptoms were worse at night and had partially responded to previous outside treatments.

The patient began experiencing wheezing after exertion, worsening lower back pain, and dyspnea approximately 3 months before admission. When she underwent pulmonary function testing at that time, the results showed severe mixed ventilatory dysfunction. She was treated with budesonide/formoterol, which provided partial relief of her symptoms. One month before admission, the patient experienced worsening cough with increased volume of sputum and ongoing back pain. At that time, she was prescribed salmeterol/fluticasone, montelukast, and intermittent albuterol, which only temporarily improved her symptoms.

Three days before hospital admission, the patient reported wheezing at rest, a severe cough, and chest tightness; the cough substantially improved after expectoration. She denied fevers or blood in her sputum. A chest CT performed on February 23, 2022, revealed left lower lobe bronchial obstruction, atelectasis, and mediastinal lymphadenopathy (Figure 1A). The patient had leukocytosis (white blood cell count, 10.81 × 10⁹/L), thrombocytosis (platelets, 552 × 10⁹/L), an elevated neutrophil percentage (81.7%), and a C-reactive protein level of 5.80 mg/L, with normal total immunoglobulin E. She reported an unintentional weight loss of 10 kg over the previous 2 months. She was admitted for further investigation with suspected lung mass and atelectasis, based on imaging findings.

A bronchoscopy revealed a neoplastic lesion obstructing the left main bronchus. An abdominal-pelvic CT with contrast showed no evidence of distant metastasis, and a bone scan was negative. A brain MRI performed on March 5, 2022, showed an abnormal signal in the left basal ganglia consistent with brain metastasis, as well as a benign-appearing subcutaneous occipital scalp nodule (Figure 2A). Histopathology of the bronchial biopsy revealed mucinous adenocarcinoma with signet ring cell features. Immunohistochemical staining revealed positive results for CK, CK7, p63, TTF-1, and Napsin A; the results were negative for CK5/6 and p40. The Ki-67 index was approximately 20%. Genomic testing revealed a rare STRN-ALK fusion, with a variant allele frequency at 5.4%, identifying it as a nonclassical fusion subtype (Table 1).

Considering the identified brain metastasis and associated symptoms, the patient was started on oral ensartinib (200 mg daily) and 4 cycles of pemetrexed and carboplatin. She had resolution of cough and wheezing, with a 10-kg weight gain, and no significant adverse events. A chest CT on September 15, 2023, demonstrated an interval decrease in the size of left main and lower lobe bronchi tumors, a decrease in the mean size of mediastinal lymph nodes, and re-expansion of the left lung (Figure 1B).

A repeat chest CT on May 8, 2022, showed improvement in pulmonary findings, and a brain MRI performed on the same day showed stable intracranial disease without worsening.

The patient then switched to maintenance ensartinib (225 mg daily) under close surveillance. A CT chest scan on June 10, 2022, demonstrated interval resolution of the bronchial mass, with stable mediastinal nodes and residual localized atelectasis.

CT scans performed on September 7, 2022, showed no new pulmonary lesions. Bilateral ground-glass opacities (GGOs) were subsequently observed on December 21, 2022, and gradually resolved during follow-up. A brain MRI performed on February 23, 2023, demonstrated no recurrence of the prior basal ganglia metastasis and a reduction in the occipital nodule, indicating stable intracranial disease. By January 29, 2024, chest CT confirmed complete resolution of the GGOs with no lymphadenopathy (Figure 1C). Most recently, imaging performed on May 19, 2025, demonstrated continued remission with no evidence of recurrence (Figure 1D).

Results and Follow-Up

The patient showed significant improvement both clinically and radiologically after treatment with combined chemotherapy and targeted therapy with ensartinib. As previously noted, after completion of 4 cycles of pemetrexed plus carboplatin and oral ensartinib (200 mg daily), the patient experienced complete resolution of cough and wheezing, a 10-kg weight gain, and no treatment-related adverse effects.

Initial imaging on February 23, 2022, had identified a left lower lobe bronchial obstruction and mediastinal lymphadenopathy. A brain MRI on March 5, 2022, reported a metastatic lesion in the left basal ganglia and a benign-appearing occipital scalp nodule, prompting immediate systemic therapy.

Repeat chest CT on September 15, 2023, demonstrated significant regression of the endobronchial mass, decreased mediastinal lymphadenopathy, and improved aeration of the previously collapsed left lung. Follow-up brain MRI on May 8, 2022, demonstrated stable intracranial disease without new lesions (Figure 2B).

Serial imaging over the subsequent 3 years showed durable disease control. On June 10, 2022, chest CT indicated the absence of the endobronchial mass, with stable mediastinal nodes and residual localized atelectasis. Imaging on September 7, 2022, showed no new pulmonary lesions. Bilateral GGOs were subsequently identified on December 21, 2022, and gradually resolved during follow-up. Brain MRI and chest CT, performed on September 15, 2023, demonstrated no recurrence of the basal ganglia metastasis, a decrease in the size of the occipital nodule, and stable thoracic findings (Figure 1B and Figure 2C). The bilateral GGOs had completely resolved by January 29, 2024 (Figure 1C).

