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Post-crizotinib management of effective ceritinib therapy in a patient with ALK-positive non-small cell lung cancer
© The Author(s). 2016
Received: 4 April 2016
Accepted: 27 July 2016
Published: 2 August 2016
We report the re-biopsied diagnosis of a patient with anaplastic lymphoma receptor tyrosine kinase (ALK)-positive lung adenocarcinoma successfully treated with ceritinib 450 mg/day taken with food following disease progression and gastrointestinal intolerance to crizotinib.
A 74-year old female patient initially diagnosed with ALK-negative lung adenocarcinoma responded to initial standard chemotherapy. The patient was subsequently re-tested by next generation sequencing (NGS) and found to have ALK EIF2AK3-ALK fusion, and responded to crizotinib, but ultimately progressed and showed intolerance to this ALK inhibitor. She was then successfully treated with ceritinib 450 mg/day taken with food, has not suffered from any further gastrointestinal side-effects, and remains on ceritinib treatment after 12 months.
Second-line ceritinib treatment, when administered at 450 mg/day with food, is both well tolerated and efficacious in a patient with previously treated lung adenocarcinoma who had discontinued crizotinib due to disease progression and gastrointestinal adverse effects (AEs).
The treatment of non-small cell lung cancer (NSCLC) has now changed dramatically in recent years and is no longer an unspecific approach based on platinum doublet chemotherapy when patients are molecularly tested and diagnosed with actionable mutations. For example, anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangement occurs in around 5 % of NSCLC cases , and is detected by several methods, including fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), quantitative polymerase chain reaction (qPCR), next generation sequencing (NGS), and reverse transcription polymerase chain reaction of cDNA (RT-PCR) . Out of those methods, FISH is the gold standard in detecting ALK rearrangement in NSCLC due to its detection of rearrangements regardless of what the variant and fusion partner, use of archival formalin-fixed paraffin embedded tissue, low tumor cell requirement (~100 tumor cells), clinical validation, and its FDA approval for clinical applications . However, FISH is costly, does not identify specific rearrangements, may miss rare rearrangements, and requires specialized training . Next-generation sequencing (NGS) is another method in detecting ALK rearrangements and refers to a variety of platforms that parallel sequences multiple analytes simultaneously; NGS has a relatively quick turnaround, low cost, and high coverage . In one case, Ali et al. identified 31 ALK positive patients who had both NGS and FISH testing done . Out of those 31 patients, 11 (35 %) were previously ALK FISH negative, indicating that NGS holds value in ALK testing in comparison with FISH . Crizotinib (Xalkori®) is approved as first-line treatment when ALK-rearrangement as detected by FISH . However, despite initial response rates of 60 % and a median PFS of 8–10 months [1, 6], patients tend to relapse after 1–2 years, often limiting its long-term use [7, 8]. This relapse is often due to developed resistance to crizotinib where in approximately 30 % of resistance cases, patients’ tumors have developed secondary mutations within the kinase domain of ALK [7, 9, 10]. Common resistance mutations include gatekeeper L1196M, G1269A, and G1202R mutations . Other mechanisms of crizotinib resistance are due to amplification of the ALK fusion gene, which can occur alone or in combination with secondary resistance mutations [8, 9]. Last, mechanisms of resistance have been attributed to alternative or bypass signaling pathways, such as the epidermal growth factor receptor (EGFR) and insulin-like growth factor-1 (IGF1R) pathways [7, 10]. Ceritinib (ZykadiaTM) is a once daily oral, small-molecule, adenosine triphosphate (ATP)-competitive ALK inhibitor that is 20 times more potent against ALK than crizotinib in preclinical studies, with activity against common secondary ALK mutations that confer resistance to crizotinib . Ceritinib was granted accelerated approval by the US FDA in 2014 for treating metastatic, ALK-positive NSCLC that has progressed on or is intolerant to crizotinib, based on response rate and duration of response . Ceritinib is currently recommended at a dose of 750 mg/day, administered orally on an empty stomach (not within 2 h of a meal) . In a Phase I study in ALK inhibitor-treated and -naïve patients with NSCLC, overall response rates (ORRs) of 56 % and 72 % respectively, were achieved, with a median duration of response of 9.7 months. Median progression free survival (PFS) was 6.9 months in prior ALK inhibitor-treated patients and 18.4 months in ALK inhibitor-naïve patients . In this case report, we present a female patient initially diagnosed with ALK-negative lung adenocarcinoma that responded to standard chemotherapy, but was subsequently re-tested by NGS and found to be ALK-positive. The patient responded to crizotinib but ultimately progressed and showed gastrointestinal intolerance to the drug. She has been treated successfully with ceritinib 450 mg/day taken with food and remains on ceritinib treatment after 12 months.
