Real world experience on treatment, outcome and toxicity of crizotinib in patients with anaplastic lymphoma kinase positive advanced non-small cell lung cancer

Background: Crizotinib has been the standard treatment for patients with anaplastic lymphoma kinase (ALK)-rearranged advanced non-small cell lung cancer (NSCLC). It demonstrated superior progression-free survival (PFS) and higher objective response rates (ORRs) vs. chemotherapy in previously treated and untreated patients with ALK-positive advanced NSCLC. This retrospective analysis reports real-world experience in treatment outcome and toxicity of crizotinib in this group of patients, with a focus on the cardiac toxicity and its management.

Methods: Twenty-two patients diagnosed with ALK-positive NSCLC, either by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), treated at Johns Hopkins Singapore International Medical Centre (JHSIMC) and Tan Tock Seng Hospital (TTSH) in Singapore, were identified and followed for a median of 18 months. Data were collected and analyzed for baseline demographics, PFS, ORR, duration of response, toxicity and overall survival (OS).

Results: Clinical profile of patients included in the study was similar with clinical trials on crizotinib. Most patients were young of mean age 42, non-smokers and with good performance status. Fifty-nine percent had prior chemotherapy. Fifty percent of patients had brain metastases (BM), either de novo or on progression. ORR of crizotinib was 64% with median total duration of treatment of 8.5 months (range, 2-73⁺ months). Median PFS for patients treated with first-line crizotinib was 15 months. Most patients with BM had brain radiation. Median time for intracranial progression from the start of crizotinib was 11 months. Those with stable or responding extracranial disease continued crizotinib after radiotherapy to the brain. Median duration of response in this group of patients was 14 months (range, 2-31 months). Median OS among patients treated with upfront crizotinib was not reached, with 7 out of 11 patients still alive at the time of data analysis (n=11, range, 1-73⁺). Toxicity was manageable with moderate rate of grade 3 or worse toxicity (n=7, 31.8%). Three patients had grade 3-4 neutropenia. Eighteen percent (n=4) of patients developed cardiotoxicities such as bradycardia, prolonged QTc interval and complete heart block. One patient who developed complete heart block required pacemaker insertion. Two patients are long term responders who have been on crizotinib for 68⁺ and 73⁺ months.

Conclusions: This retrospective analysis of a real-world experience confirms the therapeutic benefit of crizotinib in advanced ALK-positive NSCLC. Our data showed crizotinib is tolerable and effective, comparable with literature report. Occasional serious cardiac toxicity requires attention.