Case Report: A rare case of non-small cell lung cancer with STRN-ALK fusion in a patient in very poor condition treated with first-line ensartinib

Several cases of STRN-ALK fusion have been reported, and some anaplastic lymphoma kinase (ALK) inhibitors have been shown to be effective for treatment. Nevertheless, no cases of COVID-19 leading to heart failure and respiratory failure have been reported in people older than 70 years treated with ALK inhibitors. The present case report describes a 70-year-old patient with usual chronic obstructive pulmonary disease, diabetes, depression, and carotid plaque disease. Next-generation sequencing of tissue obtained by puncture biopsy revealed a STRN-ALK mutation accompanied by a TP53 mutation. The patient was treated with ensartinib and developed COVID-19 leading to heart failure and respiratory failure; nevertheless, he had a good clinical outcome and exhibited high treatment tolerability.


Introduction
The overall incidence of non-small cell lung cancer (NSCLC) is high in patients of all ages (1).Approximately 1 to 8 million cases of lung cancer are newly diagnosed each year, and 1 to 6 million deaths are related to this disease.Lung cancer is the leading cause of cancer-related death globally (2).China has the highest lung cancer-related mortality rate, with NSCLC accounting for the majority of cases (3).In 3% to 7% of patients with NSCLC, chromosomal rearrangements involving anaplastic lymphoma kinase (ALK) have been identified as oncogenic factors (4,5).The clinical outcomes and prognosis of patients treated with tyrosine kinase inhibitors (TKIs) are better than those of patients treated with conventional chemotherapy drugs (6).
With the recent development of diagnostic methods, nextgeneration sequencing (NGS) to detect ALK fusions has become more helpful in driving treatment decisions (7).Additionally, some rare ALK fusions have been detected in the clinical setting (8).This report describes a patient with STRN-ALK fusion who could not tolerate surgery and received ensartinib as first-line treatment.He thereafter developed COVID-19 (omicron variant) but nevertheless demonstrated good tolerability and clinical efficacy.

Case report
A 70-year-old man was admitted to our hospital because of an acute attack of chronic obstructive pulmonary disease (COPD) (recurrent cough and sputum for more than 5 years, aggravated by recurrence for 1 week).The patient had type 2 diabetes mellitusinternal carotid artery plaque and history of depression.The patient had smoked an average of 30 cigarettes a day for 50 years.Physical examination only found mild edema of both lower extremities.
Computed tomography (CT) of his chest on 29 September 2022 showed a mass (4.2 × 3.8 cm) in his right upper lung with cavity formation.Emphysema and microscopic nodules were present in the left upper lung and right lower lung (Figure 1).
Considering the patient's underlying concomitant diseases and poor PS score, we prescribed ensartinib at a starting dosage of 150 mg/day.One month later, repeat CT of his chest showed that the tumor was smaller and that the treatment had resulted in stable disease.The patient experienced no intolerance even after increasing the dosage to 200 mg/day.Two months later, however, he became infected with the omicron variant of SARS-CoV-2, resulting in type 1 respiratory failure and heart failure (pH, 7.326; PaCO 2 , 54 mmHg; PaO 2 , 46.6 mmHg; NT-proBNP, 778.8 ng/L).We carried out targeted treatment and continued the ensartinib.At follow-up on 13 April 2023, the tumor was stable but had slightly increased in size (5.3 × 5.5 cm) (Figure 1).We thereafter recommended increasing the dosage of ensartinib to 225 mg/day, and no additional adverse effects were noted at the subsequent telephone follow-up.

Discussion
ALK is a member of the insulin receptor family of receptor tyrosine kinases, which are expressed in different types of cancers (9).In normal cells, ALK sits on cell membranes and interacts with growth factors.EML4 is the most common ALK rearrangement in NSCLC.With advances in clinical genetic testing technology, more genes that are coexpressed with ALK have been identified (6,10,11).STRN-ALK fusion is a rare type of ALK rearrangement in NSCLC (12).
The STRN gene is located on chromosome 2 and encodes a protein with a coiled-coil domain that leads to constitutive activation of ALK via dimerization (8).Treatment options for patients who have NSCLC with rare ALK fusion often rely on past case reports.Many different ALK inhibitors have been reported to be effective for treating STRN-ALK, including crizotinib, ceritinib, ensartinib, and alectinib (8,(12)(13)(14).
We retrieved 11 reports describing cases of STRN-ALK in PubMed (Table 1).At the time of identification of the STRN-ALK mutation, gefitinib had previously been used in two cases, crizotinib in two cases, and alectinib in two cases.Of all 11 patients, 9 were male, at least 7 were Chinese, and 8 were nonsmokers.Five patients had right-sided lesions, five had left-sided lesions, and one was not described.Adenocarcinoma was present in 10 patients, and the pathologic type was not described in 1 patient.Pulmonary embolism occurred in two patients, and bone metastases were present in at least six.Most of the patients underwent NGS, mostly using tissue for testing.The STRN-ALK mutation rate ranged from 0.04% to 27.11% (15)(16)(17)(18).
Various other mutations were present in combination with STRN-ALK, including EGFR exon 19 deletion, TP53, and PIK3CA.First-line crizotinib was used in 5 of the 11 patients, with maintenance of efficacy ranging from 5 to 18 months.First-line alectinib was used in four patients, with maintenance of efficacy ranging from 5 to 17 months.One patient treated with first-line ceritinib achieved maintenance of efficacy of 26 months, and one patient treated with chemotherapy showed no effect.Three patients were treated with second-line therapy:  Ensartinib is a second-generation ALK-TKI.In the phase I/II eXalt2 trial, ensartinib demonstrated a high response rate in patients with ALK fusions resistant to prior crizotinib treatment (22).Use of ensartinib to treat NSCLC exhibiting STRN-ALK fusion has demonstrated good clinical efficacy in patients with crizotinib-resistant relapsed NSCLC (12).Our patient's lung function was so poor that he could not tolerate surgical treatment; he also had many concomitant diseases and a low PS score.
Considering our patient's advanced age and poor underlying condition, we used a dose creep of ensartinib and achieved a therapeutic response at the 150 mg dose.COVID-19 subsequently resulted in respiratory failure combined with heart failure, and ensartinib was continued at 200 mg/day with some clinical success.Notably, this is the oldest reported patient with COVID-19 who had STRN-ALK fusion and was treated by first-line ensartinib.Furthermore, the patient showed coalteration of TP53.A previous study reported that TP53 mutations disrupt the tumor suppressor function of the p53 protein and can be detected in almost all types of cancer, including ALK-positive NSCLC, in which TP53 mutations are the most common genomic alteration detected.Patients with this mutation generally have poor progression-free survival (23).In four previously reported cases of STRN-ALK treated with ALK-TKIs, the sustained response time ranged from 5 to 11 months (5, 6, 7, and 11 months, respectively) (13,14,(19)(20)(21).After 13 April 2023, we increased the dose of ensartinib to 225 mg/ day in our patient with the goal of achieving a good long-term clinical outcome.

Conclusion
This case provides valuable clinical evidence of the response to ensartinib as a first-line treatment for patients with NSCLC exhibiting rare STRN-ALK fusions.Our patient had a very poor underlying condition, advanced age, and type 1 respiratory failure and heart decompensation due to COVID-19; nevertheless, he was still able to tolerate treatment with ensartinib.The presence of the TP53 mutation may be associated with poor clinic outcomes.