Expert Review of Clinical Pharmacology
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Ceritinib for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer Lorenza Landi & Federico Cappuzzo To cite this article: Lorenza Landi & Federico Cappuzzo (2016) Ceritinib for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer, Expert Review of Clinical Pharmacology, 9:2, 203-214, DOI: 10.1586/17512433.2016.1122518 To link to this article: http://dx.doi.org/10.1586/17512433.2016.1122518
Accepted author version posted online: 18 Nov 2015. Published online: 16 Dec 2015. Submit your article to this journal
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Date: 17 March 2016, At: 23:58
EXPERT REVIEW OF CLINICAL PHARMACOLOGY, 2016 VOL. 9, NO. 2, 203–214 http://dx.doi.org/10.1586/17512433.2016.1122518
DRUG PROFILE
Ceritinib for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer Lorenza Landi and Federico Cappuzzo
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Medical Oncology Department, Istituto Toscano Tumori, Ospedale Civile, Livorno, Italy ABSTRACT
ARTICLE HISTORY
Non-small cell lung cancer (NSCLC) represents the paradigm of personalized treatment of human cancer. Several oncogenic druggable alterations have been so far identified, with anaplastic lymphoma kinase (ALK) gene rearrangements representing one of the newest and most appealing. Crizotinib is now recognized as the standard of care in ALK-positive NSCLC due to the positive results of recently published trials. Unfortunately, resistance inevitably occurs within the first year of treatment. Overcoming resistance is the major challenge in clinical oncology, and novel potent ALK inhibitors are currently under evaluation, including ceritinib. Ceritinib is an oral, potent, second-generation ALK inhibitor demonstrating activity in patients who develop resistance to crizotinib. Recent data also suggested efficacy in ALK-inhibitor-naive population, thus supporting investigation of the drug in front-line setting.
Received 20 August 2015 Accepted 17 November 2015 Published online 16 December 2015
Introduction First recognized over 25 years ago, alterations in the anaplastic lymphoma kinase (ALK) gene, caused by gene mutations, gene amplifications, or more frequently gene rearrangement – either chromosomal inversion or translocation – are responsible for the development of anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumors (IMT), neuroblastoma (NB), and other solid tumors.[1] In NSCLC, the 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.[2,3] Therefore, the identification of such genetic abnormality reinforced the role of targeted therapies in lung cancer. The EML4–ALK fusion gene is detected in 3–7% of patients with adenocarcinomas of the lung.[4] ALK gene rearrangement is associated with specific clinical pathological features, including male sex, young age, absent or minimal smoking history, adenocarcinoma histology, and usually mutual exclusivity between EML4–ALK and epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma (KRAS) gene mutations.[5–7] Although there are clinical features associated with ALK rearrangement, they do not properly select patients for ALK inhibitors and, consequently, molecular testing is mandatory.[8–10] CONTACT Federico Cappuzzo © 2015 Taylor & Francis
[email protected]
KEYWORDS
Ceritinib; ALK positive NSCLC; crizotinib; ALK-inhibitor; acquired resistance; oncogeneaddicted NSCLC
Generally, all so-far-identified ALK gene rearrangements consist of two portions. The first one is the highly conserved break-point within ALK, located in the intron immediately upstream of the exons encoding the kinase domain; the second one is the 5′-end partners contain a coiled-coil or leucine zipper domain responsible for oligomerization of fusion protein and ligandindependent activation of the ALK tyrosine kinase (TK) activity. Constitutive activation of downstream signaling pathways, such as the Rat Sarcoma/MitogenActivated Protein Kinases, phosphatidylinositide 3kinases/Protein kinase B or AKT and Janus kinase/ Signal Transducer and Activator of Transcription, results in uncontrolled cancer cell proliferation and survival.[11–13] As described for other oncogenes, such as EGFR and human epidermal receptor (HER) 2 deregulations,[14–18] preclinical experiences clearly established the role of ALK gene fusions as a true oncogenic driver and, as shown in in vivo studies, ALK inhibition determines tumor regression in mouse models.[4,19,20] The possibility of obtaining cancer arrest in patients harboring this specific molecular alteration led to the development of anti-ALK strategies. Crizotinib (PF 02341066, Xalkori; Pfizer Inc., New York, NY) was the first ALK inhibitor that was tested in a clinical setting, and results of published trials reported a response rate (RR) of 60% with a progression-free survival (PFS) of 8–10 months. [21–24] Recently, two large phase III trials demonstrated
Istituto Toscano Tumori, Ospedale Civile, viale Alfieri 36, 57100 – Livorno, Italy.
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the superiority of crizotinib over standard chemotherapy, both in first- and second-line settings, thus establishing a new standard of care in ALK-positive NSCLCs. [23,24] Unfortunately, no patient with ALK-positive NSCLC can be cured and within the first year of treatment, majority of the patients become refractory to crizotinib due to the emergence of acquired resistance, with some undefined patients experiencing long-term benefit.[23–25] Ceritinib (LDK378, Zykadia Novartis Pharmaceuticals, Basel, Switzerland) is a novel, oral, highly potent, and selective second-generation ALK inhibitor with a greater preclinical antitumor potency than crizotinib, with demonstrated efficacy in patients with NSCLC who have acquired resistance to crizotinib.[26] Shaw and coworkers recently published the results of a phase I trial in which ceritinib demonstrated impressive and durable responses in a crizotinib-resistant population.[27] Based on these findings, in April 2014, ceritinib was granted FDA-accelerated approval for the treatment of ALK-positive NSCLC patients who progress on or are intolerant to crizotinib.[28] More recently, additional data also confirmed the activity of the drug in ALK-inhibitor-naive individuals.[27,29] The aim of the present review is to discuss pharmacological characteristics and available preclinical and clinical data on ceritinib with a specific focus on ALK-positive NSCLC.
Acquired resistance to crizotinib So far, several mechanisms underlying acquired resistance to crizotinib have been elucidated, and they conventionally belong to two categories (Figure 1). [25,30,31] The first group of mechanisms can be considered as target-dependent, because they preserve the dominance of ALK signaling. ALK-dominant mechanisms
can occur through mutations in the kinase domain of ALK or ALK fusion gene amplification, the latter alone or in combination with resistance mutations.[25,30] ALK mutations account for approximately 30% of the cases of acquired resistance to crizotinib, have comparable frequencies, and seem to be associated with different sensitivity to crizotinib and other ALK inhibitors.[30] A broad spectrum of ALK mutations has been identified in preclinical and clinical models.[31] The first and most well characterized is the L1196M mutation, also called a ‘gatekeeper’ mutation for its ability to interfere with the ligand site of crizotinib.[32] Other mutations are G1202R, S1206Y, G1269A, 1151ins, F1174C, and D1203N.[32,33] Notably, as reported in the seminal phase I trial of crizotinib, different resistant mutant clones may exist in the same patient.[32] Another mechanism of resistance to crizotinib that has been described is an increase in or amplification of the number of rearranged EML4–ALK genes per cell relative to nonresistant cells.[31] In this scenario, it is possible that not all EML4–ALK fusion proteins in a tumor are inhibited by clinically achievable doses of crizotinib, thus allowing sufficient downstream signaling for tumor cell survival. The second group includes ALK nondominant, as they determine the activation of other pathways, such as EGFR or KIT through c-KIT gene amplification. [25,30,34,35] Acquired mutations in EGFR and KRAS after crizotinib therapy in EML4–ALK translocated tumors have been described, but how much these contribute to acquired resistance to crizotinib is unclear.[31] However, reports of the outgrowth of KRAS and EGFR mutated, ALK-negative tumors from patients with ALK translocated NSCLC previously treated with crizotinib might demonstrate the emergence of a separate oncogenic driver as a resistance mechanism.[25]
Figure 1. Molecular mechanisms of acquired resistance to crizotinib in ALK-positive NSCLC.
