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Ceritinib Management Review January 2017

Management of ceritinib therapy and adverse events in patients

with ALK-rearranged non-small cell lung cancer

*Raffaele Califanoa, Alastair Greystokeb, Rohit Lalc, Joyce Thompsond, Sanjay

Popate

aThe Christie Hospital NHS Foundation Trust and University Hospital of South

Manchester NHS Foundation Trust, Manchester, UK; bFreeman Hospital, Newcastle

upon Tyne, UK; cGuy's Cancer Centre, London, UK; dHeart of England NHS

Foundation Trust, Birmingham, UK; eRoyal Marsden Hospital, London, UK

*All authors contributed equally to the development of this manuscript

Corresponding author:

Dr Sanjay Popat PhD FRCP

Consultant Medical Oncologist

Royal Marsden Hospital

Fulham Road

London

SW3 6JJ

Tel: +44 (0)20 7808 2132

Fax: +44 (0)20 7808 2688

Email: [email protected]

Target journal: Lung Cancer

Word count: 5476 (max 5000 words)

Number of references: 44

Tables / figures: 1 / 0 (maximum of 6 figures and/or tables)

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N.B. Journal guidelines state that sections throughout review article should be clearly

numbered.

Abstract [264 of 300 words]

Anaplastic lymphoma kinase rearrangement (ALK+) occurs in approximately 2–7%

of patients with non-small cell lung cancer (NSCLC), contributing to a considerable

number of patients with ALK+ NSCLC worldwide. Ceritinib is a next generation ALK

inhibitor (ALKi), approved by the European Medicines Agency in 2015. In the

first-in-human, phase I study, ceritinib demonstrated rapid and durable responses in

ALK patients previously treated with a different ALKi and in those who were

ALKi-naive. As ceritinib is starting to be used routinely for the treatment of patients

with ALK+ NSCLC, experience is growing with regard to ideal therapy management.

In this review we provide a brief background to the development of ceritinib. The

optimal treatment management and adverse events associated with ceritinib in

clinical trials and in clinical practice are then discussed in detail, and where

applicable, an expert consensus on specific recommendations are made. In clinical

trials, the most common adverse events related to ceritinib are nausea, vomiting,

and diarrhea. However, the majority of these are mild and, in the opinion of the

authors, can be effectively managed with dose modifications. Based on clinical data,

ceritinib has demonstrated efficacy as a first-line therapy and in patients who have

relapsed on crizotinib, including those with brain metastases at baseline.

Unfortunately, at some point, all patients experience progressive disease, with the

central nervous system being a common site of metastases. Recommendations are

made for continuing treatment beyond disease progression as long as a clinical

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benefit to patients is observed. Here, we review management of ceritinib treatment

and adverse events and make recommendations on optimal management of

patients.

Key words: Ceritinib, anaplastic lymphoma kinase, non-small cell lung cancer,

therapy management, safety profile.

Abbreviations: AE, adverse events; ALK, anaplastic lymphoma kinase; ALKi,

anaplastic lymphoma kinase inhibitor; ALK+, anaplastic lymphoma kinase

rearrangement; ALT, alanine aminotransferase; AST, aspartate aminotransferase;

BIRC, blinded independent review committee; CT, computerized tomography; ECG,

electrocardiogram; EMA, European Medicine Agency; FDA, Food and Drug

Administration; GI, gastrointestinal; HR, hazard ratio; ILD, interstitial lung disease;

NSCLC, non-small cell lung cancer; ORR, overall response rates; PFS, progression-

free survival; PK, pharmacokinetic; QoL, quality of life; QT, Electrocardiogram q

wave to T wave interval; QTc, heart rate-corrected QT interval; SmPC, summary of

product characteristics.

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1. Introduction

Lung cancer is the leading cause of cancer-related mortality worldwide,1 with

non-small cell lung cancer (NSCLC) accounting for more than 85.0% of all cases.2

Traditional therapeutic approaches for the treatment of NSCLC have been based

around chemotherapy; however, increased understanding of oncogenic driver

mutations has led to the development of targeted therapies, dramatically improving

outcomes for patients with driver mutations.3, 4

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase encoded by the ALK

gene on chromosome 2p, that, following genetic rearrangement, acts as an

oncogenic driver for NSCLC.5, 6 ALK-rearrangement (ALK+) occurs in approximately

2–7% of patients with NSCLC.6-8 Clinical data have shown that targeting ALK+

NSCLC with ALK inhibitors (ALKi) is effective and superior to both first- and

second-line chemotherapy in this patient population.9-13

Crizotinib was the first oral ALKi, approved by the US Food and Drug Administration

(FDA) in 2011 and the European Medicines Agency (EMA) in 2012, for the treatment

of patients with advanced ALK+ NSCLC,11, 14-16 and has since become standard of

care for this patient group. Data reported from two phase III trials comparing

crizotinib with chemotherapy in treatment-naïve patients11 and in patients with

relapsed advanced or metastatic ALK+ NSCLC who previously progressed on

chemotherapy,10 demonstrated superior efficacy of crizotinib compared with standard

platinum/pemetrexed chemotherapy. However, patients receiving crizotinib usually

experience disease progression within 12 months of treatment, with the brain being

one of the most common sites of metastasis.14, 17-19

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Several next-generation ALKi are currently under development or approved for use,

including brigatinib, lorlatinib, alectinib, and ceritinib.20 Ceritinib is a highly selective

oral tyrosine kinase inhibitor that has demonstrated efficacy against several crizotinib

resistance mutations (in-vitro and in-vivo), and shown potent efficacy in patients

harboring crizotinib-resistant ALK mutations.21-24 In 2015, the EMA granted ceritinib

conditional approval for use throughout Europe. However, ceritinib was first granted

accelerated FDA approval in April 2014, based on the first-in-human, phase I study

