Ceritinib: First Global Approval

Sohita Dhillon • Madeleine Clark

Published online: 1 July 2014
ti Springer International Publishing Switzerland 2014

Abstract Ceritinib is an oral anaplastic lymphoma kinase (ALK) inhibitor developed by Novartis for the treatment of tumours characterised by genetic abnormalities in ALK. ALK is a member of the insulin receptor family of tyrosine kinases that can become oncogenic when fused to other proteins. Ceritinib has been approved in the US under ‘Breakthrough Therapy’ designation for the second-line treatment of ALK-positive non-small cell lung cancer (NSCLC). Regulatory submissions have also been made in the EU and other countries. Phase III development is ongoing worldwide to evaluate ceritinib both as a first- and second-line therapy for ALK-positive NSCLC. This article summarizes the milestones in the development of ceritinib leading to this first approval for the treatment of patients with ALK-positive metastatic NSCLC who have pro- gressed on or are intolerant to crizotinib.

1 Introduction

Aberrant kinase activation is often seen in cancer and is thought to drive the initiation and progression of

This profile has been extracted and modified from the Adis R&D Insight drug pipeline database. Adis R&D Insight tracks drug development worldwide through the entire development process, from discovery, through pre-clinical and clinical studies to market launch.

S. Dhillon (&) ti M. Clark
Adis, Level 1, 5 The Warehouse Way, Northcote, 0627 Auckland, New Zealand
e-mail: [email protected] S. Dhillon
Adis, Private Bag 65901, Mairangi Bay, 0754 Auckland, New Zealand

disease [1, 2]. Anaplastic lymphoma kinase (ALK) is a member of the insulin receptor superfamily of tyrosine kinases that can act as a dominant oncogenic driver following chromosomal rearrangements in several can- cers, including non-small cell lung cancer (NSCLC) [3, 4]. Genetic rearrangements of this driver oncogene have been seen in 4–6 % of patients with NSCLC, with most rearrangements arising from chromosomal inver- sions that generate new ALK fusion transcripts, com- monly involving echinoderm microtubule-associated protein-like 4 (EML4) as the fusion partner [2]. EML4 in the resulting chimeric protein (EML4-ALK) medi- ates ligand-independent dimerization of ALK, which results in constitutive kinase activity [1].
Research in recent years has focussed on developing treatments targeting dysregulated kinases, such as ALK, and have been found to be highly effective in subsets of patients who have tumours with specific genetic abnor- malities [1]. One such targeted therapy is crizotinib, a small molecule oral inhibitor of ALK, which is now considered the standard of care for the management of ALK-positive NSCLC [5]. However, after an initial response that usually lasts for approximately 8 months, all patients with ALK- positive NSCLC will have a relapse, highlighting the need for drugs that can suppress the growth of recurrent tumours [6].
Ceritinib is an oral ALK inhibitor developed by Novartis and approved by the US FDA in April 2014 for the treatment of patients with ALK-positive meta- static NSCLC who have progressed on or are intolerant to crizotinib [7, 8]. The recommended dosage of ceri- tinib is 750 mg administered orally once daily on an empty stomach [8]. Ceritinib received ‘Breakthrough Therapy’ designation and was approved for use based on data from a multi-centre, single-arm, open-label

Features and properties of ceritinib
Alternative names LDK 378; LDK-378; LDK378; NVP-LDK378; ZykadiaTM
Class Diamines, piperidines, pyrimidines, small-molecules, sulfones
Mechanism of Action ALK inhibitor
Route of administration Oral
Pharmacodynamics Inhibited autophosphorylation of ALK, ALK-mediated phosphorylation of STAT3 and the proliferation
of ALK-dependent cancer cells
Induces complete tumour regression in a xenograft model of EML4-ALK-positive lung cancer
Pharmacokinetics Cmax achieved in &6 h after administration of a 750 mg dose Steady state achieved in &15 days
Apparent plasma terminal tti was 41 h
Most frequent adverse events Diarrhoea, nausea, vomiting, abdominal pain ATC codes
WHO ATC code L01X-E (protein kinase inhibitors)
EphMRA ATC code L1X4 (antineoplastic protein kinase inhibitors)
Chemical name 5-Chloro-N4-[2-[(1methylethyl)sulfonyl]phenyl]-N2-[5-methyl-2-(1-methylethoxy)-4-(4-piperidinyl)phenyl]-
ALK anaplastic lymphoma kinase, Cmax peak plasma concentration, tti elimination half-life