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Furthermore, there is a consistent fraction of patients for which disease progression occurs only in the central nervous system (CNS), supporting the hypothesis of an inadequate CNS drug penetration.[36–38] Finally, in a consistent fraction not negligible proportion of patients (25%), the mechanism of resistance remains unknown. Therefore, there is an urgent need for novel and more potent compounds that are able to overcome or possibly delay resistance and contrast tumor growth in a sanctuary site of metastases, such as CNS.
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Preclinical pharmacology of ceritinib Ceritinib or 5-Chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-isopropylsulfonyl)phenyl) pyrimidine-2,4-diamine has been synthesized based on its parental compound TAE684 or 5-Chloro-N4-[2-(isopropylsulfonyl)phenyl]-N2-{2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl}-2,4-pyrimidinediamine (Figure 2).[26] In fact, despite the fact that TAE684 was a potent ALK inhibitor, its capability of generating reactive adducts limited its clinical use.[39] Three major changes in the original compound, including reverse of the piperidine at the para position of the aniline moiety, replacement of the methoxy moiety by an isopropoxy moiety, and addition of a methyl group at the position para to the isopropoxy moiety, led to ceritinib.[39] Notably, these modifications not only reduced the metabolic liability and formation of reactive metabolites, but they also improved kinase selectivity.[26] Ceritinib inhibits the autophosphorylation of ALK and its downstream signaling proteins in a dose-dependent manner, thus arresting the proliferation of ALKdependent cancer cells in both in vitro and in vivo models.[26] In enzymatic inhibition assays testing for
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ALK kinase activity, ceritinib resulted approximately 20fold more potent than crizotinib (IC50 of 0.15 nM versus and 3 nM, for ceritinib and crizotinib, respectively). Furthermore, considering a panel of more than 30 additional enzymes, ceritinib demonstrated selectivity for only two other kinases, insulin receptor (InsR) and insulin-like growth factor 1 receptor (IGF1R), even if at approximately 50-fold less potency than ALK inhibition. In addition, at a higher dose, ceritinib also inhibits ROS1.[26] Interestingly, unlike crizotinib, there was no evidence of mesenchymal–epidermal transition (c-MET) protein inhibition.[26] In two different cell lines harboring the nucleophosmin–ALK (Karpas299 human ALCL cells) and the EML4–ALK (H2228 human NSCLC cells) fusion oncogenes, ceritinib suppressed kinase activity, leading to tumor growth inhibition.[26] Ceritinib is highly active in mouse and rat xenograft models of cancers harboring typical ALK translocations, especially lung cancer and ALCL. In murine xenograft models of H2228 NSCLC and Karpas299 ALCL cells, ceritinib determined complete tumor regression when administered at 25 mg/kg daily, a dose lower than the maximum tolerated dose (MTD) established in good laboratory practice (GLP) toxicity studies (30 mg/kg in monkey and 50 mg/kg in rat). By increasing the dose at 50 mg/kg daily for 14 days, in the H2228 NSCLC model, ceritinib determined complete and long-lasting tumor response, exceeding 4.5 months. Conversely, in the same model, crizotinib at the dose of 100 mg/kg daily for 14 days produced similar tumor regression, but tumors rapidly regrew after treatment interruption.[26] More importantly, ceritinib also showed antitumor activity in crizotinib-resistant models harboring common resistant mutations in the ALK kinase domain, [31,40,41] including L1196M, G1269A, S1206Y, and I1171T; however, it was less effective against other rare acquired mutations, such as C1156Y, G1202R, 1151Tins, L1152P, and F1174C.[40,41] In addition, ceritinib also demonstrated activity in crizotinib-resistant models, even in the absence of ALK mutations or gene amplification.[40] Comparison of pharmacodynamics of crizotinib and cerinitinib is reported in Table 1.
Clinical pharmacokinetics (PKs) and metabolism
Figure 2. Chemical structure of ceritinib.
Clinical data on the PK profile of ceritinib have been elucidated in a phase I trial specifically conducted in patients with any type of cancer displaying alterations of ALK gene assessed by fluorescence in situ hybridization (FISH) in NSCLC, or by immunohistochemistry (IHC)
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Table 1. Comparison of pharmacodynamics of crizotinib and ceritinib. Assay Enzymatic ALK IGF-1R c-MET Cell-based - EML4–ALK - L1196M - G1269A - G1202R - C1156Y
CRZ IC50(nM)
LDK378 IC50(nM)
0.15 400 8
0.15 8 3200
120 810 1600 1020 350
20 60 140 490 130
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Legend: CRZ: crizotinib; LDK378: ceritinib; IGF-1 R: insulin-like growth factor 1-receptor.
using ALK-specific antibodies in other type of cancers. [27] This trial, also known as ASCEND-1 (NCT01283516), was a multicentric, international trial, and it consisted of a dose escalation phase initiated at 50 mg per day, followed by a dose expansion phase until MTD, established at 750 mg once daily. The dose escalation phase included a 3-day PK run-in period, where patients assumed a single dose followed by a full PK collection. After the PK run-in phase, ceritinib was given in a continuous daily dosing.[27] After single-dose oral administration, maximal plasma concentrations (Cmax) were achieved at approximately 6 hours after administration of the MTD, and the mean terminal half-life was approximately 40 hours, with a steady state reached at day 15. Systemic exposure increased in a greater than dose-proportional manner following repeat daily doses of 50–750 mg.[27] Compared with fasting conditions, a high-fat meal increased ceritinib area under the concentration–time curve (AUCinf) by 73% and Cmax by 41%, and a low-fat meal increased ceritinib AUCinf by 58% and Cmax by 43% . As previously described in in vitro studies,[26] ceritinib metabolism mainly depends on the CYP3A4/5 isoform. The drug inhibits CYP3A4/5 in a time-dependent fashion, thus having the potential for auto-inhibition. Recently, another phase I trial (NCT01634763) enrolling Japanese patients with locally advanced or metastatic ALK-positive tumors progressing after standard therapies or for which no additional therapy were available, provided additional data on PKs of ceritinib.[42] Similarly to ASCEND-1, the study comprised two parts: a dose escalation and a dose expansion phase. In the escalation part, ceritinib 300–750 mg was administered starting in a 3-day PK run-in period and then once daily in 21-day cycle. Results of the dose escalation phase obtained in 20 individuals (19 NSCLC, 1 IMT) confirmed a dose-proportional PK profile across all dosages and a steady state reached by day 15. The dose expansion phase of the study is currently ongoing.