As of May 19, 2025, the most recent chest CT indicated no recurrence of tumor, lymphadenopathy, or parenchymal lesions. The patient has tolerated long-term ensartinib maintenance at a consistent daily dose of 225 mg without clinical activity or radiologic evidence of disease progression. Table 2 outlines treatment milestones with intermediate imaging findings.

Discussion

This case illustrates the treatment possibilities and diagnostic difficulty of a rare STRN-ALK nonclassical fusion in lung adenocarcinoma while exploring it within brain metastases. The patient had a prolonged history of gradually worsening respiratory symptoms, ultimately progressing to complete bronchial obstruction and systemic disease, reflecting the insidious yet aggressive nature of ALK-rearranged NSCLC. Although these clinical features are often observed in advanced adenocarcinoma, the presence of an uncommon driver mutation (STRN-ALK) underscores the need for molecular profiling to optimize individualized treatments for patients.^9,10

The STRN-ALK fusion incorporates the coiled-coil domain of STRN, resulting in constitutive dimerization and activation of the ALK tyrosine kinase domain. Nonclassical fusions exhibit distinct biological behavior from canonical EML4-ALK fusions, including different responses to ALK inhibitors and resistance profiles.^5,6 Some studies suggest that STRN-ALK fusions may be less responsive to first-generation inhibitors (eg, crizotinib) due to altered intracellular localization or domain structure, which could affect drug affinity.^4,6

Although most ALK-positive NSCLC literature focuses on classical fusions, such as EML4-ALK, biologic characterization of rare nonclassical variants, such as STRN-ALK, has received less attention with respect to resistance and treatment response.¹¹ Recent evidence suggests that second-generation ALK inhibitors (eg, ceritinib and ensartinib) could be more effective in rare subtypes.⁷ This report supports the growing clinical awareness of the need for sophisticated next-generation sequencing to aid oncological decision-making in such intricate molecular environments.¹²

The notably strong efficacy of ensartinib in this patient is consistent with published data from recent clinical trials, which demonstrate improved CNS penetration, higher intracranial objective response rates (ORRs), and longer progression-free survival (PFS) than with crizotinib. Notably, in the phase 3 eXalt3 trial (NCT02767804), ensartinib significantly prolonged median progression-free survival compared with crizotinib (25.8 vs 12.7 months) and achieved a higher confirmed intracranial response rate among patients with measurable brain metastases at baseline (63.6% vs 21.1%).¹¹Given the baseline CNS involvement, this patient maintained radiologic stability of the brain lesions through February 2023 and sustained extracranial tumor control through May 2025. These long-term findings in the present case are consistent with the documented CNS activity of second-generation ALK inhibitors, including ensartinib.^11,19

This case demonstrates the durability and tolerability of ensartinib maintenance therapy for more than 3 years and suggests its potential efficacy in rare ALK fusion variants. Sustained disease control without recurrence, complete resolution of GGOs, and durable intracranial stability further support the potential for long-term systemic and CNS disease control with ensartinib.

There is a growing literature on targeted therapies for rare ALK fusion variants. This report supports continued emphasis on individualized treatment approaches informed by molecular characterization. This patient case provides real-world evidence of durable CNS and systemic disease control with ensartinib in the STRN-ALK fusion context, one of the ALK fusion subtypes with minimal published outcomes. We emphasize the importance of early and accurate recognition of nonclassical gene fusions to support treatment and prognosis in complex NSCLC cases. Future clinical trials and prospective registries should address the growing focus on rare ALK fusion subtypes, establishing the role of prognostic markers and treatment response.^9-14,19-22

Conclusion

This case demonstrates long-term disease control with ensartinib in a patient with STRN-ALK fusion-positive lung adenocarcinoma with brain metastases. The patient had a durable systemic and intracranial response for more than 3 years with good tolerability. Our findings reinforce the clinical relevance of comprehensive molecular testing to identify rare ALK fusion variants and facilitate the identification of efficacious targeted therapies. Although data on STRN-ALK fusions are limited, this case report provides real-world evidence for the potential utility of ensartinib in these rare cases.