pivotal trial in 255 ALK-positive patients, of which 163 patients had NSCLC and had progressed on were intolerant to crizotinib [7, 9]. The indication was approved under accelerated approval based on tumour response rate and the duration of response [8]. An improvement in survival and disease-related symptoms with ceritinib treatment has not been established, and verification and description of clinical benefit in con- firmatory trials may be required for continued approval of ceritinib in this indication [8]. Novartis has also submitted a regulatory application for the approval of ceritinib in the EU, and has made additional submis- sions worldwide [7].

Chemical structure of ceritinib
2Scientific Summary


Ceritinibisapotentandselectivetyrosinekinaseinhibitor[10]. Biochemical and cellular assays showed that ceritinib at clin- ically relevant concentrations inhibited ALK, insulin-like growth factor I receptor (IGF-1R), insulin receptor and ROSI [8, 10]. Of these receptor kinases, ceritinib is most active against ALK [8]. In in vitro and in vivo assays, ceritinib inhibited autophosphorylation of ALK, ALK-mediated phos- phorylation of STAT3 (a downstream signalling protein) and the proliferation of ALK-dependent cancer cells [8, 10].

In terms of anti-tumour activity, ceritinib inhibited the proliferation of cell lines expressing EML4-ALK or nucle- ophosmin (NPM)-ALK fusion proteins in vitro and the growth of EML4-ALK-positive NSCLC xenografts in rodents [8]. In a mouse xenograft tumour model derived from a lung cancer cell line (NCI-H2228) positive for EML4- ALK, complete tumour regression was noted after oral administration of ceritinib 25 mg/kg/day [11]. Following treatment with ceritinib 50 mg/kg/day for 14 days, remis- sion was maintained for [4 months in this model [11].
In addition, ceritinib 50 mg/kg/day was effective in several NCI-H2228 tumour models that were resistant to the c-MET/ALK kinase inhibitor crizotinib, suggesting that ceritinib may be active in crizotinib-relapsed patients [11]. This was supported by in vitro and in vivo data, including from cell lines established from biopsies of crizotinib- resistant NSCLC patients, which revealed that ceritinib potently overcomes crizotinib-resistance mutations, par- ticularly in cell lines harbouring the L1196M, G1269A, I1171T and S1206Y ELM4-ALK mutations [12]. However, ceritinib did not overcome the G1202R and F1174C criz- otinib-resistant ELM4-ALK mutations, and biopsies from patients with acquired resistance to ceritinib showed that and 5 of 11 patients had mutations at either G1202 or F1174 [12].


Pharmacokinetic data are available from a phase I study [13, 14]. Additional data have been obtained from the US prescribing information [8].
The absolute bioavailability of ceritinib has not been determined [8]. In patients receiving a single oral dose of ceritinib, the area under the curve (AUC) and peak plasma concentrations (Cmax) of ceritinib increased dose propor- tionally over a dose range of 50–750 mg, with Cmax achieved &4–6 h after dose administration [8].
Following once daily administration of ceritinib 50–750 mg, a slightly greater than dose-proportional increase in Cmax was observed in patients with locally advanced or metastatic cancer harbouring genetic modifi- cations in ALK [8, 13]. Ceritinib Cmax was achieved &6 h after administration of the first dose of the maximum tol- erated dose (750 mg) [13]. After once daily administration of ceritinib 750 mg, steady-state concentrations were achieved by approximately day 15 [8, 13], with a geometric mean accumulation ratio of 6.2 after 3 weeks [8].
The systemic exposure to ceritinib was increased when the drug was administered with a high-fat meal. A ceritinib dose of [600 mg administered with a meal is expected to result in systemic exposure exceeding that achieved with a 750 mg dose taken in the fasted state, which may increase