Clinical studies The remarkable activity of ceritinib in ALK-positive NSCLC has emerged in phase I and II studies. [27,29,42–44] The ASCEND-1 is the first trial to explore the activity of ceritinib in ALK-positive NSCLC.[27] As previously described, the study was a phase I trial consisting of two parts, and it enrolled patients with any type of cancers harboring ALK aberrations. Notably, in the expansion phase, patients diagnosed with ALK-rearranged NSCLC were enrolled regardless any prior ALK inhibitor, thus offering the opportunity to evaluate the drug in the front line as well as in a crizotinib-refractory setting. At the time of the initial publication, the study population included 130 patients of which 59 patients enrolled in the escalation phase and 71 patients in the expansion phase.[27] One hundred and twenty-two patients had an ALK-positive NSCLC, whereas the remaining six patients had other cancer types, such as breast cancers, soft tissue sarcomas, ALCL, and rectal adenocarcinoma. Among the patients with NSCLC, 39 were crizotinib-naïve, 83 crizotinib-pretreated and 64 subjects had brain metastases at baseline. Nineteen of the crizotinib-refractory individuals underwent repeated biopsy at the time of study entry, and in a small fraction of patients, it was possible to detect a secondary ALK mutation (N = 5) or ALK gene amplification (N = 2), whereas the majority (N = 12) retained the original ALK translocation. At a dose of 400–750 mg, ceritinib showed an impressive antitumor activity of around 60% in both crizotinib-pretreated and crizotinib-naïve cohorts. Moreover, responses were also durable (median duration of response, DOR, 8.2 months, 95% CI, 6.9–11.4) with a PFS of 7.0 months (95% CI, 5.6– 9.5). More interestingly, ceritinib demonstrated activity regardless of the presence of CNS lesions or tumor genotype, as demonstrated by the response obtained in the small fraction of patients with secondary ALK mutation or ALK amplification. Updated results of the ASCEND-1 trial, after additional accrual in the expansion cohort, have been recently presented at the European Society for Medical Oncology meeting in September 2014.[43] Overall, 246 individuals with ALK-positive NSCLC (163 crizotinib-pretreated; 83 crizotinib-naive) were enrolled in the study and received ceritinib at the MTD of 750 mg daily. In the overall population, RR was 61.8%, with a median DOR exceeding 9 months and a median PFS of 9.0 months. Interestingly, in the group of patients not previously exposed to ALK inhibitors, RR was numerically higher than the one observed in the crizotinib-pretreated group (72% versus 56.4%), as well median DOR (17.0 versus 8.3 months) and PFS (18.4
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versus 6.9 months). Furthermore, updated results of the trial provided additional information on the impact of ceritinib in brain metastases. Data from 124 subjects with CNS disease at baseline were collected and separately analyzed.[45] Systemic response, DOR, and PFS were consistent with results observed in the general population. Among the 74 evaluable patients, 10 had measurable disease and achieved a partial response (PR) (34%), whereas five patients with nonmeasurable disease obtained complete response, with an intracranial disease control rate (IDCR) of 67.5%. At the time of presentation, median intracranial DOR (IDOR) and PFS (IPFS) were not estimable for the ALK-inhibitor-naive group; conversely, in the crizotinib-pretreated group, they resulted of 6.9 months and 7.0 months, respectively. Similarly, early results obtained in the escalatingdose population of the phase I Japanese trial showed an RR of 55% in patients receiving ceritinib, 300– 750 mg.[42] Although inclusion criteria allowed to enroll any type of cancer with ALK alterations, all but one of the 20 patients had a diagnosis of NSCLC. Among them, only four patients were ALK-inhibitornaive, whereas nine were pretreated with crizotinib and six with two other second-generation inhibitors, such as alectinib (four patients) and ASP3026 (two patients). Interestingly, antitumor activity was observed irrespective of prior ALK inhibitor. Notably, even the patient with IMT achieving PR to ceritinib had previously received the ALK-inhibitor ASP3026. Further, two confirmatory phase II studies in crizotinib-resistant patients and in crizotinib-naïve patients rapidly completed accrual, and their results have been recently presented at the annual meeting of the American Society of Clinical Oncology.[29,44] Both trials had whole body (WB) and intracranial (I) RR, as assessed by investigators, as their primary end point. The ASCEND-2 (NCT01685060) enrolled 140 ALK-positive NSCLC individuals pretreated with at least one prior chemotherapy regimen and who progressed ≤30 days from last treatment with crizotinib.[44] The vast majority of patients was Caucasian (60%) and presented with asymptomatic brain metastases (71.4%), of which approximately one-third had not received palliative radiotherapy. In the overall population, WB RR was approximately 40% with an overall systemic DCR of 77%, whereas median DOR and PFS were 9.7 and 5.7 months, respectively. By splitting the results according to the presence of brain metastases, efficacy measures numerically favored the group of patients without CNS involvement (RR 52% versus 33%; PFS 11.3 versus 5.4 months). However, in the small group of patients with measurable disease, the ICDR reached 80%, with
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complete or PRs observed in five out of the six patients not previously treated with radiotherapy, thus supporting the potential of ceritinib in controlling intracranial lesions. The other study, ASCEND-3 (NCT01685138), included 124 ALK inhibitor-naïve individuals pretreated with no more of three lines of chemotherapy.[29] Also, in this trial, there was a consistent fraction of patients (40%) presenting with brain metastases. The trial confirmed the activity of ceritinib in terms of systemic disease control (WB RR 63%; WB DCR 89.5%) and PFS (11.1 months). Moreover, IDCR resulted of 80% with intracranial activity matching or exceeding systemic responses in patients with measurable disease. Taken into account, these data supported the activity of ceritinib in ALK-positive NSCLC regardless of brain metastases or prior therapy with crizotinib. To further confirm the efficacy of ceritinib in NSCLC, two large phase III trials comparing ceritinib versus chemotherapy, having PFS as the primary end point, are currently ongoing. The ASCEND-4 (NCT01828099) compares ceritinib versus standard cisplatin-pemetrexed or carboplatin-pemetrexed as front-line treatment, whereas the ASCEND-5 (NCT01828112) compares ceritinib versus pemetrexed or docetaxel in subjects previously exposed to platinum-doublet chemotherapy and crizotinib. Finally, an expanded access protocol (NCT01947608) is continuing recruitment in US countries. Table 2 summarizes the main trials with ceritinib.
Safety Data about the safety profile of ceritinib are mainly derived from the above-mentioned ASCEND-1 trial. [27,46] As of December 2012, safety data were available for 131 patients treated at dose levels ranging from 50 to 750 mg daily.[27] Treatment with ceritinib was manageable, with a lower incidence of drug-related adverse events (AEs) observed at lower doses. The most common AEs, irrespective of causality, were gastrointestinal disorders, such as nausea, vomiting, and diarrhea, each occurring in 50% of patients. Most of these AEs were of grades 1–2, with grades 3–4 drug-related AEs of any cause, consisting of increased transaminases (18%), increased lipase (5%), hypokalemia (5%), nausea (5%), and diarrhea (8%). Other less common AEs (all grades) included fatigue (41%), decrease appetite (25%), constipation (24%), and abdominal pain (23%). At data cutoff of December 2012, only 2% of patients discontinued treatment due to unresolved toxicity.[27] All serious adverse events (SAEs) related to study drug and first-cycle dose-limiting toxicities (DLTs)
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Table 2. Summary of the main trials with ceritinib. Trial NCT01283516 (ASCEND-1)
#
I
303
Ceritinib
MTD/ safety
100
Ceritinib
PK/safety ● ALK-positive1,2 Chinese NSCLC pts, CRZ- and CTpretreated
25
Ceritinib
PKs/ safety
● Japanese patients with tumors characterized by
LDK378 + AUY922
MTD
● ALK-positive1 NSCLC progressed during or following
PK/safety ● ALK-positive NSCLC pretreated with CT and CRZ
RR
● ALK-positive1 NSCLC CRZ- and CT-pretreated
Completed (data presented)
NCT02040870 I/II
NCT01634763
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NCT01772797
I
Ib
22
Treatment
End points
Ph.
