In lung cancer, ALK rearrangement was discovered in 2007 when two groups independently reported a new inversion in chromosome 2p, which results in the fusion of the N-terminal portion of the echinoderm microtubule-associated protein-like 4 (EML4) gene with the kinase domain of ALK in non-small-cell lung cancer (NSCLC).1,2 This chromosomal inversion creates a novel oncogene with constitutive kinase activity. Constitutive activation of downstream signaling pathways, such as the Ras/MAPK, PI3K/AKT, and JAK/STAT, result in uncontrolled cancer cells proliferation and survival.
The EML4-ALK gene rearrangement occurs at a frequency of 4% in an unselected Non-small Cell Lung Cancer (NSCLC) population and is more common in young patients (<50 years old), with never- or light-smoker history and in signet ring or acinar adenocarcinoma histology. Unlike EGFR, there appears to be no association with ethnicity. The EML4-ALK rearrangement - often abbreviated to ALK gene rearrengement - appears to be almost mutually exclusive with EGFR and KRAS mutations.
The small molecule crizotinib is an ALK, MET and ROS1 inhibitor which was the first ALK inhibitor tested in clinical setting with reported response rate (RR) of 60% and a progression-free survival (PFS) of 8-10 months.3-5 Recently, the phase III study PROFILE 007 demonstrated the superiority of crizotinib versus second-line chemotherapy in patients who progressed after standard front-line platinum-based chemotherapy, thus establishing a new standard of care in ALK positive NSCLC.5 Crizotinib is currently approved by the FDA for ALK positive advanced NSCLC patients for any line of treatment and is approved by EMA only for pre-treated patients.
Nevertheless, despite initial dramatic responses, after a median time of 10 months, virtually all patients become refractory to crizotinib due to the emergence of acquired resistance. Mechanisms of resistance include acquired mutations within the ALK tyrosine kinase domain and amplification of the ALK fusion gene.
Ceritinib is a new oral highly potent and selective ALK inhibitor. Shaw et al, conducted a phase 1 study of Ceritinib to determine safety, maximum tolerated dose (MTD), pharmacokinetic properties and anti-tumour effects in patients with ALK-rearranged tumours.6 The study included a dose escalation phase followed by an expansion phase in which all participants were treated with the MTD. Ceritinib was administered daily in 21-day cycles and treatment continued until progressive disease (PD), unacceptable toxicity or withdrawal of consent.
The majority of patients were young (median age 53) women (60%) who had never smoked (62%) reflecting the known associations of ALK positive tumours with these patient characteristics. Although the study was open to patients with any ALK positive tumour, the vast majority (94%) of patients enrolled within the study had NSCLC. In the study, ALK rearrangement had to be confirmed with break-apart FISH test. Forty-nine percent of patients had brain metastases and, notably, two-thirds of patients (68%) had received previous treatment with Crizotinib.
130 patients were treated: 59 in the dose escalation phase and 71 in the expansion phase. In the dose escalation phase, dose-limiting toxicity included diarrhoea, vomiting, nausea, dehydration, raised aspartate transaminase (AST) and raised alkaline phosphatase (ALP) all of which resolved with discontinuation of the drug. All patients restarted the drug except one with identified progressive disease (PD). Common adverse events of any grade and cause included nausea (82%), diarrhoea (75%), vomiting (65%), fatigue (47%) and increased alanine aminotransferase (ALT). Grade 3/4 toxicities leading to discontinuation of ceritinib were raised ALT (21%), raised AST (11%), diarrhoea (7%) and raised lipase (7%). These all reversed with discontinuation of the drug. Four cases of interstitial lung disease - possibly related to ceritinib - were noted but resolved with discontinuation of the drug and standard management. More than a half (51%) of the patients required a dose reduction (DR) with a median dose interruption of 7.3 days. At the highest dose of 750mg, 62% required a DR, two-thirds of which occurred in cycle 3 or later. There were no treatment-related deaths.