(ASCEND-1; NCT01283516), which established 750 mg/day as the recommended

dose in patients with ALK+ NSCLC. In this study, 83 ALKi-naïve patients and 163

ALKi-pretreated patients with ALK+ NSCLC achieved overall response rates (ORR)

of 72.0% and 56.0%, respectively. Median progression-free survival (PFS) was 18.4

months in patients who were ALKi-naïve and 6.9 months in pre-treated patients.25

Additionally, ceritinib treatment resulted in whole body and intracranial efficacy in

patients with brain metastases at baseline.25

The ASCEND-2 (NCT01685060), and ASCEND-3 (NCT01685138) phase II studies

investigated the efficacy of ceritinib in patients with ALK+ NSCLC who had

progressed on chemotherapy and crizotinib, and in patients who had received up to

three lines of prior chemotherapy but no prior ALKi treatment, respectively. Results

from these studies were consistent with those of ASCEND-1.26,27

The recent randomized, multicenter, open-label, phase III ASCEND-5 study

(NCT01828112), compared the efficacy of ceritinib versus chemotherapy in patients

with advanced ALK+ NSCLC, who had previously been treated with both platinum

doublet chemotherapy and crizotinib.28 In this study, ceritinib treatment resulted in a

significantly longer PFS compared with chemotherapy (blinded independent review

committee [BIRC]: median 5.4 vs. 1.6 months, respectively, hazard ratio [HR]=0.49,

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P<0.001 and was associated with a greater improvement in lung cancer specific

symptoms and quality of life (QoL).28 Most recently, data have been presented from

the ongoing, prospective phase III ASCEND-4 trial in which treatment naive patients

with ALK+ metastatic NSCLC were randomized to receive either ceritinib or

platinum-pemetrexed chemotherapy.12 Ceritinib demonstrated a significant and

clinically meaningful improvement in PFS compared with chemotherapy (median

PFS by BIRC of 16.6 months vs. 8.1 months, respectively; HR=0.55, p <0.001).12

Intracranial ORR was also significantly improved with ceritinib versus chemotherapy

(72.7% vs. 27.3%, respectively).12

Across clinical trials, ceritinib has demonstrated durable and potent efficacy with

predictable and manageable toxicities in patients with ALK+ NSCLC, with the

application of dose interruption or reductions as required. In ASCEND-4 and

ASCEND-5, adverse events (AEs) requiring dose adjustment or interruption/delay

were reported in 69.3% (n=131) and 80.0% (n= 92) of patients treated with ceritinib,

respectively.12, 28

As ceritinib is now routinely being used for the treatment of patients with ALK+

NSCLC, practical guidance and recommendations from practicing physicians for its

optimal use are required. Here we report the experience and recommendations from

expert physicians with substantial experience of ceritinib treatment in patients with

ALK+ NSCLC. These recommendations were agreed during a round-table

discussion in conjunction with review of the available evidence.

2. Methods

The panel discussion of expert physicians was held over a two hour long

teleconference on the 30th September 2016 and included five oncologists (the

authors), all of whom have substantial experience of treating patients with ceritinib in

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clinical trials and in clinical practice, including routine care and Novartis named

patient programs. The discussion followed a structured flow, based primarily upon

the ceritinib Summary of Product Characteristics (SmPC) and key areas of current

interest in the literature, including disease progression in the brain and treatment

with ALK inhibitors beyond disease progression. The panel presented their personal

experiences of treating patients with ceritinib in clinical practice and discussed any

divergence from the recommended actions of the SmPC. All discussions are

reported herein.

3. Administration, special populations, and drug–drug interactions

3.1 Ceritinib administration

As established in ASCEND-1, and approved based on the maximum tolerated dose,

the recommended starting dose stated on the label for ceritinib is 750 mg/day.29, 30

The summary of product characteristics (SmPC) states that ceritinib should be taken

on an empty stomach, at the same time each day.29, 30 In our experience, some

patients prefer to take ceritinib at night to minimize the disruption caused by

gastrointestinal (GI) disturbances. Patients who take ceritinib in the morning have

usually fasted for ~10 hours. In contrast, patients taking ceritinib at night generally do

so 2–4 hours after their evening meal, and we have found that ceritinib is often better

tolerated this way. Furthermore, when ceritinib is taken at night, patients who

experience GI disturbances can go to bed and rest, reducing the impact on their

daily activities.

Fat intake has been shown to alter the bioavailability of ceritinib in food-effect studies

conducted in healthy adults. Ceritinib bioavailability AUC0–∞ was increased by 58.0%

after the intake of a low-fat meal, by 73.0% after the intake of a high-fat meal, and by

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54.0% after the intake of a light snack, compared with the fasted state.31 Data have

recently been reported from an ongoing food-effects study that is assessing the

steady-state pharmacokinetic (PK) exposure, safety, and efficacy of ceritinib at

doses of 450 mg or 600 mg taken with a low-fat meal compared with 750 mg of

ceritinib taken in a fasted state (NCT02299505). In this study, the steady-state PK of

ceritinib was comparable in patients receiving 450 mg ceritinib with a low-fat meal

versus 750 mg ceritinib taken in a fasted state. Relative to patients treated with

750 mg ceritinib fasted, patients in the 600 mg ceritinib fed treatment arm showed

~25% higher steady-state PK exposure to ceritinib. In this study, the incidence of

GI-related AEs were lowest in the 450 mg-fed group (no grade 3/4 GI AEs).32

However, the efficacy part of this study is ongoing and the impact of these data

remains a focus of the study. At present, we therefore recommend that patients

commence ceritinib at the currently approved dosage of 750 mg on an empty

stomach. Nonetheless, we have found that some patients tolerate ceritinib best when

taken with a light snack (e.g. a cracker/small piece of unbuttered toast). These

patients should be advised only to consume a very small quantity of low-fat food to

avoid any potential risk of increasing ceritinib concentrations above intended levels.