Key eligibility criteria
● ALK-positive1 NSCLC CRZ- and CT-pretreated ● ALK-positive1 NSCLC CT-pretreated and CRZ-naive ● Other tumors ALK positive1,2 other than NSCLC
genetic alterations in ALK1§
Status Active, not recruiting (data presented)
Active, recruiting
Available data for dose escalating cohort Recruiting (expansion cohort) Active, not recruiting
therapy with an ALKi
NCT02299505
IR
300
NCT01685060 (ASCEND-2)
II
140
Ceritinib 450–600 mg daily^ vs. 750 mg daily^ Ceritinib
NCT01685138 (ASCEND-3)
II
124
Ceritinib
RR
● ALK-positive1 NSCLC CT-pretreated and CRZ-naïve
Completed (data presented)
NCT01964157
II
32
Ceritinib
RR
● ROS1 positive NSCLC pretreated with at least 1 plati-
Active, recruiting
Active, recruiting
num regimen ● Korean pts NCT02336451 (ASCEND-7)
II
NCT01828099
III
125
Ceritinib
RR
● ALK-positive1 NSCLC pretreated with CT and ALK-
Active, recruiting
inhibitors ● Metastases to the brain pr leptomeninges 348
LDK378 PFS vs. CDDP/PEM or CBDCA/PEM NCT01828112 III 236 LDK378 PFS vs. PEM or DCT NCT01947608 ETP Not Ceritinib RR and specified safety
● Untreated ALK-positive2 NSCLC
Recruiting
● ALK positive1 NSCLC CT pretreated and CRZ naive
Recruiting
● ALK-positive1,2 NSCLC pretreated with ALKi or ALKi
Expanded access available
naive *
ETP: expanded treatment protocol; PEM: pemetrexed; DCT: docetaxel; CDDP/PEM: cisplatin/pemetrexed; CBDCA/PEM: carboplatin/pemetrexed; MTD: maximum tolerated dose; PK: pharmacokinetic; DLT: dose-limiting toxicities; RR: response rate; PFS: progression-free survival; ALK-positive: presence of ALK rearrangement, pts: patients, using FISH (Vysis ALK Break Apart FISH Probe Kit Abbott Molecular Inc., Les Plaines, IL, USA) (1) or by immunohistochemistry (2) test using rabbit monoclonal primary antibody assay (D5F3)(Ventana Medical Systems, Inc, Tucson, AZ, USA); CRZ: crizotinib; ALKi: ALK inibitor; § only for NSCLC; *in US countries where ALKi are not approved or available; ^450 or 600 mg daily taken with a low-fat meal versus 750 mg daily taken in fasted state.
defined the MTD occurring at dose levels of 400 mg or higher. SAEs related to ceritinib, as described in the initial report, included one case each of transaminase elevation (400 mg), vomiting (500 mg), dehydration (600 mg), QT prolongation, and interstitial lung disease (750 mg); the latter, occurring in the setting of fever, recovered with antibiotics and ceritinib discontinuation. First-cycle DLTs defining the MTD were: hypophosphatemia (400 mg), ALT elevation (400 mg), nausea with dehydration (600 mg), diarrhea (600 and 750 mg), and vomiting (750 mg).[46] In contrast to crizotinib, treatment with ceritinib was not associated with edema, hypogonadism,
neuropathy, and visual disorders.[27] At study update, the incidence of any grade and any type of AEs was consistent with the one previously reported,[46] with gastrointestinal toxicity being the most typical and frequent. More in details, diarrhea, nausea and vomiting of any grade occurred in 87%, 82%, and 61% of individuals, respectively. Other AEs included fatigue (42% of any grade), abdominal pain (38% of any grade), and transaminase elevation (40% of any grade). At the MTD of 750 mg, 62% of subjects required at least one dose reduction; however, median time of treatment interruption was 1 week, and only 6% of patients permanently discontinued
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treatment due to unresolved AEs. The same results emerged from both ASCEND-2 and ASCEND-3 studies, in which most common AEs of grade 1 or 2 were nausea, vomiting, and diarrhea occurring in up to 80% of treated patients, with a similar drug discontinuation rate due to AEs (7.9% and 7.3%, respectively). [29,44] The safety results of the Japanese phase I study mirrored those observed in the ASCEND-1 population.[42] DLTs, occurring at 600 and 750 mg, consisted of grade 3 lipase increase and grade 3 hepatic injury. MTD was confirmed at 750 mg daily. The vast majority of patients experienced gastrointestinal AEs of any grade, including nausea (95%), diarrhea (75%), vomiting (75%), decreased appetite (53%), and fatigue (37%), whereas grades 3–4 AEs were increased transaminases and hepatic abnormal function, in 2 and 3 patients, respectively. As the vast majority of patients described above had a diagnosis of NSCLC, two-thirds of them were previously exposed to crizotinib and chemotherapy, while the rest were crizotinib-naïve, it is possible to argue that the same toxicity profile will be expected in other ongoing trials with ceritinib in ALK-positive pretreated NSCLC.
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Acquired resistance to ceritinib Although ceritinib has demonstrated impressive activity, once again, tumors become capable of circumventing the drug inhibition.[40,47] Fibroulet et al. reassessed the ALK status of 11 tumor samples obtained from eight patients who failed therapy with ceritinib. Five specimens were positive for secondary mutations, including F1174C, F1174V, and G1202R. More interestingly, F1174C and G1202R were identified in two different metastatic sites of the same patients, thus supporting the intra-patient heterogeneity of resistance mechanisms.[32,40] In addition, the occurrence of a novel ALK mutation, the G1123D, was responsible for acquired resistance to ceritinib in a 58-year-old man who further responded to alectinib.[47]
Other second-generation ALK inhibitors Beyond ceritinib, several novel second-generation ALK inhibitors are currently being investigated in clinical trials, both in crizotinib-refractory and in crizotinibnaïve settings.[48] Among them, alectinib (Alecensa™, CH/RO5424802) and brigatinib (AP26113) have produced interesting results and are currently in advanced phase of clinical development.[49–52]
Drug interactions As previously described, Ceritinib is a CYP3A4/5 inhibitor and also a potent reversible inhibitor of CYP2A6, 2B6, 2C8, 2C9, and 3A4/5.[26,27] As a consequence, a potential increase in the exposure of drugs metabolized by these enzymes can be observed. Moreover, the potential effect of low and moderate CYP3A4/5 inhibitors or inducers on ceritinib clearance is unknown, and clinical studies exploring drug–drug interaction are still lacking. In general, patients with advanced cancer are often older than 50 years and might present several comorbidities, such as cardiovascular-disease, hypertension, gastrointestinal disorders, diabetes, or cancerrelated conditions, including pain or symptomatic brain metastasis, both requiring active and essential therapy with different classes of drugs. This general assumption must be taken into account when considering a patient for a new therapy. In all of the ongoing trials (www.clinicaltrials.gov), caution is advised when ceritinib is co-administered with drugs that are moderate inhibitors or inducers of CYP3A4/5, whereas co-administration with strong inducers of CYP3A4/5 is prohibited. Moreover, clinical protocols recommend to limit or completely avoid, whenever possible, the duration of concomitant treatment due to the risk of increased toxicity or decreased efficacy of ceritinib.
Alectinib Alectinib is a novel, potent, second-generation ALK inhibitor, which gained FDA breakthrough therapy designation for ALK-positive NSCLC owing to the encouraging results that emerged from an ongoing phase I/II trial.[53] In this study including 37 patients with ALK-rearranged NSCLC who progressed after crizotinib and chemotherapy, a PR was observed in 48% of all patients and 59.5% of the subgroup of patients receiving doses of 460 mg or higher twice a day. Sixteen of these ALK-rearranged NSCLC patients had CNS metastases, and alectinib demonstrated rapid benefit in brain metastases in a number of patients, including those resistant to crizotinib. The most common AEs of the drug were fatigue, myalgia, cough, liver enzyme elevation, peripheral edema, and rash.[53] The activity of alectinib in crizotinib-refractory ALK-positive NSCLC has been further investigated in the global phase II trial NP28673. A total of 138 individuals were enrolled in the study, of which 84 presented with brain metastases at baseline. In the overall population, RR and DCR were 50% and 77%, respectively; response was also durable (median DOR, 11.2 months), whereas PFS was approximately
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9 months. Alectinib also produced regression of brain metastases in more than 40% of cases, confirming the strong activity of the drug even in the presence of intracranial disease.[51] Finally, the ALEX trial (NCT 02075840), a phase III trial comparing head-to-head alectinib versus crizotinib just completed accrual, and its results might better define the impact of these second-generation ALK inhibitors as front-line treatment of ALK-positive NSCLC.
