To the Editor: Anaplastic lymphoma kinase (ALK) fusion oncogene occurs in 3% to 7% of patients with non-small cell lung cancer (NSCLC), with the most common companion being echinoderm microtubule-associated protein-like 4.[1] Ceritinib is an oral, small-molecule, adenosine triphosphate (ATP)-competitive drug, and tyrosine kinase inhibitor of ALK (ALK-TKI) that is 20 times more potent than crizotinib in enzymological tests.[2] To date, there are few prospective clinical trials of neoadjuvant targeted therapy in patients with ALK-positive locally advanced NSCLC. Therefore, the value of ceritinib in ALK-positive stage IIIA (N2) NSCLC is unknown. In this study, we reported the efficiency of ceritinib used as initial neoadjuvant targeted therapy in patients with ALK-positive IIIA (N2) NSCLC.

A 48-year-old woman was admitted to our hospital with a chief complaint of cough for over four months in April 2021. She did not have a history of smoking or family history. Full body positron emission tomography-computed tomography (PET-CT) showed a mass in the lower lobe dorsal segment of right lung extending to the oblique fissure. In addition, the right hilar and mediastinal (4R area) lymph nodes were enlarged with increased metabolism [Figure 1A]. Chest CT also showed a right lower lobe mass with enlarged hilar and mediastinal lymph nodes [Figure 1B]. Bronchoscopy showed enlargement of the 11R (right interlobular lymph node) and 4R (right lower paratracheal lymph node) areas of lymph nodes. Biopsy reported positive cytokeratin (CK) 7, thyroid transcription factor, Napsin A [Figure 1F], and cytokeratin 5/6 as well as ALK Ventana (+) [Figure 1F], CK (pan) (+), and Ki-67 (+, approximately 5%). The mass was considered to be malignant tumor with metastasis to the lymph nodes. No obvious metastasis was found in other organs. The amplification refractory mutation system revealed ALK-positivity. The final diagnosis was lung adenocarcinoma with clinical stage cT2aN2M0, IIIA (eighth edition, Union for International Cancer Control/American Joint Committee on Cancer).

Figure 1:

(A) PET-CT and bronchoscope examination for a patient in April, 2021. (B) CT examination for the patient in April, 2021. (C) CT examination for the patient in June, 2021. (D) CT examination for the patient in January, 2022. (E) PET-CT examination for the patient in January, 2022. (F) Hematoxylin and eosin (HE) staining before and after operation and immunohistochemistry staining on Napsin A, and ALK before neoadjuvant ceritinib treatment (original magnification 200 ×). The red arrow represented a mass in the right lower lobe. The blue arrow showed enlargement of the 11R (right interlobular lymph node). The yellow arrow showed enlargement of 4R (right lower paratracheal lymph node). ALK: Anaplastic lymphoma kinase; CT: Computed tomography; HE: Hematoxylin and eosin; PET-CT: Positron emission tomography-computed tomography.

A thoracic surgeon was consulted, and it was determined that N2 NSCLC with mediastinal lymph node metastases would not achieve a radical tumor resection (R0 resection). Therefore, a dose of 450 mg of ceritinib was orally administered once daily for 28 days per cycle in May 2021. Chest CT after one month (June 2021) of commencing treatment showed significant partial response changes compared to the previous CT [Figure 1C]. The clinical stage of this patient turned to cT1aN2M0. At this time, we proposed video-assisted thoracic surgery (VATS) or radical radiotherapy, but the patient refused, thus necessitating continued ceritinib treatment. Therefore, the ceritinib was continued for this patient with grade I nausea and grade I liver insufficiency. The CT results (January 2022) were similar to those obtained in June 2021 [Figure 1D]. Another PET-CT was performed in January 2022 and a significant decrease in the standardized uptake value (SUV) was reported in the primary tumor and lymph node metastasis compared to that observed in the previous scan. Besides, the fluorodeoxyglucose metabolism was also reduced in January 2022, considering the tumor activity was basically inhibited [Figure 1E]. Thus, the patient was considered down-staged to clinical complete response (CR) after 7 cycles of ceritinib treatment.

In January 2022, VATS with right lung cancer radical resection (right lower lobe resection plus lymph node dissection) was performed based on the results of a multidisciplinary treatment discussion. Postoperative pathology showed no tumor residue. No metastasis was found in the lymph nodes and no cancer tissue was found in the resection margin (pathological analysis showed CR) [Figure 1F]. Considering the lymph node was dissected completely, postoperative radiotherapy was not performed.

Although there are many controversies regarding the treatment of stage IIIA (N2) NSCLC, neoadjuvant therapy is recommended as early as possible in patients in whom surgical resection is possible, mainly based on the following points: (1) improving patients’ treatment compliance and increasing probability of surgery; (2) increasing likelihood of complete surgical resection; (3) reducing the potential of clinical metastasis; and (4) patient response to neoadjuvant chemotherapy can reduce tumor staging. With respect to the IIIA (N2) ALK-positive NSCLC, there is no available information on the role of ALK-TKIs in neoadjuvant clinical trials. A small retrospective case cohort (n = 11) reported the efficacy of neoadjuvant crizotinib (250 mg twice daily for a median duration of 30 days) in patients with pathologically confirmed N2 ALK-positive NSCLC. 18.2% (2/11) of patients exhibited pathological CR.[3] Another case reported that one patient with stage IIIA (N2) ALK-positive NSCLC was treated with crizotinib as neoadjuvant and adjuvant targeted therapy combined with surgery, and the overall survival was 68 months.[4] Zhang et al[5] first reported a clinically successful case involving neoadjuvant alectinib, where the patient achieved both radiologic and pathologic regressions without apparent adverse events. The role of ceritinib as neoadjuvant targeted therapy in IIIA NSCLC patients was not performed in clinical trials. In this study, we reported ceritinib used in neoadjuvant targeted therapy as the first-line treatment, and the patient acquired surgical radical resection with pathological CR.

Although this patient obtained a pathological CR from the neoadjuvant targeted therapy with ceritinib, our results are limited to case reports. One may question the optimal duration of treatment and the optimal drug selection for neoadjuvant ALK-TKI, or whether longer exposure to targeted therapies may translate into higher clinical efficacy without compromising therapeutic interventions. To obtain more optimized results, we need to conduct large-scale randomized controlled trials to investigate the role of ALK-TKIs in the neoadjuvant therapy.

In conclusion, this study reported a case of stage IIIA-N2 ALK-positive NSCLC patient treated with ceritinib which illustrated the feasibility and remarkable clinical efficacy of ceritinib as neoadjuvant targeted therapy. The patient showed a remarkable decline in radiographic staging after ceritinib neoadjuvant therapy, which is necessary for complete resection. This treatment model for stage IIIA ALK-positive NSCLC urgently needs to be further examined; therefore, additional clinical trials are needed to evaluate the role of ceritinib in stage IIIA ALK-positive NSCLC.

Declaration of patient consent

The authors certify that they have obtained consent forms from the patient. The consent form included permission to report the images and other clinical information in the journal. The patient understands that her name and initials will not be published, and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.

Funding

This work was supported by a grant from the Natural Science Foundation of Zhejiang Province (No. LGF22H160005).

Conflicts of interest

None.

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