Disease Flare After Treatment Discontinuation in a Patient With EML4-ALK Lung Cancer and Acquired Resistance to Crizotinib
Authors: Oana Pop, Augustin Pirvu, Anne-Claire Toffart, Denis Moro-Sibilot
Journal: Journal of Thoracic Oncology (2012)

In January 2010, a 50-year-old woman was found to have left cervical, left supraclavicular, and bulky mediastinal lymph nodes associated with an upper left lung mass measuring 3 cm. The biopsy of a supraclavicular node showed a poorly differentiated adenocarcinoma. The patient was treated with six cycles of a pemetrexed-cisplatin and bevacizumab combination followed by a bevacizumab maintenance treatment until August 2010, with partial response to treatment. At the time of progression, the histological and molecular characteristics of the tumor were reviewed and fluorescent in situ hybridization analysis demonstrated an echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement. The patient was randomized in a docetaxel part of a trial comparing chemotherapy with crizotinib. A partial response was achieved after 6 weeks and lasted for 3 months. Thereafter, the disease progressed with the appearance of left cervical nodes. The patient was switched to crizotinib treatment with a quick dramatic response. After 6 weeks of treatment, we observed a complete disappearance of cervical lymph nodes and a near-complete response on the computed tomography scan of the chest, with a dramatic improvement of quality of life (Fig. 1A and B). After 5.5 months of treatment, the disease relapsed with the reappearance of a left supraclavicular lymph node, mediastinal nodes, and brain metastases. Crizotinib treatment was stopped in May 2011. Fifteen days later, the patient was referred to the "emergency room" with a left-sided neurological deficit and a massive enlargement of cervical lymph nodes. A body computed tomography scan disclosed cerebral edema and growth of brain metastasis associated with chest and abdominal massive progression of the tumor (Fig. 2A and B). The diagnosis of the disease flare was advocated and a brain radiotherapy followed by a new line of chemotherapy was initiated.FIGURE 2A, Chest CT scan performed 15 days after stopping crizotinib treatment showing flare- up disease with dramatic progression of left lung tumor (arrow); (B), Abdominal CT scan showing flare-up disease with the appearance of three liver metastasis (arrows). CT scan performed on June 14, 2011, 15 days after stopping crizotinib treatment. CT, computed tomography.View Large Image Figure ViewerDownload (PPT) Acquired resistance to tyrosine kinase inhibitors (TKIs) may occur in patients who initially respond to TKI treatment. This resistance was associated with the development of a secondary T790M mutation in the endothelial growth factor receptor (EGFR) setting. Currently, six different mutations within the ALK tyrosine kinase domain that confer resistance to multiple ALK inhibitors have been identified.1Inamura K Takeuchi K Togashi Y et al.EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers.J Thorac Oncol. 2008; 3: 13-17Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar, 2Koivunen JP Mermel C Zejnullahu K et al.EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer.Clin Cancer Res. 2008; 14: 4275-4283Crossref PubMed Scopus (833) Google Scholar, 3Chaft JE Oxnard GR Sima CS Kris MG Miller VA Riely GJ Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design.Clin Cancer Res. 2011; 17: 6298-6303Crossref PubMed Scopus (351) Google Scholar, 4Soda M Takada S Takeuchi K et al.A mouse model for EML4-ALK-positive lung cancer.Proc Natl Acad Sci USA. 2008; 105: 19893-19897Crossref PubMed Scopus (452) Google Scholar, 5Shaw AT Yeap BY Solomon BJ et al.Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis.Lancet Oncol. 2011; 12: 1004-1012Abstract Full Text Full Text PDF PubMed Scopus (782) Google Scholar Not every cell is resistant, and if the kinase inhibitor is stopped, growth is accelerated in the sensitive clone, resulting in rapid progression. This mechanism has been described previously in EGFR-mutant lung cancers that have developed acquired resistance to EGFR TKI, and we believe that the current clinical case suggests that tumor flare may also occur in EML4-ALK tumors resistant to crizotinib. In patients with acquired clinical resistance to EGFR TKI therapy, a 23% flare rate during the EGFR TKI washout period has been recently reported. This tumor flare was defined as hospitalization or death attributable to disease progression. Chaft et al.3Chaft JE Oxnard GR Sima CS Kris MG Miller VA Riely GJ Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design.Clin Cancer Res. 2011; 17: 6298-6303Crossref PubMed Scopus (351) Google Scholar characterized the flare as association of a shorter time to progression on initial TKI, preceding symptoms of disease progression and presence of central nervous system and pleural disease. Our case corresponds to Chaft's description of flare disease after crizotinib treatment cessation. The possibility of a tumor flare should be taken into account in cases of EML4-ALK tumors. Despite progressive disease, the kinase inhibitor might be continued until a new treatment is initiated.