Rapid Postoperative Relapse in ALK-Positive Locally Advanced NSCLC Patient with Complete Pathological Response to Neoadjuvant Crizotinib
Authors: Chao Zhang, Yi-Long Wu, Wen-Zhao Zhong
Journal: Journal of Thoracic Oncology (2019)

In the April 2019 issue of the Journal of Thoracic Oncology, we reported cases of ALK-positive locally advanced NSCLC from two institutions in which neoadjuvant crizotinib showed quite acceptable efficacy and tolerability.1Zhang C. Li S.L. Nie Q. et al.Neoadjuvant crizotinib in resectable locally advanced non-small cell lung cancer with ALK rearrangement.J Thorac Oncol. 2019; 14: 726-731Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar Herein, we further describe the pathological evaluation and dynamic detection of circulating tumor DNA (ctDNA) in one patient receiving neoadjuvant crizotinib. Figure 1 summarizes the details of the entire therapeutic process. The patient is a 34-year-old male patient in whom lung adenocarcinoma and metastatic mediastinal lymph nodes were diagnosed and who received neoadjuvant crizotinib for 2 months. No apparent adverse event was observed during neoadjuvant treatment. Complete surgical resection was successfully performed. Pathological evaluation showed a complete pathological response for this patient. The patient received adjuvant crizotinib for 3.6 months and discontinued treatment because of a personal issue. Postoperative dynamic blood samples were collected at 1, 4, and 6 months after surgery, and no positive findings were obtained until the last blood sample, which showed an ALK receptor tyrosine kinase gene (ALK) T1151M missense mutation (0.3%) along with a sensitive echinoderm microtubule associated protein like 4 gene (EML4)-ALK fusion (0.6%). Meanwhile, positron emission computed tomography was performed. We found multiple enlarged lymph nodes and a suspected hilar lesion with a significantly increased standardized uptake value. No evidence of malignancies in other sites was found. The patient refused to undergo a biopsy. Considering the empty window of crizotinib and lack of relevant evidence regarding T1151M mutations, we suggested using crizotinib in the first-line setting. After 3 months' treatment with crizotinib, a computed tomography scan showed major tumor regression (–80%); the patient continues taking crizotinib. So far, the efficacy of neoadjuvant chemotherapy in NSCLC is still limited, and deciding how to manage sequential treatment after surgery remains challenging. Ng and Camidge made an inspirational comment based on the results of CTONG 1104 (ADJUVANT), suggesting sequential therapeutic classification regarding ctDNA/molecular residue disease.2Ng T.L. Camidge D.R. Lung cancer's real adjuvant EGFR targeted therapy questions.Lancet Oncol. 2018; 19: 15-17Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Last year, Zhong et al. presented the results of CTONG 1103 (EMERGING) (2018 ESMO meeting), showing that a neoadjuvant plus adjuvant EGFR tyrosine kinase inhibitor may be a better therapeutic modality than a chemotherapy regimen in locally advanced NSCLC. In this subsequent report, it seems that neither complete pathological response nor ctDNA may be an effective predictor for locally advanced NSCLC harboring ALK rearrangement. The biological nature of the driver mutation itself could be one of the reasons leading to an impaired clinical outcome.3Chaft J.E. Dagogo-Jack I. Santini F.C. et al.Clinical outcomes of patients with resected, early-stage ALK-positive lung cancer.Lung Cancer. 2018; 122: 67-71Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar The other reason may be lower efficacy of crizotinib compared with that of next-generation ALK tyrosine kinase inhibitors.4Hirsch F.R. Scagliotti G.V. Mulshine J.L. et al.Lung cancer: current therapies and new targeted treatments.Lancet. 2017; 389: 299-311Abstract Full Text Full Text PDF PubMed Scopus (1737) Google Scholar Additionally, the acquired mutation ALK T1151M, which has been reported to be sensitive only to ensartinib,5Horn L. Infante J.R. Reckamp K.L. et al.Ensartinib (X-396) in ALK-positive non-small cell lung cancer: results from a first-in-human phase I/II, multicenter study.Clin Cancer Res. 2018; 24: 2771-2779Crossref PubMed Scopus (110) Google Scholar was first reported as being sensitive to crizotinib clinically. Considering the significantly lower incidence of ALK fusion than of EGFR mutation, future trials designed to evaluate potential biomarkers for perioperative treatment should definitely be cautious about the clinical discrepancy caused by different molecules. Neoadjuvant Crizotinib in Resectable Locally Advanced Non–Small Cell Lung Cancer with ALK RearrangementJournal of Thoracic OncologyVol. 14Issue 4PreviewLocally advanced NSCLC is one of the most heterogeneous conditions, with multidimensional treatments involved. Neoadjuvant therapy had been commonly considered an optimal management strategy for patients with operable locally advanced. However, as targeted therapy has been widely applied in advanced NSCLC, neoadjuvant targeted therapy has remained poorly explored in locally advanced disease. Full-Text PDF Open Archive