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Brigatinib Brigatinib (AP26113) is an orally active kinase inhibitor that potently inhibits mutant activated forms of ALK and EGFR in cell culture models. Preclinical data showed that this agent had a 100-fold selectivity for ALK-positive versus ALK-negative cell lines. In addition, brigatinib was active against several ALK mutations, including the L1196M gatekeeper mutation.[52] In a recent phase I/II study including 79 NSCLC patients with ALK translocation and pretreated with crizotinib, brigatinib showed an impressive RR of 72% with a median PFS of 56 weeks. Of note, 6 of 12 patients with measurable brain lesions at baseline obtained a PR, demonstrating the CNS penetration of the agent. The most common AEs were fatigue (36%), nausea (45%), and diarrhea (36%), which were generally grade 1 or 2 in severity. Early onset (
ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: http://www.tandfonline.com/loi/ierj20
Ceritinib for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer Lorenza Landi & Federico Cappuzzo To cite this article: Lorenza Landi & Federico Cappuzzo (2016) Ceritinib for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer, Expert Review of Clinical Pharmacology, 9:2, 203-214, DOI: 10.1586/17512433.2016.1122518 To link to this article: http://dx.doi.org/10.1586/17512433.2016.1122518
Accepted author version posted online: 18 Nov 2015. Published online: 16 Dec 2015. Submit your article to this journal
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Date: 17 March 2016, At: 23:58
EXPERT REVIEW OF CLINICAL PHARMACOLOGY, 2016 VOL. 9, NO. 2, 203–214 http://dx.doi.org/10.1586/17512433.2016.1122518
DRUG PROFILE
Ceritinib for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer Lorenza Landi and Federico Cappuzzo
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Medical Oncology Department, Istituto Toscano Tumori, Ospedale Civile, Livorno, Italy ABSTRACT
ARTICLE HISTORY
Non-small cell lung cancer (NSCLC) represents the paradigm of personalized treatment of human cancer. Several oncogenic druggable alterations have been so far identified, with anaplastic lymphoma kinase (ALK) gene rearrangements representing one of the newest and most appealing. Crizotinib is now recognized as the standard of care in ALK-positive NSCLC due to the positive results of recently published trials. Unfortunately, resistance inevitably occurs within the first year of treatment. Overcoming resistance is the major challenge in clinical oncology, and novel potent ALK inhibitors are currently under evaluation, including ceritinib. Ceritinib is an oral, potent, second-generation ALK inhibitor demonstrating activity in patients who develop resistance to crizotinib. Recent data also suggested efficacy in ALK-inhibitor-naive population, thus supporting investigation of the drug in front-line setting.
Received 20 August 2015 Accepted 17 November 2015 Published online 16 December 2015
Introduction First recognized over 25 years ago, alterations in the anaplastic lymphoma kinase (ALK) gene, caused by gene mutations, gene amplifications, or more frequently gene rearrangement – either chromosomal inversion or translocation – are responsible for the development of anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumors (IMT), neuroblastoma (NB), and other solid tumors.[1] In NSCLC, the 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.[2,3] Therefore, the identification of such genetic abnormality reinforced the role of targeted therapies in lung cancer. The EML4–ALK fusion gene is detected in 3–7% of patients with adenocarcinomas of the lung.[4] ALK gene rearrangement is associated with specific clinical pathological features, including male sex, young age, absent or minimal smoking history, adenocarcinoma histology, and usually mutual exclusivity between EML4–ALK and epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma (KRAS) gene mutations.[5–7] Although there are clinical features associated with ALK rearrangement, they do not properly select patients for ALK inhibitors and, consequently, molecular testing is mandatory.[8–10] CONTACT Federico Cappuzzo © 2015 Taylor & Francis
[email protected]
KEYWORDS
Ceritinib; ALK positive NSCLC; crizotinib; ALK-inhibitor; acquired resistance; oncogeneaddicted NSCLC
Generally, all so-far-identified ALK gene rearrangements consist of two portions. The first one is the highly conserved break-point within ALK, located in the intron immediately upstream of the exons encoding the kinase domain; the second one is the 5′-end partners contain a coiled-coil or leucine zipper domain responsible for oligomerization of fusion protein and ligandindependent activation of the ALK tyrosine kinase (TK) activity. Constitutive activation of downstream signaling pathways, such as the Rat Sarcoma/MitogenActivated Protein Kinases, phosphatidylinositide 3kinases/Protein kinase B or AKT and Janus kinase/ Signal Transducer and Activator of Transcription, results in uncontrolled cancer cell proliferation and survival.[11–13] As described for other oncogenes, such as EGFR and human epidermal receptor (HER) 2 deregulations,[14–18] preclinical experiences clearly established the role of ALK gene fusions as a true oncogenic driver and, as shown in in vivo studies, ALK inhibition determines tumor regression in mouse models.[4,19,20] The possibility of obtaining cancer arrest in patients harboring this specific molecular alteration led to the development of anti-ALK strategies. Crizotinib (PF 02341066, Xalkori; Pfizer Inc., New York, NY) was the first ALK inhibitor that was tested in a clinical setting, and results of published trials reported a response rate (RR) of 60% with a progression-free survival (PFS) of 8–10 months. [21–24] Recently, two large phase III trials demonstrated
Istituto Toscano Tumori, Ospedale Civile, viale Alfieri 36, 57100 – Livorno, Italy.
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the superiority of crizotinib over standard chemotherapy, both in first- and second-line settings, thus establishing a new standard of care in ALK-positive NSCLCs. [23,24] Unfortunately, no patient with ALK-positive NSCLC can be cured and within the first year of treatment, majority of the patients become refractory to crizotinib due to the emergence of acquired resistance, with some undefined patients experiencing long-term benefit.[23–25] Ceritinib (LDK378, Zykadia Novartis Pharmaceuticals, Basel, Switzerland) is a novel, oral, highly potent, and selective second-generation ALK inhibitor with a greater preclinical antitumor potency than crizotinib, with demonstrated efficacy in patients with NSCLC who have acquired resistance to crizotinib.[26] Shaw and coworkers recently published the results of a phase I trial in which ceritinib demonstrated impressive and durable responses in a crizotinib-resistant population.[27] Based on these findings, in April 2014, ceritinib was granted FDA-accelerated approval for the treatment of ALK-positive NSCLC patients who progress on or are intolerant to crizotinib.[28] More recently, additional data also confirmed the activity of the drug in ALK-inhibitor-naive individuals.[27,29] The aim of the present review is to discuss pharmacological characteristics and available preclinical and clinical data on ceritinib with a specific focus on ALK-positive NSCLC.
Acquired resistance to crizotinib So far, several mechanisms underlying acquired resistance to crizotinib have been elucidated, and they conventionally belong to two categories (Figure 1). [25,30,31] The first group of mechanisms can be considered as target-dependent, because they preserve the dominance of ALK signaling. ALK-dominant mechanisms
can occur through mutations in the kinase domain of ALK or ALK fusion gene amplification, the latter alone or in combination with resistance mutations.[25,30] ALK mutations account for approximately 30% of the cases of acquired resistance to crizotinib, have comparable frequencies, and seem to be associated with different sensitivity to crizotinib and other ALK inhibitors.[30] A broad spectrum of ALK mutations has been identified in preclinical and clinical models.[31] The first and most well characterized is the L1196M mutation, also called a ‘gatekeeper’ mutation for its ability to interfere with the ligand site of crizotinib.[32] Other mutations are G1202R, S1206Y, G1269A, 1151ins, F1174C, and D1203N.[32,33] Notably, as reported in the seminal phase I trial of crizotinib, different resistant mutant clones may exist in the same patient.[32] Another mechanism of resistance to crizotinib that has been described is an increase in or amplification of the number of rearranged EML4–ALK genes per cell relative to nonresistant cells.[31] In this scenario, it is possible that not all EML4–ALK fusion proteins in a tumor are inhibited by clinically achievable doses of crizotinib, thus allowing sufficient downstream signaling for tumor cell survival. The second group includes ALK nondominant, as they determine the activation of other pathways, such as EGFR or KIT through c-KIT gene amplification. [25,30,34,35] Acquired mutations in EGFR and KRAS after crizotinib therapy in EML4–ALK translocated tumors have been described, but how much these contribute to acquired resistance to crizotinib is unclear.[31] However, reports of the outgrowth of KRAS and EGFR mutated, ALK-negative tumors from patients with ALK translocated NSCLC previously treated with crizotinib might demonstrate the emergence of a separate oncogenic driver as a resistance mechanism.[25]
Figure 1. Molecular mechanisms of acquired resistance to crizotinib in ALK-positive NSCLC.
