Targeting Anaplastic Lymphoma Kinase (ALK) gene in Non-Small Cell Lung Cancer


Lung cancer is the leading cause of death in the US, accounting for almost 27% of all cancer-related mortalities. Non-Small Cell Lung Cancer (NSCLC) constitutes 85-90% of all lung cancers. Anaplastic Lymphoma Kinase (ALK) gene re-arrangements leading to formation of a new fusion oncogene EML4-ALK has been observed in about 5% of NSCLC. Characteristics of tumors harboring ALK rearrangements include younger age of onset, adenocarcinoma histology and minimal association with smoking. Targeting cancers harboring ALK rearrangement with ALK inhibitors has led to therapeutic benefit.

Crizotinib, an ALK and MET inhibitor, was the first agent approved in this class. Treatment of tumors harboring ALK rearrangement with crizotinib results in response rates of 60%, translating in improvement of both progression-free survival (PFS) and overall survival (OS). Unfortunately, response typically lasts for about 8-10 months due to emergence of resistance to Crizotinib. Various mechanism of resistance have been postulated including activation of alternate pathways bypassing the original aberration, as well as mutations affecting biding of the drug to the kinase domain. Thus there has been an increasing interest in development of agents to overcome this resistance.

Ceritinib, a novel ALK inhibitor, was recently approved for use in metastatic ALK positive NSCLC after progression on crizotinib or intolerance to crizotinib based on objective response rate.

Efficacy of ceritinib was established by a multicenter, single-arm open label study published earlier this year in New England Journal of Medicine. In this phase I study, a total of 130 patients were enrolled, of which 59 patients were enrolled in dose escalation phase and 71 in the expansion phase. All tumor types demonstrating ALK rearrangement in at-least 15% cells by FISH were included in the study. NSCLC was the major tumor subtype enrolled (122 patients, 94%). Dose escalation ranged from 50 mg to 750 mg given orally once a day in 21-day cycles and 750 mg was determined to be the maximum tolerated dose (MTD). One hundred and fourteen patients with NSCLC were treated with a daily oral dose of at-least 400 mg of the study drug. Partial response was seen in 65 patients (75%), complete response in one patient (1%), stable disease in 25 patients (22%) and progressive disease in 12 patients (11%) on first staging scans after 6 weeks of therapy. Eleven patients (10%) could not be assessed as they withdrew from the study prior to first staging scans. Of the 122 patients with NSCLC, 83 patients (68%) had received prior therapy with crizotinib. Response rates were similar in both groups irrespective of prior exposure to crizotinib (62% in crizotinib naïve vs 56% in patients with prior crizotinib therapy). Additionally there were also some cases with prior crizotinib therapy exhibiting a response in central nervous system metastases. Among the cohort of 114 patients who received at-least 400 mg of ceritinib median overall PFS for the entire group was 7 months. Median PFS was 6.9 months in the subgroup of 80 patients with prior crizotinib therapy and though Median PFS was not reached, it was observed to be 10.4 months (with data censored for 53% patients) in 34 patients with no prior crizotinib therapy. OS data was immature at the time of data cut-off. Common adverse effects included nausea (82%), diarrhea (75%), vomiting (65%), fatigue (47%) and elevated liver function tests (11-22%), which reversed to normal after discontinuation of the drug, while 62% of patients required at least one dose reduction.

FDA approval of ceretinib on April 29, 2014 was based on data cut-off point of October 13, 2013 with a total of 163 patients with ALK positive NSCLC enrolled and a median follow-up of 6.9 months. Assessment by a blinded independent review committee determined an overall response rate (ORR) of 43.6%, complete response rate (CR) of 2.5%, partial response rate of 41.1% and duration of response of 7.1 months. The current approval is for metastatic ALK positive NSCLC with failure or intolerance to crizotinib at a dose of 750 mg daily orally.

An ongoing trial is evaluating the efficacy of ceretinib in first-line compared to standard of care cytotoxic chemotherapy in advanced ALK positive NSCLC (NCT01828099). Another study is designed in second-line setting after progression on chemotherapy and crizotinib in the same patient population (NCT01828112).

In addition to ALK directed therapy, several other targets in lung cancer are under investigation at Roswell Park Comprehensive Cancer Center. Click here to learn more about these studies.