the likelihood of adverse reactions. It is recommended that ceritinib be administered on an empty stomach, i.e. it should not be administered within 2 h of a meal [8].
Ceritinib is 97 % bound to human plasma proteins, independent of its concentration [8]. After a single dose of ceritinib 750 mg in patients, the apparent volume of dis- tribution of ceritinib was 4,230 L. The mean in vitro blood:plasma ratio of ceritinib is 1.35, indicating that it has a slight preferential distribution to red blood cells relative to plasma [8].
Ceritinib is metabolized largely by cytochrome P450 (CYP) 3A [8]. The parent drug was the main (82 %) cir- culating component in human plasma after a single, radiolabelled dose of oral ceritinib 750 mg. The majority (92.3 %) of a radiolabelled dose of ceritinib was recovered in the faeces (68 % as unchanged parent compound) and 1.3 % of the dose was recovered in the urine [8]. The geometric mean apparent plasma terminal elimination half- life of ceritinib was 41 h, following a single oral dose of 750 mg in patients [8]. The pharmacokinetics of ceritinib were non-linear over time, with lower mean apparent clearance at steady state after 750 mg once daily admin- istration than after a single dose of 750 mg (33.2 vs. 88.5 L/h) [8].

2.2.1Special Populations

Population pharmacokinetic analyses showed that age, gender, race and body weight had no clinically relevant effect on the systemic exposure to ceritinib [8]. The steady- state AUC24 and Cmax values of ceritinib did not differ markedly between Asian and Caucasian patients with advanced ALK-positive NSCLC [14].
The pharmacokinetics properties of ceritinib have not been assessed in patients with hepatic impairment [8]. However, as ceritinib is eliminated largely by the liver, patients with hepatic impairment may have increased exposure to the drug. According to a population pharma- cokinetic analysis, the exposure to ceritinib was similar between patients with mild hepatic impairment (n = 48) and those with normal hepatic function (n = 254), where mild hepatic impairment was defined as total bilirubin less than or equal to the upper limit of normal [ULN]
and aspartate aminotransferase [AST] [ULN, or total bilirubin [1.0–1.5 times the ULN and any level of AST, and normal hepatic function was defined as total bilirubin BULN and AST BULN. Therefore, no dosage adjustment is needed in patients with mild hepatic impairment. The pharmacokinetic properties of ceritinib have not been evaluated in patients with moderate to severe hepatic impairment and the recommended dose for these patients has not been determined [8].

As the elimination of ceritinib via the kidney is low, no pharmacokinetic study has been undertaken in patients with renal impairment [8]. A population pharmacokinetic analysis showed that the exposure to ceritinib was similar between patients with mild (creatinine clearance [CLCR] 60 to \90 mL/min; n = 97) or moderate (CLCR 30 to \60 mL/min; n = 22) renal impairment and those with normal renal function (CLCR C90 mL/min; n = 183). Patients with severe renal impairment (CLCR \30 mL/min) were not included in this trial [8].
The pharmacokinetic properties of ceritinib have not been evaluated in paediatric patients [8]