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Furthermore, there is a consistent fraction of patients for which disease progression occurs only in the central nervous system (CNS), supporting the hypothesis of an inadequate CNS drug penetration.[36–38] Finally, in a consistent fraction not negligible proportion of patients (25%), the mechanism of resistance remains unknown. Therefore, there is an urgent need for novel and more potent compounds that are able to overcome or possibly delay resistance and contrast tumor growth in a sanctuary site of metastases, such as CNS.
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Preclinical pharmacology of ceritinib Ceritinib or 5-Chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-isopropylsulfonyl)phenyl) pyrimidine-2,4-diamine has been synthesized based on its parental compound TAE684 or 5-Chloro-N4-[2-(isopropylsulfonyl)phenyl]-N2-{2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl}-2,4-pyrimidinediamine (Figure 2).[26] In fact, despite the fact that TAE684 was a potent ALK inhibitor, its capability of generating reactive adducts limited its clinical use.[39] Three major changes in the original compound, including reverse of the piperidine at the para position of the aniline moiety, replacement of the methoxy moiety by an isopropoxy moiety, and addition of a methyl group at the position para to the isopropoxy moiety, led to ceritinib.[39] Notably, these modifications not only reduced the metabolic liability and formation of reactive metabolites, but they also improved kinase selectivity.[26] Ceritinib inhibits the autophosphorylation of ALK and its downstream signaling proteins in a dose-dependent manner, thus arresting the proliferation of ALKdependent cancer cells in both in vitro and in vivo models.[26] In enzymatic inhibition assays testing for
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ALK kinase activity, ceritinib resulted approximately 20fold more potent than crizotinib (IC50 of 0.15 nM versus and 3 nM, for ceritinib and crizotinib, respectively). Furthermore, considering a panel of more than 30 additional enzymes, ceritinib demonstrated selectivity for only two other kinases, insulin receptor (InsR) and insulin-like growth factor 1 receptor (IGF1R), even if at approximately 50-fold less potency than ALK inhibition. In addition, at a higher dose, ceritinib also inhibits ROS1.[26] Interestingly, unlike crizotinib, there was no evidence of mesenchymal–epidermal transition (c-MET) protein inhibition.[26] In two different cell lines harboring the nucleophosmin–ALK (Karpas299 human ALCL cells) and the EML4–ALK (H2228 human NSCLC cells) fusion oncogenes, ceritinib suppressed kinase activity, leading to tumor growth inhibition.[26] Ceritinib is highly active in mouse and rat xenograft models of cancers harboring typical ALK translocations, especially lung cancer and ALCL. In murine xenograft models of H2228 NSCLC and Karpas299 ALCL cells, ceritinib determined complete tumor regression when administered at 25 mg/kg daily, a dose lower than the maximum tolerated dose (MTD) established in good laboratory practice (GLP) toxicity studies (30 mg/kg in monkey and 50 mg/kg in rat). By increasing the dose at 50 mg/kg daily for 14 days, in the H2228 NSCLC model, ceritinib determined complete and long-lasting tumor response, exceeding 4.5 months. Conversely, in the same model, crizotinib at the dose of 100 mg/kg daily for 14 days produced similar tumor regression, but tumors rapidly regrew after treatment interruption.[26] More importantly, ceritinib also showed antitumor activity in crizotinib-resistant models harboring common resistant mutations in the ALK kinase domain, [31,40,41] including L1196M, G1269A, S1206Y, and I1171T; however, it was less effective against other rare acquired mutations, such as C1156Y, G1202R, 1151Tins, L1152P, and F1174C.[40,41] In addition, ceritinib also demonstrated activity in crizotinib-resistant models, even in the absence of ALK mutations or gene amplification.[40] Comparison of pharmacodynamics of crizotinib and cerinitinib is reported in Table 1.
Clinical pharmacokinetics (PKs) and metabolism
Figure 2. Chemical structure of ceritinib.
Clinical data on the PK profile of ceritinib have been elucidated in a phase I trial specifically conducted in patients with any type of cancer displaying alterations of ALK gene assessed by fluorescence in situ hybridization (FISH) in NSCLC, or by immunohistochemistry (IHC)
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Table 1. Comparison of pharmacodynamics of crizotinib and ceritinib. Assay Enzymatic ALK IGF-1R c-MET Cell-based - EML4–ALK - L1196M - G1269A - G1202R - C1156Y
CRZ IC50(nM)
LDK378 IC50(nM)
0.15 400 8
0.15 8 3200
120 810 1600 1020 350
20 60 140 490 130
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Legend: CRZ: crizotinib; LDK378: ceritinib; IGF-1 R: insulin-like growth factor 1-receptor.
using ALK-specific antibodies in other type of cancers. [27] This trial, also known as ASCEND-1 (NCT01283516), was a multicentric, international trial, and it consisted of a dose escalation phase initiated at 50 mg per day, followed by a dose expansion phase until MTD, established at 750 mg once daily. The dose escalation phase included a 3-day PK run-in period, where patients assumed a single dose followed by a full PK collection. After the PK run-in phase, ceritinib was given in a continuous daily dosing.[27] After single-dose oral administration, maximal plasma concentrations (Cmax) were achieved at approximately 6 hours after administration of the MTD, and the mean terminal half-life was approximately 40 hours, with a steady state reached at day 15. Systemic exposure increased in a greater than dose-proportional manner following repeat daily doses of 50–750 mg.[27] Compared with fasting conditions, a high-fat meal increased ceritinib area under the concentration–time curve (AUCinf) by 73% and Cmax by 41%, and a low-fat meal increased ceritinib AUCinf by 58% and Cmax by 43% . As previously described in in vitro studies,[26] ceritinib metabolism mainly depends on the CYP3A4/5 isoform. The drug inhibits CYP3A4/5 in a time-dependent fashion, thus having the potential for auto-inhibition. Recently, another phase I trial (NCT01634763) enrolling Japanese patients with locally advanced or metastatic ALK-positive tumors progressing after standard therapies or for which no additional therapy were available, provided additional data on PKs of ceritinib.[42] Similarly to ASCEND-1, the study comprised two parts: a dose escalation and a dose expansion phase. In the escalation part, ceritinib 300–750 mg was administered starting in a 3-day PK run-in period and then once daily in 21-day cycle. Results of the dose escalation phase obtained in 20 individuals (19 NSCLC, 1 IMT) confirmed a dose-proportional PK profile across all dosages and a steady state reached by day 15. The dose expansion phase of the study is currently ongoing.