Further to the above recommendations, and as ceritinib is metabolized through the

CYP3A pathway,29 patients should always be instructed to avoid eating certain fruits

such as star anise and grapefruit as these have the potential to interact with CYP3A

and, consequently, may increase the bioavailability of ceritinib.29, 30

Due to the substantial size of ceritinib capsules, many of our patients report a

triggering of the pharyngeal reflex. As such, we advise that patients are warned of

this possibility prior to starting ceritinib therapy.

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3.2 Special patient populations

3.2.1 Hepatic impairment

As ceritinib elimination primarily occurs via the liver,33 plasma concentrations of

ceritinib may be increased in cases of hepatic impairment. Although no dose

adjustments are recommended in mild-to-moderate cases, ceritinib is not

recommended for patients with moderate-to-severe hepatic impairment.29, 30

3.2.2 Renal impairment

PK data have shown that ceritinib exposure is similar in patients with

mild-to-moderate renal impairment (creatinine clearance of 60–<90 and 30–

<60 mL/minute, respectively) to that of patients with normal renal function. Therefore,

in these patients, no dose adjustments of ceritinib are required.33 However, as there

are no clinical data available on ceritinib treatment in patients with

moderate-to-severe renal impairment (creatinine clearance of <30 mL/minute),

caution should be exercised in these patients.29, 30

3.2.3 GI disorders

Due to the GI toxicity reported with ceritinib, it has been our experience that extra

care is needed in patients who have pre-existing active GI disorders such as Crohn’s

disease, short bowel syndrome, or diarrhea at baseline.

3.3 Drug–drug interactions

As is standard practice, we advise that prior to the commencement of ceritinib

treatment, a detailed drug history for patients is taken and carefully considered for

possible drug–drug interactions.

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3.3.1 CYP3A, CYP29C, and P-glycoprotein inhibitors

As reported in the literature and labeling information, drug interactions can occur

when ceritinib is co-administered with agents that are substrates of CYP3A,

CYP2C9, and P-glycoprotein inhibitors.33 Ceritinib competitively inhibits the

metabolism of CYP3A and may therefore reduce the clearance of drugs that are

substrates of this enzyme.29, 30 The SmPC advises to avoid concomitant use of strong

CYP3A inhibitors during treatment with ceritinib (e.g. clarithromycin), and if

concomitant use is unavoidable, to reduce the dose of ceritinib by approximately

one-third (dose not clinically verified), rounded to the nearest 150 mg dosage

strength. Patients should be carefully monitored for safety.29, 30 Similarly, in-vitro,

ceritinib is a substrate of P-glycoprotein and, as such, levels of ceritinib may

accumulate if co-administered with drugs that inhibit P-glycoprotein. In such cases,

careful monitoring for AEs is required.29, 30, 34

3.3.2 Anti-arrhythmic medicinal products

In clinical trials, prolongation of the QT interval with ceritinib treatment has been

observed.25, 26 The SmPC states that ceritinib should be used with caution in patients

who have or may develop prolongation of the QT interval, including those taking anti-

arrhythmic medications.29, 30 In patients with congestive heart failure,

bradyarrhythmias or electrolyte abnormalities and those taking anti-arrhythmic

medicinal products, the QT interval should also be carefully monitored.29, 30 We

recommend that for all patients electrocardiogram (ECG) assessments are carried

out prior to commencement of ceritinib therapy and before the end of the second and

third months of treatment, after which, further ECGs can be performed as clinically

indicated.

2.3.3 Common drug interactions

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From our clinical experience with ceritinib, there are a number of relatively common

drug–drug interactions for consideration prior to commencing ceritinib treatment.

Care should be taken when initiating ceritinib therapy alongside some anti-emetics

such as dolasteron, ondansetron, palonosetron and mirtazapine, and where

possible, alternatives to these medication should be used. Similarly, proton-pump

inhibitors such as omeprazole can be switched to a histamine H2-receptor

antagonist such as ranitidine. In addition, in our experience, taking corticosteroids

such as dexamethasone in combination with ceritinib can lead to hyperglycemia (a

known AE related to ceritinib) in some patients. For this reason, we aim to lower the

dose of dexamethasone over time in these patients. Regularly evolving guidance for

drug–drug interactions is available online (http://medicine.iupui.edu/clinpharm/ddis/).

4. Routine follow-up

Prior to prescribing ceritinib, we ensure that the patient has a positive diagnosis of

ALK+ NSCLC confirmed by an accredited laboratory. Computerized tomography

(CT) scans of the chest and upper abdomen are carried out at baseline. We also

perform an ECG to document baseline QT interval and baseline heart rate. Baseline

laboratory assessments include: full blood counts, serum creatinine, urea levels, total

bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline

phosphatase, non-fasting glucose, electrolytes, and levels of blood amylase.

Upon commencement of ceritinib therapy, patients are seen every 2 weeks for the

first 2 months to assess toxicity and tolerability. Subsequently, patients are seen

every 1–2 months. During these visits, routine blood tests are carried out; it is

particularly important to monitor liver function closely, as liver toxicity can change

rapidly. ECGs are carried out every month and CT scans every 2–3 months. At least

one third of patients with advanced non-small cell lung cancer have occult and

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http://medicine.iupui.edu/clinpharm/ddis/


asymptomatic brain metastases. For asymptomatic patients, our approach is to

discuss the possibility and implications of brain metastases and ask if they would like

us to investigate further, with brain imaging on an individualized basis. We

recommend that follow-up brain imaging is also individualized and advise regular

evaluation every 3–4 months. We suggest that patients are seen by the same

physician at each follow-up visit during early stages of treatment, until AEs have

stabilized. It is our experience that stability is usually achieved by 6 months after

treatment initiation.