2.2.2Potential Drug Interactions

In vitro studies showed that ceritinib is a substrate of CYP3A4 and the efflux transporter P-glycoprotein (P-gp) and may inhibit CYP3A4 and CYP2C9 [8]. Ceritinib is not a substrate of breast cancer resistance protein (BCRP), multidrug resistance protein (MRP2), organic cation transporter (OCT1), organic anion transporter (OAT2) or organic anion transporting polypeptide (OATP1B1). At clinically relevant concentrations, ceritinib does not inhibit apical efflux transporters, P-gp, BCRP, MRP2, hepatic uptake transporters OATP1B1 and OATP1B3, renal anio- nic transporters OAT1 and OAT3, or organic cationic transporters OCT1 and OCT2 [8].
Strong CYP3A4/P-gp inhibitors (e.g. ketoconazole) may increase systemic exposure to ceritinib; therefore, con- comitant administration of ceritinib with strong CYP3A4 inhibitors should be avoided [8]. However, if coadminis- tration of ceritinib and strong CYP3A4 inhibitors, includ- ing certain antiretrovirals (e.g. ritonavir), macrolide antibiotics (e.g. telithromycin), antifungals (e.g. ketocona- zole) and nefazodone is unavoidable, ceritinib dose should be reduced by approximately one-third and rounded to the nearest 150 mg dose strength. Grapefruit and grapefruit juice should not be consumed during ceritinib therapy, as they may inhibit CYP3A [8].
Strong CYP3A4/P-gp inducers (e.g. rifampin [rifampi- cin]) may decrease ceritinib exposure; consequently con- comitant use of ceritinib with strong CYP3A4 inducers (e.g. carbamazepine, phenytoin, rifampin and St. John’s Wort) should be avoided [8].
At clinical concentrations, ceritinib may inhibit CYP3A and CYP2C9, according to in vitro studies; therefore, coadministration of the drug with CYP3A and CYP2C9 substrates known to have narrow therapeutic indices or substrates largely metabolized by these enzymes should be avoided [8]. If concomitant use of ceritinib with these agents is unavoidable, dose reduction of CYP3A substrates with narrow therapeutic indices (e.g. alfentanil, cyclo- sporine [ciclosporin], dihydroergotamine) and CYP2C9

substrates with narrow therapeutic indices (e.g. phenytoin, warfarin) should be considered [8].

2.3Therapeutic Trials

An ongoing, single-arm phase I study (NCT01283516) assessed the maximum tolerated dosage (primary objec- tive), safety, pharmacokinetics and efficacy of ceritinib [13]. Initial data from the study included those from a dose- escalation phase (n = 59 patients) that determined the maximum tolerated dose of ceritinib, and an expansion phase (n = 71), during which patients were treated with the previously determined maximum tolerated dose. In the dose-escalation phase, patients received a single ceritinib dose, followed by a 3-day pharmacokinetic evaluation period, after which they continued with once daily administration of ceritinib 50–750 mg in 21-day cycles [13].
As of 19 October 2012, 130 patients had received ce- ritinib therapy, including 122 patients with advanced ALK- positive NSCLC and eight patients with other primary cancers. The maximum tolerated dosage of ceritinib was determined to be 750 mg once daily [13]. In patients treated with ceritinib C400 mg once daily (n = 114), the overall response rate (ORR) after a median follow-up of 9.5 months was 58 % (ORR of 56 % in patients [n = 80]
who had received prior crizotinib therapy and 62 % in crizotinib-naive patients [n = 34]) [13]. Of the 114 patients, one (1 %) achieved a complete response, 65 (57 %) achieved partial responses and 25 (22 %) had stable disease following ceritinib therapy; the median progres- sion-free survival (PFS) across all patients was 7 months. In 66 patients who had a partial or complete response, the median duration of response (DOR) was 8.2 months and 64 % of patients had a DOR of C6 months. In the subgroup of patients with ALK-positive NSCLC (n = 78) who received ceritinib 750 mg once daily (the maximum tol- erated dose), the ORR was 59 % (ORR of 56 % in patients who had received prior crizotinib therapy [n = 50] and 64 % in patients who were crizotinib-naı¨ve [n = 28]). Partial response was achieved in 59 % of patients and stable disease in 18 % of ceritinib recipients [13].
As of July 2013 when recruitment to the study was closed, 255 patients (246 with advanced ALK-positive NSCLC and nine patients with other cancers) had received ceritinib 750 mg once daily [15]. Analyses conducted at a data cut-off of 31 October 2013 showed that in patients with NSCLC who had progressed on or were intolerant to prior crizotinib therapy (n = 163 primary efficacy popu- lation; median follow-up 6.9 months), treatment with ce- ritinib was associated with an ORR of 54.6 % as assessed by the investigators and an ORR of 43.6 % as assessed by a blinded independent review committee (BIRC) [8, 15, 16].