References

1. Lin JJ, Gainor JF. Current opportunities and challenges in ALK-positive lung cancer. Transl Lung Cancer Res. 2024;13(1):1-4. doi:10.21037/tlcr-2023-4
2. Mok T, Camidge DR, Gadgeel SM, et al. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Ann Oncol. 2020;31(8):1056-1064. doi:10.1016/j.annonc.2020.04.478
3. Desai A, Lovly CM. Strategies to overcome resistance to ALK inhibitors in non-small cell lung cancer: a narrative review. Transl Lung Cancer Res. 2023;12(3):615-628. doi:10.21037/tlcr-22-708
4. Yi F, Fang Z, Liang H, et al. Diagnostic accuracy of blood eosinophils in comparison to other common biomarkers for identifying sputum eosinophilia in patients with chronic cough. World Allergy Organ J. 2023;16(9):100819. doi:10.1016/j.waojou.2023.100819
5. Ou SHI, Zhu VW, Nagasaka M. Catalog of 5’ fusion partners in ALK-positive NSCLC circa 2020. JTO Clin Res Rep. 2020;1(1):100015. doi:10.1016/j.jtocrr.2020.100015
6. Smolle E, Taucher V, Lindenmann J, Jost PJ, Pichler M. Current knowledge about mechanisms of drug resistance against ALK inhibitors in non-small cell lung cancer. Cancers (Basel). 2021;13(4):699. doi:10.3390/cancers13040699
7. Zhang L, Xiao P, Meng F, Zhong D. STRN-ALK fusion in lung adenocarcinoma with brain metastasis responded well to ensartinib: A case report. Curr Oncol. 2022;29(10):6749-6753. doi:10.3390/curroncol29100530
8. Metro G, Lunardi G, Bennati C, et al. Alectinib’s activity against CNS metastases from ALK-positive non-small cell lung cancer: a single institution case series. J Neurooncol. 2016;129(2):355-361. doi:10.1007/s11060-016-2184-z
9. Penault-Llorca F, Socinski MA. Emerging molecular testing paradigms in non-small cell lung cancer management-current perspectives and recommendations. Oncologist. 2025;30(3):oyae357. doi:10.1093/oncolo/oyae357
10. Yuan X, Wang Y, Yang M, et al. A retrospective study of ensartinib-treated ALK-positive locally advanced or metastatic NSCLC patients in China. Lung Cancer Manag. 2023;12(4):LMT61. doi:10.2217/lmt-2023-0005
11. Horn L, Wang Z, Wu G, et al. Ensartinib vs crizotinib for patients with anaplastic lymphoma kinase-positive non-small cell lung cancer: a randomized clinical trial. JAMA Oncol. 2021;7(11):1617-1625. doi:10.1001/jamaoncol.2021.3523
12. Ma Y, Pan H, Liu Y, et al. Ensartinib in advanced ALK-positive non-small cell lung cancer: a multicenter, open-label, two-staged, phase 1 trial. J Thorac Dis. 2022;14(12):4751-4762. doi:10.21037/jtd-22-1606
13. Lin JJ, Horan JC, Tangpeerachaikul A, et al. NVL-655 is a selective and brain-penetrant inhibitor of diverse ALK-mutant oncoproteins, including lorlatinib-resistant compound mutations. Cancer Discov. 2024;14(12):2367-2386. doi:10.1158/2159-8290.CD-24-0231
14. Kong C, Yin X, Zou J, Ma C, Liu K. The application of different machine learning models based on PET/CT images and EGFR in predicting brain metastasis of adenocarcinoma of the lung. BMC Cancer. 2024;24(1):454. doi:10.1186/s12885-024-12158-0
15. Poei D, Ali S, Ye S, Hsu R. ALK inhibitors in cancer: mechanisms of resistance and therapeutic management strategies. Cancer Drug Resist. 2024;7:20. doi:10.20517/cdr.2024.25
16. Murray BW, Zhai D, Deng W, et al. TPX-0131, a potent CNS-penetrant, next-generation Inhibitor of wild-type ALK and ALK-resistant mutations. Mol Cancer Ther. 2021;20(9):1499-1507. doi:10.1158/1535-7163.MCT-21-0221
17. Pan Y, Deng C, Qiu Z, Cao C, Wu F. The resistance mechanisms and treatment strategies for ALK-rearranged non-small cell lung cancer. Front Oncol. 2021;11:713530. doi:10.3389/fonc.2021.713530
18. Bordi P, Tiseo M, Rofi E, et al. Detection of ALK and KRAS mutations in circulating tumor DNA of patients with advanced ALK-positive NSCLC with disease progression during crizotinib treatment. Clin Lung Cancer. 2017;18(6):692-697. doi:10.1016/j.cllc.2017.04.013
19. Nelson TA, Wang N. Targeting lung cancer brain metastases: a narrative review of emerging insights for anaplastic lymphoma kinase (ALK)-positive disease. Transl Lung Cancer Res. 2023;12(2):379-392. doi:10.21037/tlcr-22-638
20. Chen MF, Chaft JE. Early-stage anaplastic lymphoma kinase (ALK)-positive lung cancer: a narrative review. Transl Lung Cancer Res. 2023;12(2):337-345. doi:10.21037/tlcr-22-631
21. Vavalà T, Novello S. Alectinib in the treatment of ALK-positive non-small cell lung cancer: an update on its properties, efficacy, safety and place in therapy. Ther Adv Med Oncol. 2018;10:1758835918789364. doi:10.1177/1758835918789364
22. Zhou C, Zhang X, Yan X, et al. Impact of lung adenocarcinoma subtypes on survival and timing of brain metastases. Front Oncol. 2024;14:1433505. doi:10.3389/fonc.2024.1433505