5. Management of adverse events

5.1 Safety profile of ceritinib

To date, the most commonly reported AEs with ceritinib across clinical trials are

nausea and vomiting, diarrhea, elevated ALT, and elevated AST, with the majority of

these being grade 1/2 (Table1).25, 26, 35

In the ASCEND-1 study, serious AEs (SAEs) suspected to be study-drug related

were reported in 12.0% of patients. Among the 246 patients, 26 (11.0%)

discontinued treatment due to an AE, of which nine were suspected to be study drug

related.25 Safety signals observed during the phase II studies were consistent with

those reported in ASCEND-1. In ASCEND-2 and ASCEND-3, treatment

discontinuations due to AEs suspected to be study-drug related were reported in

7.9% and 8.9% of patients, respectively; SAEs suspected to be study-drug related

were reported in 17.1% and 11.3% of patients, respectively.26, 27 Similarly, in the

larger phase III ASCEND-4 and -5 randomized studies of ceritinib versus

chemotherapy, AEs were reported as the primary reason for treatment

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discontinuation in 5.3% and 5.2% of patients, respectively, and SAEs suspected to

be related to study drug were reported in 15.9% and 11.3% of patients,

respectively.12, 28 The majority of AEs reported across clinical trials were low grade

and were managed with dose modifications.

In our experience, patients tend to tolerate AEs better when they are prepared and

informed. For this reason, we raise our patients’ awareness of the possible AEs with

ceritinib and educate them on AE reporting and management. Additionally, prior to

ceritinib treatment, we provide our patients with supporting materials (e.g.

information leaflets from Cancer Research UK). We also inform them of a hotline to

contact in the event of AEs, from which they can obtain advice on whether or not to

stop treatment and/or visit their local clinic, depending upon the type and severity of

reaction they are reporting.

5.2 Nausea and vomiting

Nausea and vomiting have commonly been reported in patients receiving ceritinib

across clinical trials. In ASCEND-1, any grade nausea and vomiting were reported in

77.0% and 57.0% of patients, respectively. However, the majority of reported events

were low grade, with grade 3/4 nausea and vomiting reported in just 6.0% and 4.0%

of patients, respectively. One patient discontinued treatment due to nausea.25

Results from the ASCEND-2 and -3 studies were consistent with those of

ASCEND-1.26 Similarly, in the ASCEND-4 and ASCEND-5 studies, grade 3/4 nausea

was reported in 2.6% and 7.8% of patients, and grade 3/4 vomiting was reported in

5.3% and 7.8%, respectively.12, 28 In the ASCEND-5 study, vomiting was reported as

the primary reason for ceritinib discontinuation in 0.9% of patients.28 In clinical

practice we find that patients rarely experience vomiting but frequently become

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nauseated, especially within the first few months of treatment. This has also been

reported in the literature, where it is suggested that the first 1–2 weeks of treatment

are often the most difficult time for patients experiencing AEs.36 As described in the

SmPC, anti-emetic medications are recommended for the management of nausea

and vomiting. In severe cases (grade 3 or above), it is advised that ceritinib is

withheld until symptoms improve. Subsequently, ceritinib can be reinitiated with a

dose reduction of one decrement.29, 30 Although recommended, we have found that

anti-emetic medications are generally of little benefit, with the exception of

granisetron patches, which can be costly and as such, are typically only prescribed

to patients with severe symptoms. In cases of severe or intolerable nausea and

vomiting, we usually find that dose reductions are the most effective management

strategy.

5.3 Diarrhea

Diarrhea is extremely common in patients receiving ceritinib, with 80.0–87.0% of

patients reporting cases of diarrhea across clinical trials.25, 26 Additionally, GI

disturbances including diarrhea are the most common reason for dose modifications,

accounting for around 38.0% of patients in clinical trials.30 In ASCEND-1, diarrhea

was the most commonly reported AE and was generally reported early on in

treatment; 80.0% (N=198) of patients reported diarrhea at any grade and 6.0% of

patients reported severe (grade 3/4) cases, with a median time to onset of 4 days.25

Similarly, in the ASCEND-4 and ASCEND-5 studies, diarrhea was the most

commonly reported AE (Table 1) with grade 3/4 cases reported in 5.3% and 4.3% of

patients, respectively. In clinical practice, we have found that the vast majority (90–

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95%) of the patients we treat experience grade 1/2 diarrhea, which can significantly

impact their daily lives.

As detailed in trial protocols and in the SmPC, patients should be monitored and

managed with standards of care including anti-diarrheal medication and fluid

replacement. In severe cases (grade 3 or above) ceritinib should be withheld until

symptoms improve and subsequently reinitiated at a lower dose.29, 30

Although not given prophylactically, in our clinics we prescribe antidiarrheal

medication (loperamide) at the same time as ceritinib. We inform patients of the

likelihood of diarrhea, and advise that anti-diarrheal medication is taken as required,

commencing at the first loose motion. We have found that patients experiencing

ongoing diarrhea are highly unlikely to be able to continue treatment for more than 6

months. If diarrhea becomes chronic and unmanageable, we recommend reducing

the dose of ceritinib. In our experience, this is particularly important in patients with a

history of irritable bowel syndrome or other causes of diarrhea, who are likely to

require dose reductions very early on in treatment.

We find that patients experiencing diarrhea also commonly report symptoms of

increased urgency, which can severely impact their everyday activities, often forcing

them to remain at home. For this reason we strongly advise that patients are

carefully evaluated whilst receiving treatment, with physicians paying special

attention to the impact of diarrhea on QoL, and the dose of ceritinib reduced if

diarrhea is not adequately controlled with loperamide.

Approximately 50% of the patients that come into our clinics with GI symptoms, also

report symptoms of abdominal pain. These symptoms generally respond to

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management of the underlying GI AE and we would only recommend employing a

ceritinib dose reduction if abdominal pain was severe.

5.4 Pneumonitis and interstitial lung disease (ILD)

Pneumonitis or (ILD) have been reported in approximately 3.2% of patients and

infrequently is severe, life threatening, or fatal.29, 30 Across clinical studies, events of

any grade pneumonitis or ILD have been reported in 1.0–4.0% of patients treated

with ceritinib, 25, 26 with grade 3/4 events reported in ~3% of patients.25 Patients with

pulmonary symptoms indicative of pneumonitis or ILD should be monitored and any

other potential causes, such as intercurrent infection, should be excluded. Ceritinib

treatment should be permanently discontinued in severe treatment-related cases.