Investigator-assessed complete and partial response rates in ceritinib recipients were 1.2 and 53.4 %, respectively [8, 15, 16], and BIRC-assessed rates were 2.5 and 41.1 % [8, 16]. The median investigator- and BIRC-assessed DOR in these patients were 7.4 and 7.1 months [8, 15, 16] and the median investigator-assessed PFS was 8.2 months [15].
In patients who were ALK inhibitor naı¨ve (n = 83; median follow-up 7.6 months), the investigator-assessed ORR in ceritinib recipients was 66.3 %, with 1.2 and
65.1% of patients experiencing complete and partial responses, respectively, and 22.9 % of patients with stable disease [15]. The DOR and PFS rates at 12 months were
65.2and 61.3 %, and median DOR and PFS had not been reached [15].
Benefit of ceritinib therapy was also seen in patients with ALK-positive NSCLC who had brain metastases at baseline (n = 124) [15]. In ceritinib recipients who had prior ALK inhibitor therapy and brain metastases at base- line (n = 98), the ORR was 50.0 %, overall intracranial response rate (OIRR) was 40 %, median DOR was 6.9 months and median PFS was 6.7 months. In ceritinib recipients who were ALK inhibitor-naı¨ve and had brain metastases at baseline (n = 26), the ORR was 69.2 %, OIRR was 75 %, median PFS was 8.31 months, 6-month DOR rate was 65.9 % and median DOR had not been reached [15].

Key clinical trials of ceritinib conducted by Novartis

upon discontinuation of ceritinib. Four cases of interstitial lung disease (ILD) possibly related to ceritinib were observed, which resolved with standard treatments and discontinuation of ceritinib. One case of asymptomatic grade 3 corrected QT prolongation possibly related to ce- ritinib therapy was also observed. Of the 130 patients who received treatment, 66 patients required at least one dose reduction; eight patients permanently discontinued the treatment due to an adverse event. No treatment-related deaths were reported in the study. In patients receiving ceritinib 750 mg once daily, 50 of 81 patients required at least one dose reduction, of whom 32 patients required dose reductions in cycle 3 or later [13].
Updated safety results from the study showed that in 255 ALK-positive patients (including 246 patients with NSCLC) who received ceritinib 750 mg once daily (med- ian duration of exposure 6 months), the most common any- grade adverse reactions were gastrointestinal in nature, with diarrhoea (86 %), nausea (80 %), vomiting (60 %) and abdominal pain (54 %) reported most frequently [8, 15]. The most common grade 3 or 4 adverse reactions in ceritinib recipients were diarrhoea (6 %), fatigue (5 %), nausea (4 %), vomiting (4 %) and ILD (3 %) [8, 15]. Serious adverse reactions occurring in at least 2 % of patients were convulsion, pneumonia, ILD/pneumonitis, dyspnoea, dehydration, hyperglycaemia and nausea. Fatal

Drugs Indication Phase Status Location Trial identifier(s)

Ceritinib Non-small cell lung cancer (ALK-positive
disease, second-line therapy)
III Active—
Multinational NCT01828112; EudraCT2012-
005637-36; CLDK378A2303

Ceritinib Non-small cell lung cancer (ALK-positive
disease, first-line therapy)
III Active—
Multinational NCT01828099; EudraCT2013-
000319-26; CLDK378A2301

Ceritinib Non-small cell lung cancer (ALK-positive
disease, first-line therapy)
II Active—no longer
Multinational NCT01685138; EudraCT2012-
003474-36; CLDK378A2203

Ceritinib Non-small cell lung cancer (ALK-positive
disease, second-line therapy)
II Active—no longer
Multinational NCT01685060; EudraCT2012-
003432-24; CLDK378A2201

Ceritinib Non-small cell lung cancer (ALK-positive
I Active—no longer
Multinational NCT01283516; CLDK378X2101

