FDA Approval: Ceritinib for the Treatment of Metastatic Anaplastic Lymphoma Kinase–Positive Non–Small Cell Lung Cancer

Abstract

On April 29, 2014, the FDA granted accelerated approval to ceritinib (ZYKADIA; Novartis Pharmaceuticals Corporation), a breakthrough therapy-designated drug, for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. The approval was based on a single-arm multicenter trial enrolling 163 patients with metastatic ALK-positive NSCLC who had disease progression on (91%) or intolerance to crizotinib. Patients received ceritinib at a starting dose of 750 mg orally once daily. The objective response rate (ORR) by a blinded independent review committee was 44% (95% CI, 36-52), and the median duration of response (DOR) was 7.1 months. The ORR by investigator assessment was similar. Safety was evaluated in 255 patients. The most common adverse reactions and laboratory abnormalities included diarrhea (86%), nausea (80%), increased alanine transaminase (80%), increased aspartate transaminase (75%), vomiting (60%), increased glucose (49%), and increased lipase (28%). Although 74% of patients required at least one dose reduction or interruption due to adverse reactions, the discontinuation rate due to adverse reactions was low (10%). With this safety profile, the benefit-risk analysis was considered favorable because of the clinically meaningful ORR and DOR.

Overcoming crizotinib resistance in ALK-rearranged NSCLC with the second-generation ALK-inhibitor ceritinib

“…Interestingly, patients with untreated CNS lesions after crizotinib treatment showed response to ceritinib. [20,22] Ceritinib also showed similar efficacy in crizotinibtreated patients without ALK rearrangements, implying that crizotinib-resistant tumors may remain ALK-dependent which would be susceptible to a more potent ALKinhibitor such as ceritinib. [22] During the dose-escalation phase, dose-limiting adverse reactions were observed in six patients (diarrhea, nausea, vomiting, hypophosphatemia, and transaminitis).…”

“…Ceritinib can only partially overcome resistance to crizotinib of tumors harboring C1156Y. [20]. One of these mutations is identified in 5 out of 11 biopsies from patients that acquire ceritinib resistance after treatment.…”

“…[21] Also in BA/F3 models transfected with these mutants, ceritinib was unable to reverse resistance to crizotinib in the C1156Y, 1151Tins, L1152P, F1174C, and G1202R mutants, but was about 100-1000 times more potent in L1196M, S1206Y, G1269A, and G1269S mutants and somewhat less against I1171T mutants. [20] By evaluating the difference between the molecular structures of ceritinib and crizotinib, it was possible to explain how ceritinib could overcome the most common mutations that lead to crizotinib resistance ( Figure 3). The G1269 site is situated just proximal to D1270 of the activation loop DFG-motif.…”

“…Currently, a dose-optimizing study is being performed to improve the dose regimen of ceritinib in NSCLC patients with crizotinib-resistant EML4-ALK translocations. [20] Several distinct differences can be seen when comparing the safety and toxicity profiles of ceritinib and crizotinib. The ceritinib-treated group had a higher percentage of patients presenting with all grade GI disorders with the exception of constipation (29% in ceritinib, 42% in crizotinib), higher percentage of patients with fatigue (52% vs. 27%), but a lower percentage of patients with vision disorders (9% vs. 60%) and respiratory disorders (4% vs. 26%).…”

How might treatment of ALK-positive non-small cell lung cancer change in the near future?

“…On this basis, highly effective small molecules ALK-TK inhibitors (-TKIs) have been developed, with crizotinib being the first approved agent by both FDA and EMA for the treatment of ALK-rearranged (ALK-positive), advanced NSCLC [2]. More recently, next-generation ALK-TKIs such as ceritinib and alectinib have demonstrated efficacy in ALK-positive NSCLCs pretreated with crizotinib, which has led to their approval by FDA (ceritinib and alectinib) and EMA (ceritinib) for patients who are resistant or intolerant to crizotinib [3][4][5]. Therefore, at the present time, crizotinib followed by either ceritinib or alectinib appears to be the optimal treatment of ALK-positive advanced NSCLC.…”