In our experience, some patients have localized infiltrative changes on CT scans, but

it is often difficult to determine whether this is drug related, or a result of disease

progression or infection. Although relatively rare, we do see patients with classical

signs of pneumonitis, and in these cases we recommend permanently withholding

ceritinib and treating the patient with respiratory specialist input. In all

mild-to-moderate-cases, our preference is to continue ceritinib therapy cautiously

and, where possible, commence steroid treatment, taking care to monitor blood

glucose levels. From previous experience, patients with mild symptoms can be

managed with steroids, but in the event of more severe cases, we would advise that

patients are assessed further by a respiratory specialist to help determine the

underlying aetiology of the infiltrative changes detected in scans, and potentially

discontinue ceritinib permanently.

5.5 Hepatotoxicity

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Drug-induced hepatotoxicity is common in patients receiving ceritinib therapy. In

clinical trials reported in the literature, any grade elevations in ALT and AST were

reported in approximately 44.0% and 33.0% of patients, respectively.25, 26 In

ASCEND-1, increases in ALT and AST were the most commonly reported grade 3/4

AEs, occurring in 30.0% and 10.0% of patients, respectively;25 two patients

discontinued ceritinib treatment due to elevated transaminases.25 Similarly, in the

ASCEND-4 and ASCEND-5 studies, grade 3/4 increases in ALT were reported in

30.7% and 20.9% of patients, respectively, and grade 3/4 increases in AST were

reported in 16.9% and 13.9% of patients, respectively.12, 28 In clinical practice, we find

that around 60–70% of our patients experience transaminitis, most commonly of

grade 1/2.

As advised in the SmPC, patients should be monitored with liver laboratory tests

including ALT, AST, and total bilirubin prior to the start of treatment, every 2 weeks

for the first month, and monthly thereafter, with more frequent testing for elevations

grade ≥2.29, 30

In our experience, levels of ALT may take longer to return to normal than other

parameters. Additionally, in patients with Gilbert’s syndrome, bilirubin levels are often

mildly abnormal at the start of therapy but may increase in the presence of

ceritinib-induced GI AEs. As such, direct and indirect bilirubin levels should be

evaluated when monitoring liver function in these patients.

5.6 Cardiac toxicity

4.6.1 Corrected QT interval prolongation

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Prolongation of the corrected QT interval (QTc) of any grade has been reported in

6.5% of patients receiving ceritinib (grade 3/4 in ~0.8% of patients).29, 30 In

ASCEND-2, any grade QTc prolongation was reported in 7.9% of patients, with one

(0.7%) grade 3 case reported. In clinical practice, we do not find QTc prolongation to

be a frequent problem. As such, we commonly perform ECG assessments during the

first and second cycles of ceritinib treatment, but following this, would only

investigate with ECG assessment if clinically indicated.

In patients who are receiving ceritinib treatment, regular monitoring for QT

prolongation is advised;29, 30 in cases where QTc is >500 ms, ceritinib treatment

should be withheld until heart rate recovers to baseline or to a QTc <480 ms,

electrolytes should be corrected if necessary, following which, ceritinib can be

reinitiated with a dose reduction of one decrement.29, 30 In patients with a QTc of >500

ms or >60 ms change from baseline, torsade de pointes, polymorphic ventricular

tachycardia, or signs/symptoms of serious arrhythmia, ceritinib should be

permanently discontinued.29, 30 As specified in the SmPC, treatment with ceritinib is

not recommended for patients who have congenital long QT syndrome or who are

taking medications known to prolong the QTc.

4.6.2 Bradycardia

According to the SmPC, cases of bradycardia (60 bpm) have been reported in

10/525 (1.9%) patients treated with ceritinib in clinical studies.29, 30 However, in

clinical practice we find that bradycardia is relatively common and can be effectively

managed in patients with a heart rate of >45 bpm, with monthly monitoring for heart

rate and blood pressure, and advice about taking care whilst exercising. In our

experience, we have not yet required any dose reductions of ceritinib due to

bradycardia.

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As stated in the SmPC, use of ceritinib in combination with other agents known to

cause bradycardia (e.g. beta blockers, non-dihydropyridine calcium channel

blockers, clonidine, and digoxin) should be avoided where possible. In cases of non-

life-threatening bradycardia, ceritinib should be withheld until recovery to

asymptomatic bradycardia or to a heart rate of ≥60 bpm. In the event of

life-threatening bradycardia, ceritinib should be permanently discontinued unless

associated with a concomitant medication known to cause bradycardia or

hypotension. In such cases, ceritinib should be withheld until recovery and if the

concomitant medication can be adjusted or discontinued, ceritinib should be

reinitiated with a dose reduction of two decrements, and the patient carefully

monitored.

4.6.3 Pericarditis

According to the SmPC, cases of pericarditis (including pericardial effusion) have

been reported in 5.9% of patients across clinical trials. In our experience, cases of

pericarditis can be difficult to identify from ECG and echocardiogram assessments.

In some cases, the use of non-steroidal anti-inflammatory drugs may be of benefit.

However, in severe cases, ceritinib should be withheld until the patient has

recovered, as confirmed by resolution of pericarditis symptoms and/or the return of

ECG readings to baseline. If the concomitant medication can be adjusted or

discontinued, ceritinib can be reinitiated with a dose reduction of two decrements

and the patient carefully monitored.

4.7 Hyperglycemia

Across ceritinib trials, any grade hyperglycemia was reported in 5.0–9.0% of

patients.25, 26 In ASCEND-1 and ASCEND-2, grade 3/4 hyperglycemia was reported

in 6.1% and 2.9% of patients, respectively.25, 26 These data are consistent with

19


reports seen in clinical practice. However, in our experience, we additionally find that

the risk of hyperglycemia is increased in patients with diabetes or glucose

intolerance and in patients taking corticosteroids.