2.4Adverse Events

The most common-adverse events in patients (n = 130 at a data cut-off of 19 October 2012) receiving ceritinib 50–750 mg once daily during the phase I study, regardless of ceritinib relationship, were nausea (82 %), diarrhoea (75 %), vomiting (65 %), fatigue (47 %) and increased alanine aminotransferase (ALT) levels (35 %) [13]. The most frequent grade 3 or 4 adverse events suspected to be treatment related were increased ALT levels (21 %), increased AST levels (11 %), diarrhoea (7 %) and increased lipase levels (7 %), all of which were reversible

adverse reactions, including pneumonia (in four patients), respiratory failure, ILD/pneumonitis, pneumothorax, gas- tric haemorrhage, general physical health deterioration, pulmonary tuberculosis, cardiac tamponade and sepsis (in one patient each), were reported in 5 % of ceritinib recipients [8]. Other clinically significant adverse reactions occurring in at least 2 % of ceritinib recipients included neuropathy (17 %), vision disorder (9 %), prolonged QT interval (4 %) and bradycardia (3 %) [8]. The most com- mon laboratory abnormalities of grade 3 or 4 severity in ceritinib recipients included increased ALT (27 %), AST (13 %), glucose (13 %) and lipase (10 %) levels [15]. At

least 1 dose reduction was required in 59 % of patients and 9.4 % of patients discontinued treatment because of adverse events [15].

2.5Ongoing Clinical Trials

Novartis is conducting a phase III clinical trial to investi- gate the efficacy of oral ceritinib in patients with ALK- positive, advanced NSCLC that has progressed despite treatment with chemotherapy (platinum doublet) and criz- otinib (NCT01828112) [17]. Initiated in June 2013, the randomised, open-label study is recruiting 236 patients in several countries, including the US, France, Germany, Hong Kong and the UK [17].
In July 2013, Novartis initiated a randomised, open- label phase III trial to compare ceritinib with standard treatment (pemetrexed plus cisplatin or carboplatin) in 348 previously-untreated patients with advanced, ALK-positive NSCLC (NCT01828099) [18]. Enrolment is underway in several countries, including Austria, Denmark, France, Germany and the UK [18].
In December 2012, Novartis initiated a single-arm, open-label, phase II trial of oral ceritinib in patients with ALK-positive NSCLC who have not previously received treatment with crizotinib (NCT01685138) [19]. Ceritinib 750 mg will be dosed once daily in 105 patients [19].
Novartis has also initiated a single-arm, open-label phase II trial of ceritinib in patients with chemotherapy- and crizotinib-refractory ALK-positive NSCLC (NCT01685060); a total of 141 patients have been enrolled in the study [20]. The primary objective of the study is to assess the efficacy of ceritinib, in terms of investigator- assessed ORR (based on Response Evaluation Criteria In Solid Tumors v1.0) [21]. Patients included must have received cytotoxic therapy (1–3 lines, including 1 platinum doublet) and progressed on crizotinib as the last treatment prior to study entry [21]. Patients with an Eastern Coop- erative Oncology Group performance status of 0–2 and stable CNS metastases were eligible for the study [21]. The primary analysis is to be undertaken after all patients have completed 6 cycles of 28 days of treatment or discontinued therapy earlier [20, 21].
Several other studies are planned/underway to assess the efficacy and/or safety of ceritinib, including a phase II study involving South Korean patients (NCT01964157 [22]), a phase I/II study in Chinese patients (NCT02040870 [23]), phase I studies in Japanese patients (NCT01634763 [24]), paediatric patients (NCT01742286 [25]) and patients with hepatic impairment (NCT01950481 [26]), and a phase Ib trial assessing the preliminary efficacy of the combina- tion of ceritinib with the HSP90 heat-shock protein inhib- itor AUY 922 (NCT01772797 [27]). An expanded treatment protocol is also available in several countries

worldwide to provide ceritinib to patients with ALK- positive NSCLC who have been pretreated with an ALK inhibitor (NCT01947608 [28]).

3Current Status

Ceritinib received its first global approval in the US on 29 April 2014 for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intol- erant to crizotinib.

Disclosure The preparation of this report was not supported by any external funding. During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the authors on the basis of scientific completeness and accuracy. S. Dhillon and M. Clarke are salaried employees of Adis, Springer SBM.


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