Clinical studies The remarkable activity of ceritinib in ALK-positive NSCLC has emerged in phase I and II studies. [27,29,42–44] The ASCEND-1 is the first trial to explore the activity of ceritinib in ALK-positive NSCLC.[27] As previously described, the study was a phase I trial consisting of two parts, and it enrolled patients with any type of cancers harboring ALK aberrations. Notably, in the expansion phase, patients diagnosed with ALK-rearranged NSCLC were enrolled regardless any prior ALK inhibitor, thus offering the opportunity to evaluate the drug in the front line as well as in a crizotinib-refractory setting. At the time of the initial publication, the study population included 130 patients of which 59 patients enrolled in the escalation phase and 71 patients in the expansion phase.[27] One hundred and twenty-two patients had an ALK-positive NSCLC, whereas the remaining six patients had other cancer types, such as breast cancers, soft tissue sarcomas, ALCL, and rectal adenocarcinoma. Among the patients with NSCLC, 39 were crizotinib-naïve, 83 crizotinib-pretreated and 64 subjects had brain metastases at baseline. Nineteen of the crizotinib-refractory individuals underwent repeated biopsy at the time of study entry, and in a small fraction of patients, it was possible to detect a secondary ALK mutation (N = 5) or ALK gene amplification (N = 2), whereas the majority (N = 12) retained the original ALK translocation. At a dose of 400–750 mg, ceritinib showed an impressive antitumor activity of around 60% in both crizotinib-pretreated and crizotinib-naïve cohorts. Moreover, responses were also durable (median duration of response, DOR, 8.2 months, 95% CI, 6.9–11.4) with a PFS of 7.0 months (95% CI, 5.6– 9.5). More interestingly, ceritinib demonstrated activity regardless of the presence of CNS lesions or tumor genotype, as demonstrated by the response obtained in the small fraction of patients with secondary ALK mutation or ALK amplification. Updated results of the ASCEND-1 trial, after additional accrual in the expansion cohort, have been recently presented at the European Society for Medical Oncology meeting in September 2014.[43] Overall, 246 individuals with ALK-positive NSCLC (163 crizotinib-pretreated; 83 crizotinib-naive) were enrolled in the study and received ceritinib at the MTD of 750 mg daily. In the overall population, RR was 61.8%, with a median DOR exceeding 9 months and a median PFS of 9.0 months. Interestingly, in the group of patients not previously exposed to ALK inhibitors, RR was numerically higher than the one observed in the crizotinib-pretreated group (72% versus 56.4%), as well median DOR (17.0 versus 8.3 months) and PFS (18.4
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versus 6.9 months). Furthermore, updated results of the trial provided additional information on the impact of ceritinib in brain metastases. Data from 124 subjects with CNS disease at baseline were collected and separately analyzed.[45] Systemic response, DOR, and PFS were consistent with results observed in the general population. Among the 74 evaluable patients, 10 had measurable disease and achieved a partial response (PR) (34%), whereas five patients with nonmeasurable disease obtained complete response, with an intracranial disease control rate (IDCR) of 67.5%. At the time of presentation, median intracranial DOR (IDOR) and PFS (IPFS) were not estimable for the ALK-inhibitor-naive group; conversely, in the crizotinib-pretreated group, they resulted of 6.9 months and 7.0 months, respectively. Similarly, early results obtained in the escalatingdose population of the phase I Japanese trial showed an RR of 55% in patients receiving ceritinib, 300– 750 mg.[42] Although inclusion criteria allowed to enroll any type of cancer with ALK alterations, all but one of the 20 patients had a diagnosis of NSCLC. Among them, only four patients were ALK-inhibitornaive, whereas nine were pretreated with crizotinib and six with two other second-generation inhibitors, such as alectinib (four patients) and ASP3026 (two patients). Interestingly, antitumor activity was observed irrespective of prior ALK inhibitor. Notably, even the patient with IMT achieving PR to ceritinib had previously received the ALK-inhibitor ASP3026. Further, two confirmatory phase II studies in crizotinib-resistant patients and in crizotinib-naïve patients rapidly completed accrual, and their results have been recently presented at the annual meeting of the American Society of Clinical Oncology.[29,44] Both trials had whole body (WB) and intracranial (I) RR, as assessed by investigators, as their primary end point. The ASCEND-2 (NCT01685060) enrolled 140 ALK-positive NSCLC individuals pretreated with at least one prior chemotherapy regimen and who progressed ≤30 days from last treatment with crizotinib.[44] The vast majority of patients was Caucasian (60%) and presented with asymptomatic brain metastases (71.4%), of which approximately one-third had not received palliative radiotherapy. In the overall population, WB RR was approximately 40% with an overall systemic DCR of 77%, whereas median DOR and PFS were 9.7 and 5.7 months, respectively. By splitting the results according to the presence of brain metastases, efficacy measures numerically favored the group of patients without CNS involvement (RR 52% versus 33%; PFS 11.3 versus 5.4 months). However, in the small group of patients with measurable disease, the ICDR reached 80%, with
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complete or PRs observed in five out of the six patients not previously treated with radiotherapy, thus supporting the potential of ceritinib in controlling intracranial lesions. The other study, ASCEND-3 (NCT01685138), included 124 ALK inhibitor-naïve individuals pretreated with no more of three lines of chemotherapy.[29] Also, in this trial, there was a consistent fraction of patients (40%) presenting with brain metastases. The trial confirmed the activity of ceritinib in terms of systemic disease control (WB RR 63%; WB DCR 89.5%) and PFS (11.1 months). Moreover, IDCR resulted of 80% with intracranial activity matching or exceeding systemic responses in patients with measurable disease. Taken into account, these data supported the activity of ceritinib in ALK-positive NSCLC regardless of brain metastases or prior therapy with crizotinib. To further confirm the efficacy of ceritinib in NSCLC, two large phase III trials comparing ceritinib versus chemotherapy, having PFS as the primary end point, are currently ongoing. The ASCEND-4 (NCT01828099) compares ceritinib versus standard cisplatin-pemetrexed or carboplatin-pemetrexed as front-line treatment, whereas the ASCEND-5 (NCT01828112) compares ceritinib versus pemetrexed or docetaxel in subjects previously exposed to platinum-doublet chemotherapy and crizotinib. Finally, an expanded access protocol (NCT01947608) is continuing recruitment in US countries. Table 2 summarizes the main trials with ceritinib.
Safety Data about the safety profile of ceritinib are mainly derived from the above-mentioned ASCEND-1 trial. [27,46] As of December 2012, safety data were available for 131 patients treated at dose levels ranging from 50 to 750 mg daily.[27] Treatment with ceritinib was manageable, with a lower incidence of drug-related adverse events (AEs) observed at lower doses. The most common AEs, irrespective of causality, were gastrointestinal disorders, such as nausea, vomiting, and diarrhea, each occurring in 50% of patients. Most of these AEs were of grades 1–2, with grades 3–4 drug-related AEs of any cause, consisting of increased transaminases (18%), increased lipase (5%), hypokalemia (5%), nausea (5%), and diarrhea (8%). Other less common AEs (all grades) included fatigue (41%), decrease appetite (25%), constipation (24%), and abdominal pain (23%). At data cutoff of December 2012, only 2% of patients discontinued treatment due to unresolved toxicity.[27] All serious adverse events (SAEs) related to study drug and first-cycle dose-limiting toxicities (DLTs)
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Table 2. Summary of the main trials with ceritinib. Trial NCT01283516 (ASCEND-1)
#
I
303
Ceritinib
MTD/ safety
100
Ceritinib
PK/safety ● ALK-positive1,2 Chinese NSCLC pts, CRZ- and CTpretreated
25
Ceritinib
PKs/ safety
● Japanese patients with tumors characterized by
LDK378 + AUY922
MTD
● ALK-positive1 NSCLC progressed during or following
PK/safety ● ALK-positive NSCLC pretreated with CT and CRZ
RR
● ALK-positive1 NSCLC CRZ- and CT-pretreated
Completed (data presented)
NCT02040870 I/II
NCT01634763
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NCT01772797
I
Ib
22
Treatment
End points
Ph.