The SmPC states that fasting serum glucose should be measured before starting

ceritinib treatment and periodically thereafter,29, 30 although in clinical practice we find

that a non-fasting random blood glucose test can often suffice. In cases of persistent

hyperglycemia >13.9 mmol/L (250 mg/dL) despite optimal anti-hyperglycemic

therapy, ceritinib should be withheld until hyperglycemia is adequately controlled,

then reinitiated with dose reduction of one decrement.29, 30 If adequate glucose

control cannot be achieved, ceritinib should be permanently discontinued.29, 30

In our experience, ketoacidosis is of particular concern and is most commonly seen

in patients who are taking corticosteroids. In these patients, metformin or insulin

treatments can be initiated; however, as metformin can increase the incidence of

diarrhea, special attention should be paid to GI symptoms and dose reductions

employed, if necessary.

4.8 Other adverse events

4.8.1 Creatinine increased

Raised blood creatinine is very common, affecting ~10% of patients receiving

ceritinib.29, 30 In ASCEND-1, 17.0% (N =42) of patients reported increased levels of

blood creatinine, all of which were grade 1/2. In cases observed in clinical practice,

we have measured or estimated glomerular filtration rate and patients have been

closely monitored; however, dose reductions have not usually been required. We

have not observed any cases of complex renal cysts as a result of ceritinib

treatment.

20


4.8.2 Lipase/amylase elevation

In ASCEND-1, increased levels of amylase and lipase at any grade were reported in

a total of 7.3% and 9.8% of patients, respectively.25 According to guidelines set out in

the SmPC, patients should be monitored for amylase elevations prior to the start of

ceritinib treatment and periodically thereafter, as clinically required. Since lipase is

not a routine test in most hospitals, amylase alone is usually sufficient. In cases of

grade 3/4 lipase or amylase elevation, ceritinib should be withheld until levels return

to grade 1 or below, following which, treatment can be reinitiated with dose reduction

of one decrement.29, 30

4.8.3 Fatigue and asthenia

Fatigue and asthenia are reported across clinical trials with ceritinib and affect

approximately 50% of patients, which can impact on patients’ overall QoL and their

ability to drive.29, 30 In ASCEND-1, any grade fatigue and asthenia were reported in

43.0% and 19.1% of patients, with grade 3 events occurring in 5.0% and 1.0% of

patients, respectively. These findings were supported by data from the ASCEND-2

trial.

In our experience, fatigue and asthenia do not generally require treatment. However,

we suggest that in severe or intolerable cases, patients take a short (2–3 days)

treatment break, allowing for recovery from fatigue, following which, ceritinib can be

reinitiated.

6. Management of brain metastases

21


Brain metastases are a common and challenging site of disease progression in

patients with ALK+ NSCLC.11 In a retrospective analysis of patients with ALK+

NSCLC who were treated with crizotinib, disease progression in the brain occurred in

41.0% of patients.37 This high incidence of disease progression in the brain in

patients receiving crizotinib is thought to be due to the limited penetration of the

blood–brain barrier by crizotinib, reported previously.38

Ceritinib has been shown to cross the blood–brain barrier in preclinical, in-vivo

studies,29, 30 and has demonstrated intracranial activity in clinical trials. The ASCEND-

1 trial included a retrospective analysis of the intracranial activity of ceritinib in

patients with baseline brain metastases. A total of 94 (26%) patients with ALK+

NSCLC had confirmed brain metastases at baseline, and at least one post-baseline

tumor assessment (Magnetic resonance imaging or CT). Intracranial disease control

was reported in 15/19 (78.9%) ALKi-naïve patients and in 49/75 (65.3%) patients

who had received ALKi treatment prior to ceritinib. Of the 94 patients with confirmed

baseline brain metastases, 11 had measurable brain lesions and had not received

any prior radiotherapy to the brain, six of whom achieved a partial intracranial

response.25 Consistent with data from ASCEND-1, ceritinib has also demonstrated

efficacy in patients with brain metastases in the phase II and III trials.26, 27, 39 Similarly,

in ASCEND-4, ceritinib demonstrated overall intracranial disease control in 72.7%

(n=16/22) of patients with measurable baseline brain metastases.12

Although promising data regarding the treatment of patients with brain metastases

have been reported, as is the nature of the disease, patients can experience disease

progression in the brain while receiving ceritinib, and in our experience, this is very

common. Many of the patients we see already have brain metastases prior to

22


commencing ceritinib, while others develop central nervous system progression

while receiving ceritinib.

As physicians, we discuss with the patient the need for baseline and/or subsequent

brain imaging and we find that some patients prefer to be actively screened for the

development of brain metastases, while others prefer to have scans only as clinically

needed. In either case, we recommend that physicians discuss the potential for brain

metastases with their patients and explain the consequences of receiving a positive

diagnosis, such as no longer being allowed to drive a motor vehicle. In patients who

develop brain metastases while taking ceritinib, we recommend a multi-disciplinary

approach with localized treatment (e.g. radiotherapy or neurosurgery), especially if

extracranial disease remains controlled. This is supported by findings from a recent

report in which patients with ALK+ NSCLC who had progressed with brain

metastases, demonstrated prolonged survival following radiotherapy to the brain

(stereotactic/whole–brain) and ongoing drug therapy beyond progression.40 Further

evidence is required to optimize the treatment of patients with brain metastases

(particularly for those with disease progression at multiple sites or leptomeningeal

disease) with next generation ALKi.

