ALK-Rearranged Squamous Cell Carcinoma of the Lung Treated with Two Lines of ALK Inhibitors

Abstract

In March 2014 a 51-year-old male nonsmoker received the diagnosis of locally advanced squamous cell carcinoma (SCC) of the left lung, grade 2, cT2cN2cM0, stage IIIA. The patient underwent three cycles of neoadjuvant chemotherapy (cisplatin, 75 mg/m2/d on day 1 of a 21-day cycle, and gemcitabine, 1000 mg/m2/d on days 1 and 8 of a 21-day cycle) with a partial response; as a result, he underwent radical surgery (pneumonectomy and lymphadenectomy) in June 2014. The histologic type was confirmed as SCC, grade 3. The final stage after surgery was defined as ypT1ypN1. In November 2015 the patient relapsed (in the contralateral lung and mediastinal lymph node). Two other cycles of chemotherapy (cisplatin, 75 mg/m2/d on day 1 of a 21-day cycle, and gemcitabine, 1000 mg/m2/d on days 1 and 8 of a 21-day cycle) were administered but the patient progressed. In consideration of the fact that the patient had no history of smoking, testing for EGFR and anaplastic lymphoma kinase gene (ALK) was performed. The tumor was determined to be EGFR wild type, but it included the fusion gene echinoderm microtubule associated protein like 4 gene (EML4)–ALK rearrangement. In consideration of the molecular results, a second-line therapy with first-generation ALK inhibitor (crizotinib, 250 mg twice a day) was administered. The patient achieved a partial response after four cycles of crizotinib (February–June 2015 [Fig. 1]), but then he progressed (in bone and brain) after eight cycles in October 2015. He received stereotactic brain radiotherapy and bisphosphonates. In consideration of the oligoprogression of the disease, crizotinib was continued. In December 2015 the patient progressed in the contralateral lung and bones; brain metastasis were stable after radiotherapy. So a third-line therapy with a second-generation ALK inhibitor (ceritinib, 750 mg daily) was administered beginning in February 2016. In March 2016 a computed tomography scan (performed after 2 months of therapy) showed good partial response of the target thoracic lesions (see Figs. 2 and 3), progression disease of the bone metastasis, and stable brain disease. In consideration of the mixed response, ceritinib was continued. The patient died of sepsis in June 2016.Figure 3Another target lesion of the right lung before (A) and after (B) two cycles of ceritinib.View Large Image Figure ViewerDownload Hi-res image Download (PPT) ALK rearrangement is identified in approximately 5% of patients affected by lung adenocarcinoma and allows treating patients with anti-ALK targeted therapy. ALK rearrangement has been associated with several clinicopathological characteristics: never-smoker or light smoker, younger age at diagnosis, adenocarcinoma histologic type, signet ring cells, and mutual exclusivity from other major driver genes.1Shaw A.T. Yeap B.Y. Mino-Knudson M. Digumarthy S.R. et al.Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.J Clin Oncol. 2009; 27: 4247-4253Crossref PubMed Scopus (1641) Google Scholar ALK-rearranged SCCs are extremely rare tumors; very few cases of ALK-rearranged SCC tumors that responded to crizotinib in first- or second-line therapy are described in the literature.2Yamamoto Y. Kodama K. Maniwa T. Takeda M. Kishima H. Anaplastic lymphoma kinase-positive squamous cell carcinoma of the lung: a case report.Mol Clin Oncol. 2016; 5: 61-63PubMed Google Scholar, 3Mikes R.E. Jordan F. Hutarew G. Studnicka M. First line crizotinib in anaplastic lymphoma kinase (ALK) rearranged squamous cell lung cancer.Lung Cancer. 2015; 90: 614-616Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 4Wang Q. He Y. Yang X. Wang Y. Xiao H. Extraordinary response to crizotinib in a woman with squamous cell lung cancer after two courses of failed chemotherapy.BMC Pulm Med. 2014; 14: 83Crossref PubMed Scopus (16) Google Scholar, 5Wang W. Song Z. Zhang Y. Response to crizotinib in a squamous cell lung carcinoma patient harbouring echinoderm microtubule-associated protein-like 4-anaplastic lymphoma translocation: a case report.Thorac Cancer. 2016; 7: 355-357Crossref PubMed Scopus (14) Google Scholar So far, the present case is the first report of a patient with SCC harboring EML4-ALK rearrangement who received two lines of therapy with ALK inhibitors with partial response. Because of the lack of data available in the literature and the rarity of this condition, nowadays the molecular analysis of ALK status in SCC is not routinely recommended. Further studies are required.