114 patients with NSCLC received at least 400mg of ceritinib. Overall response rate (RR) was 58% (1% complete response [CR] and 57% partial response [PR]). 22% and 11% of patients had stable disease (SD) and PD, respectively. Ten percent of participants were not evaluable for response. 78 patients with NSCLC were treated at the dose of 750mg and achieved an overall response rate of 59%. Notably, RR was 56% and 62% for crizotinib-pretreated and crizotinib-naïve patients, respectively. The median duration of response was 8.2 months; although 47% of those with a response were censored at the time of data cut-off. Two-thirds (64%) of the patients had duration of response of longer than 6 months. For the 114 patients who received at least 400mg of ceritinib, PFS was 7.0 months (6.9 and 10.4 months for the crizotinib-pretreated and crizotinib naïve population, respectively). Notably, there was no difference in PFS between patients with or without brain metastases (6.9 vs 7.0 months, p=0.37).
Overall survival data was not mature at time of publication. Re-biopsy at progression after crizotinib was obtained for 19 patients: 2 showed ALK gene amplification, 5 had resistance mutations in the ALK tyrosine kinase domain, whilst no new genetic alteration could be identified in the remaining patients.
Although numbers are small, it is important to note that tumour response was noted in these patients regardless of molecular status. This suggests that crizotinib-resistant tumours may remain ALK dependent and more potent targeting may produce a continued response, even in the brain - one of the commonest sites of relapse in ALK positive patients treated with crizotinib.
Ceritinib is highly effective in advanced ALK rearranged NSCLC, including crizotinib-pretreated patients. The fact that responses were seen independently of previous crizotinib exposure or identified known crizotinib resistance mechanisms is particularly encouraging. On the basis of these results, on 29th April 2014 the FDA granted accelerated approval to ceritinib for the treatment of patients with ALK positive advanced NSCLC who progressed on crizotinib or are intolerant to crizotinib.
Updated results of this study were presented at the 2014 ASCO annual meeting. A total of 246 patients with ALK positive NSCLC were treated at the 750mg dose, two-thirds (67%) of which had received previous 2 or more anticancer therapies. RR was ≥60% (55.4% vs 69.5% in the crizotinib pre-treated and crizotinib-naïve population, respectively). Median duration of response for all patients was 9.7 months (7.4 months vs not estimable for crizotinib pre-treated and crizotinib-naïve population, respectively) and updated PFS was 7 months (6.9 months vs not estimable for crizotinib pre-treated and crizotinib-naïve population, respectively).
Phase 3 studies evaluating first-line ceritinib vs platinum/pemetrexed chemotherapy in untreated ALK positive advanced NSCLC (NCT01828099) and ceritinib in patients previously treated with chemotherapy and crizotinib (NCT01828112) are currently recruiting. The results of these investigations are eagerly awaited.
Should we use ceritinib as first-line in advanced ALK positive NSCLC, instead of crizotinib?
Should we use ceritinib in crizotinib-naïve pre-treated ALK-positive patients or reserve it as treatment at progression after crizotinib?
- Soda, M., Choi, Y.L., Enomoto, M. et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007; 448 (7153):561–66
- Rikova, K., Guo, A., Zeng, Q. et al. Global survey of phosphotyrosine signaling identifies oncogenic kinase in lung cancer. Cell 2007; 131 (6): 1190–203
- Kwak, E.L. et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010; 363(18): 1693–1703
- Camidge, D.R. et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol, 2012; 13(12): 1011–19
- Shaw, A.T. et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med, 2013; 368(25): 2385–94
- Ceritinib in ALK-Rearranged Non-Small-Cell Lung Cancer, Shaw et al. NEJM March 27, 2014 Vol. 370 No. 13, 370:1189-1197
Dr Howell declares no conflict of interest. Dr Califano has received honoraria from Novartis Oncology.
The content of this article reflects the personal opinion of the author and is not necessarily the official position of the European Society for Medical Oncology.