7. Development of ceritinib resistance and treatment beyond progression

As with other ALKi, patients receiving ceritinib treatment ultimately develop acquired

resistance; several somatic mutations associated with ceritinib resistance have been

identified.21, 41, 42 In 2014, Gainor et al. identified resistance mutations in 5/11 (45.0%)

patients with ceritinib-resistant ALK+ NSCLC, which included mutations in G1202R,

F1174C, and F1174V. One patient also had an F1174V mutation at a separate post-

ceritinib biopsy site.41

23


There is much debate in the literature on the benefits of continuing ALKi treatment

beyond disease progression. However, positive benefits of treatment beyond

disease progression in patients receiving crizotinib have been demonstrated.37, 43 In a

pooled analysis of the PROFILE 1001 and 1005 trials, 120/194 crizotinib-treated

patients (62.0%) continued treatment beyond progression. Although there were

some confounding factors, these patients had significantly longer overall survival

(OS) from the time of progressive disease than those who did not continue treatment

beyond progression (median OS 16.4 vs. 3.9 months, respectively; p<0.0001).37

A clinical benefit of continuing ceritinib treatment beyond disease progression has

also been reported. Tan et al. presented data on 91 patients with ALK+ NSCLC who

experienced progressive disease following treatment with ceritinib during the

ASCEND-1 and -2 trials, and continued to receive ceritinib beyond disease

progression. In these patients, treatment beyond progression resulted in a

significantly longer post-progression survival (12.0 months vs. 4.2 months,

respectively; p<0.001) and reduction of the risk of death greater than 50.0%.44

From our experience of treating patients with ceritinib, we would recommend

continuing ceritinib treatment where there is ongoing clinical benefit, especially

where progression is amenable to local therapy, such as isolated brain progression.

In the absence of data from randomized clinical trials, we advise that the decision to

continue treatment with ceritinib beyond disease progression occurs on a

patient-by-patient basis. In patients experiencing slowly growing poly-progressive

disease (multiple sites) without clinical deterioration, we commonly continue

treatment with ceritinib. In patients with oligo-progressive disease (progression at a

limited number of sites with controlled disease at other disease sites)45, we would

prefer to treat individual sites with radiotherapy/surgery and continue with ceritinib

24


treatment. In patients with rapid disease progression in multiple sites, a switch to an

alternative systemic, and preferably personalized genotype-directed therapy, should

be considered. We recommend a subsequent biopsy at the time of disease

progression for ALK genotyping to gain information on the molecular resistance

mechanism, in order to ascertain whether treatment with another ALKi may be

appropriate. At present, there is limited evidence as to the utility of immune

checkpoint inhibitors in patients with ALK+ NSCLC, and if used in preference to

chemotherapy, patients should be monitored carefully for early disease progression.

8. Conclusions

Ceritinib was rapidly approved following phase I clinical trials and has demonstrated

durable efficacy in patients with ALK+ NSCLC, offering an additional treatment

option for patients who have progressed on first-line crizotinib therapy. From our own

experiences in clinical practice, we advise that gathering a thorough drug history

prior to starting patients on ceritinib treatment is important in order to reduce the

chance of AE due to drug interactions. Additionally, regular discussions between

oncologists and their patients are recommended during treatment to ensure that

potential toxicities have been explored with patients as well as toxicity-minimizing

strategies and schedules for regular treatment reviews. Based on our own

experience, we encourage early review for potential side effects to assist in

minimizing any impact of AEs on the patient’s QoL, and help to avoid any

unnecessary dose reductions or early discontinuations of this effective treatment.

Conflict of interest

Dr S. Popat has received honoraria for consultancy from Novartis, Pfizer,

AstraZeneca, Roche, Boehringer Ingelheim, and Eli Lilly, and has received travel

expenses from MSD, outside of the submitted work. He acknowledges NHS funding

25


to the Royal Marsden Hospital NIHR-Biomedical Research Centre. Dr R. Califano

has received honoraria for consultancy from Novartis and Pfizer. Dr A. Greystoke

acts as a consultant for Novartis, and Pfizer, from whom he has received personal

fees outside of the submitted work. Dr J. Thompson has received honoraria for

consultancy from Novartis and Pfizer. Dr R. Lal has nothing to disclose.

Author contributions

All authors contributed equally to the development of this article.

Acknowledgments

The authors would like to acknowledge Sarah Jackson, PhD of QXV Comms, an

Ashfield Company, part of UDG Healthcare plc, for medical writing support that was

fully funded by Novartis Europharm Limited.

26


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38. Costa DB, Kobayashi S, Pandya SS, Yeo WL, Shen Z, Tan W, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol. 2011;29(15):e443-e5.39. Felip E, Crino L, Kim DW, Spigel DR, Nishio M, Mok T, et al. 141PD: Whole body and intracranial efficacy of ceritinib in patients (pts) with crizotinib (CRZ) pretreated, ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) and baseline brain metastases (BM): Results from ASCEND-1 and ASCEND-2 trials. J Thorac Oncol. 2016;11(4 Suppl):S118-9.40. Johung KL, Yeh N, Desai NB, Williams TM, Lautenschlaeger T, Arvold ND, et al. Extended Survival and Prognostic Factors for Patients With ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastasis. J Clin Oncol. 2016;34(2):123-9.41. Gainor JF, Dardaei L, Yoda S, Friboulet L, Leshchiner I, Katayama R, et al. Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer. Cancer Discovery. 2016;6(10):1118-33.42. Qian M, Zhu B, Wang X, Liebman M. Drug resistance in ALK-positiveNon-small cell lungcancer patients. Semin Cell Dev Biol. 2016;[Epub ahead of print].43. Takeda M, Okamoto I, Nakagawa K. Clinical impact of continued crizotinib administration after isolated central nervous system progression in patients with lung cancer positive for ALK rearrangement. J Thorac Oncol. 2013;8(5):654-7.44. Tan D, Liu G, Kim DW, Thomas M, Felip E, Signorovitch J, et al. 178P: Continuation of ceritinib beyond disease progression is associated with prolonged post-progression survival (PPS) in ALK+ NSCLC. Journal of Thoracic Oncology. 2016;11(4):S134-S5.45. Juan O, Popat S. Ablative Therapy for Oligometastatic Non-Small Cell Lung Cancer. Clin Lung Cancer. 2017.