A 74 year-old Caucasian female never-smoker initially presented with a pleural effusion and was diagnosed with invasive adenocarcinoma following a pleural biopsy. The pleural biopsy performed revealed dense fibrous tissue with invasive adenocarcinoma with mucin production and associated psammomatous calcifications. The patient was initially treated with carboplatin, paclitaxel, and bevacizumab with good response, and she continued on maintenance bevacizumab for four years after diagnosis. Subsequently treatment was switched to pemetrexed but had to be stopped due to secondary fatigue and failure to thrive. Molecular (EGFR/ALK) testing was carried out on tissue procured from the initial right pleural biopsy. Using this sample with 35 % viable tumor tissue, the patient was found to be both EGFR wild-type and ALK-negative by FISH.
This case study validates the importance of broad diagnostic testing for actionable mutations in lung cancer patients who have progressed on first-line therapy, including in those who may have already been tested and found to be negative for oncogenic driver mutations. For instance, re-biopsy may often provide specimens of superior quality for molecular testing if original tumor biopsy samples were heterogeneous in nature. Mutations not previously detected may also have arisen during treatment. Targeted treatment options are available for those patients where actionable mutations are revealed, and as in this case, crizotinib provides responses in many patients found to be ALK-rearrangement positive. However, crizotinib treatment may need to be discontinued due to progression through drug resistance caused by either secondary kinase mutations or alternative genetic driver mutations. As an increasing number of ALK inhibitors are approved for the treatment of patients with lung cancer, such as crizotinib, ceritinib, and alectinib, the selection of sequential treatments will need to be based not only on patient’s resistance mutation profiles but also on consideration of potential tolerability to subsequent treatment options.
This study demonstrates the safety, tolerability and efficacy of second-line ceritinib treatment, when administered with food at a lower than recommended dose of 450 mg/day, in a patient with previously treated lung adenocarcinoma who had discontinued crizotinib due to disease progression and gastrointestinal adverse events. Sequentially administered ceritinib at this lower dose is being well tolerated in this responding patient, with no gastrointestinal intolerance, and she remains on ceritinib therapy to date. As recent data has become available from the J-ALEX study (ASCO, 2016) , it may very well be that alectinib will be one of the first line choices for ALK positive patients. As well, there are ongoing studies on Ceritinib in comparison to crizotinib, and these results are awaited. It is an exciting time for our patients with ALK positive tumors with a number of options. How we determine the sequence of therapy is still under investigation. Ceritinib, discussed here, certainly has dramatic activity against ALK positive lung cancer.
ALK, anaplastic lymphoma kinase; CNS, central nervous system; CT, Computed tomography; EGFR, epidermal growth factor receptor; FISH, fluorescence in situ hybridization; NGS, next-generation sequencing; NSCLC, non-small cell lung cancer; ORR, overall response rate; PFS, progression-free survival
We thank the nursing staff of the University of Chicago Medical Center, for their skill and dedication in helping the patient presented in this case report.
We declare that there has been no funding for this project.
Availability of data and materials
The clinical information presented in this case report was obtained through University of Chicago’s medical records. These medical records are readily available to be shared by the University of Chicago’s Section of Hematology/Oncology in accordance with guidelines.
BW, IM and RS conceived of the study and participated in its design and coordination. BW, IM and RS participated in patient care, reviewed the literature, prepared the figures, helped to draft and read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Ethics approval and consent to participate
All clinical and research data presented here was performed in accordance with the Declaration of Helsinki to ensure and safeguard the health, well-being, and rights of the patient. The study was approved by University of Chicago's Institutional Review Board under IRB protocols 9571 and 13473A. The patient was consented to participate in the study according to the guidelines of the IRB protocols.
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