29


Table 1. All-causality AEs reported across ceritinib clinical trials based on any grade AEs in ≥20% of patients

ASCEND-11 ASCEND-22 ASCEND-33 ASCEND-44 ASCEND-55

AE N=246 N=140 N=124 N=189 N=115

Preferred term

All

grades,

n (%)

Grades 3/4,

n (%)

All

grades, n

(%)

Grades 3/4,

n (%)

All

grades,

n (%)

Grades 3/4,

n (%)

All

grades,

n (%)

Grades

3/4,

n (%)

All

grades,

n (%)

Grades

3/4,

n (%)

Diarrhea213

(86.6)15 (6.1) 112 (80.0) 9 (6.4) 106 (85.5) 4 (3.2) 160 (84.7) 10 (5.3) 83 (72.2) 5 (4.3)

Nausea205

(83.3)15 (6.1) 114 (81.4) 9 (6.4) 96 (77.4) 8 (6.5) 130 (68.8) 5 (2.6) 76 (66.1) 9 (7.8)

Vomiting150

(61.0)11 (4.5) 88 (62.9) 6 (4.3) 89 (71.8) 8 (6.5) 125 (66.1) 10 (5.3) 60 (52.2) 9 (7.8)

ALT increased109

(44.3)73 (29.7) 61 (43.6) 24 (17.1) 62 (50.0) 26 (21.0) 114 (60.3) 58 (30.7) 49 (42.6) 24 (20.9)

Fatigue106

(43.1)12 (4.9) 51 (36.4) 9 (6.4) 47 (37.9) 10 (8.1) 55 (29.1) 8 (4.2) 31 (27.0) 6 (5.2)

Abdominal pain 94 (38.2) 3 (1.2) 44 (31.4) 2 (1.4) 46 (37.1) 1 (0.8) 47 (24.9) 4 (2.1) 25 (21.7) 1 (0.9)

30


Decreased

appetite93 (37.8) 4 (1.6) 57 (40.7) 5 (3.6) 66 (53.2) 4 (3.2) 64 (33.9) 2 (1.1) 48 (41.7) 2 (1.7)

AST increased 81 (32.9) 25 (10.2) 45 (32.1) 7 (5.0) 53 (42.7) 12 (9.7) 100 (52.9) 32 (16.9) 42 (36.5) 16 (13.9)

Constipation 75 (30.5) 0 (0.0) 40 (28.6) 3 (2.1) 31 (25.0) 0 36 (19.0) 0 NR NR

Weight

decreased41 (17.0) 4 (2.0) 48 (34.3) 6 (4.3) 43 (34.7) 2 (1.6) 45 (23.8) 7 (3.7) 34 (29.6) 3 (2.6)

Cough 71 (29.0) 0 (0.0) 30 (21.4) 0 27 (21.8) 0 46 (24.3) 0 NR NR

Dyspnea 62 (25.2) 10 (4.1) 29 (20.7) 8 (5.7) 30 (24.2) 4 (3.2) 29 (15.3) 4 (2.1) NR NR

Abdominal pain

upper59 (24.0) 2 (0.8) NR NR NR NR 39 (20.6) 3 (1.6) NR NR

Headache 51 (20.7) 4 (1.6) NR NR 26 (21.0) 1 (0.8) 31 (16.4) 0 NR NR

Back pain 50 (20.3) 1 (0.4) NR NR 28 (22.6) 3 (2.4) 36 (19.0) 3 (1.6) 25 (21.7) 1 (0.9)

Pyrexia 37 (15.0) 0 29 (20.7) 4 (2.9) NR NR 34 (18.0) 0 NR NR

Asthenia 47 (19.1) 2 (1.0) 25 (17.9) 6 (4.3) NR NR 33 (17.5) 5 (2.6) 26 (22.6) 6 (5.2)

GGT increased 14 (5.7) 7 (2.8) 25 (17.9) 17 (12.1) 34 (27.4) 24 (19.4) 70 (37.0) 54 (29.0) 26 (22.6) 24 (20.9)

Rash 33 (13.0) 0 22 (15.7) 0 25 (20.2) 1 (0.8) NR NR NR NR

31


AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl-transferase; NR, not reported (in ≥20% of

patients).

1Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, et al. Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer

(ASCEND-1): updated results from the multicentre, open-label, phase 1 trial. Lancet Oncol. 2016;17(4):452–63.

2Crino L, Ahn MJ, De Marinis F, Groen HJ, Wakelee H, Hida T, et al. Multicenter Phase II Study of Whole-Body and Intracranial Activity With Ceritinib in

Patients With ALK-Rearranged Non-Small-Cell Lung Cancer Previously Treated With Chemotherapy and Crizotinib: Results From ASCEND-2. J Clin Oncol.

2016.3 Felip E, Orlov S, Park K, Yu C-J, Tsai C-M, Nishio M, et al. Phase II study of ceritinib in ALKi-naïve patients (pts) with ALK-rearranged (ALK+) non-

small cell lung cancer (NSCLC): Whole body responses in the overall pt group and in pts with baseline brain metastases (BM). Annals of Oncology.

2016;27(suppl 6):12080.4Soria J-C, Tan DSW, Chiari R, Wu Y-L, Paz-Ares L, Wolf J, et al. First-line ceritinib versus platinum-based chemotherapy in

advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. The Lancet. 2017;389(10072):917–929.

5Scagliotti G, Kim TM, Crinò L, Liu G, Gridelli C, Novello S, et al. Ceritinib vs chemotherapy (CT) in patients (pts) with advanced anaplastic lymphoma kinase

(ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC) previously treated with CT and crizotinib (CRZ): Results from the confirmatory phase 3

ASCEND-5 study. Annals of Oncology. 2016;27(suppl 6).

32

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