Key eligibility criteria
● ALK-positive1 NSCLC CRZ- and CT-pretreated ● ALK-positive1 NSCLC CT-pretreated and CRZ-naive ● Other tumors ALK positive1,2 other than NSCLC
genetic alterations in ALK1§
Status Active, not recruiting (data presented)
Active, recruiting
Available data for dose escalating cohort Recruiting (expansion cohort) Active, not recruiting
therapy with an ALKi
NCT02299505
IR
300
NCT01685060 (ASCEND-2)
II
140
Ceritinib 450–600 mg daily^ vs. 750 mg daily^ Ceritinib
NCT01685138 (ASCEND-3)
II
124
Ceritinib
RR
● ALK-positive1 NSCLC CT-pretreated and CRZ-naïve
Completed (data presented)
NCT01964157
II
32
Ceritinib
RR
● ROS1 positive NSCLC pretreated with at least 1 plati-
Active, recruiting
Active, recruiting
num regimen ● Korean pts NCT02336451 (ASCEND-7)
II
NCT01828099
III
125
Ceritinib
RR
● ALK-positive1 NSCLC pretreated with CT and ALK-
Active, recruiting
inhibitors ● Metastases to the brain pr leptomeninges 348
LDK378 PFS vs. CDDP/PEM or CBDCA/PEM NCT01828112 III 236 LDK378 PFS vs. PEM or DCT NCT01947608 ETP Not Ceritinib RR and specified safety
● Untreated ALK-positive2 NSCLC
Recruiting
● ALK positive1 NSCLC CT pretreated and CRZ naive
Recruiting
● ALK-positive1,2 NSCLC pretreated with ALKi or ALKi
Expanded access available
naive *
ETP: expanded treatment protocol; PEM: pemetrexed; DCT: docetaxel; CDDP/PEM: cisplatin/pemetrexed; CBDCA/PEM: carboplatin/pemetrexed; MTD: maximum tolerated dose; PK: pharmacokinetic; DLT: dose-limiting toxicities; RR: response rate; PFS: progression-free survival; ALK-positive: presence of ALK rearrangement, pts: patients, using FISH (Vysis ALK Break Apart FISH Probe Kit Abbott Molecular Inc., Les Plaines, IL, USA) (1) or by immunohistochemistry (2) test using rabbit monoclonal primary antibody assay (D5F3)(Ventana Medical Systems, Inc, Tucson, AZ, USA); CRZ: crizotinib; ALKi: ALK inibitor; § only for NSCLC; *in US countries where ALKi are not approved or available; ^450 or 600 mg daily taken with a low-fat meal versus 750 mg daily taken in fasted state.
defined the MTD occurring at dose levels of 400 mg or higher. SAEs related to ceritinib, as described in the initial report, included one case each of transaminase elevation (400 mg), vomiting (500 mg), dehydration (600 mg), QT prolongation, and interstitial lung disease (750 mg); the latter, occurring in the setting of fever, recovered with antibiotics and ceritinib discontinuation. First-cycle DLTs defining the MTD were: hypophosphatemia (400 mg), ALT elevation (400 mg), nausea with dehydration (600 mg), diarrhea (600 and 750 mg), and vomiting (750 mg).[46] In contrast to crizotinib, treatment with ceritinib was not associated with edema, hypogonadism,
neuropathy, and visual disorders.[27] At study update, the incidence of any grade and any type of AEs was consistent with the one previously reported,[46] with gastrointestinal toxicity being the most typical and frequent. More in details, diarrhea, nausea and vomiting of any grade occurred in 87%, 82%, and 61% of individuals, respectively. Other AEs included fatigue (42% of any grade), abdominal pain (38% of any grade), and transaminase elevation (40% of any grade). At the MTD of 750 mg, 62% of subjects required at least one dose reduction; however, median time of treatment interruption was 1 week, and only 6% of patients permanently discontinued
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treatment due to unresolved AEs. The same results emerged from both ASCEND-2 and ASCEND-3 studies, in which most common AEs of grade 1 or 2 were nausea, vomiting, and diarrhea occurring in up to 80% of treated patients, with a similar drug discontinuation rate due to AEs (7.9% and 7.3%, respectively). [29,44] The safety results of the Japanese phase I study mirrored those observed in the ASCEND-1 population.[42] DLTs, occurring at 600 and 750 mg, consisted of grade 3 lipase increase and grade 3 hepatic injury. MTD was confirmed at 750 mg daily. The vast majority of patients experienced gastrointestinal AEs of any grade, including nausea (95%), diarrhea (75%), vomiting (75%), decreased appetite (53%), and fatigue (37%), whereas grades 3–4 AEs were increased transaminases and hepatic abnormal function, in 2 and 3 patients, respectively. As the vast majority of patients described above had a diagnosis of NSCLC, two-thirds of them were previously exposed to crizotinib and chemotherapy, while the rest were crizotinib-naïve, it is possible to argue that the same toxicity profile will be expected in other ongoing trials with ceritinib in ALK-positive pretreated NSCLC.
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Acquired resistance to ceritinib Although ceritinib has demonstrated impressive activity, once again, tumors become capable of circumventing the drug inhibition.[40,47] Fibroulet et al. reassessed the ALK status of 11 tumor samples obtained from eight patients who failed therapy with ceritinib. Five specimens were positive for secondary mutations, including F1174C, F1174V, and G1202R. More interestingly, F1174C and G1202R were identified in two different metastatic sites of the same patients, thus supporting the intra-patient heterogeneity of resistance mechanisms.[32,40] In addition, the occurrence of a novel ALK mutation, the G1123D, was responsible for acquired resistance to ceritinib in a 58-year-old man who further responded to alectinib.[47]
Other second-generation ALK inhibitors Beyond ceritinib, several novel second-generation ALK inhibitors are currently being investigated in clinical trials, both in crizotinib-refractory and in crizotinibnaïve settings.[48] Among them, alectinib (Alecensa™, CH/RO5424802) and brigatinib (AP26113) have produced interesting results and are currently in advanced phase of clinical development.[49–52]
Drug interactions As previously described, Ceritinib is a CYP3A4/5 inhibitor and also a potent reversible inhibitor of CYP2A6, 2B6, 2C8, 2C9, and 3A4/5.[26,27] As a consequence, a potential increase in the exposure of drugs metabolized by these enzymes can be observed. Moreover, the potential effect of low and moderate CYP3A4/5 inhibitors or inducers on ceritinib clearance is unknown, and clinical studies exploring drug–drug interaction are still lacking. In general, patients with advanced cancer are often older than 50 years and might present several comorbidities, such as cardiovascular-disease, hypertension, gastrointestinal disorders, diabetes, or cancerrelated conditions, including pain or symptomatic brain metastasis, both requiring active and essential therapy with different classes of drugs. This general assumption must be taken into account when considering a patient for a new therapy. In all of the ongoing trials (www.clinicaltrials.gov), caution is advised when ceritinib is co-administered with drugs that are moderate inhibitors or inducers of CYP3A4/5, whereas co-administration with strong inducers of CYP3A4/5 is prohibited. Moreover, clinical protocols recommend to limit or completely avoid, whenever possible, the duration of concomitant treatment due to the risk of increased toxicity or decreased efficacy of ceritinib.
Alectinib Alectinib is a novel, potent, second-generation ALK inhibitor, which gained FDA breakthrough therapy designation for ALK-positive NSCLC owing to the encouraging results that emerged from an ongoing phase I/II trial.[53] In this study including 37 patients with ALK-rearranged NSCLC who progressed after crizotinib and chemotherapy, a PR was observed in 48% of all patients and 59.5% of the subgroup of patients receiving doses of 460 mg or higher twice a day. Sixteen of these ALK-rearranged NSCLC patients had CNS metastases, and alectinib demonstrated rapid benefit in brain metastases in a number of patients, including those resistant to crizotinib. The most common AEs of the drug were fatigue, myalgia, cough, liver enzyme elevation, peripheral edema, and rash.[53] The activity of alectinib in crizotinib-refractory ALK-positive NSCLC has been further investigated in the global phase II trial NP28673. A total of 138 individuals were enrolled in the study, of which 84 presented with brain metastases at baseline. In the overall population, RR and DCR were 50% and 77%, respectively; response was also durable (median DOR, 11.2 months), whereas PFS was approximately
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9 months. Alectinib also produced regression of brain metastases in more than 40% of cases, confirming the strong activity of the drug even in the presence of intracranial disease.[51] Finally, the ALEX trial (NCT 02075840), a phase III trial comparing head-to-head alectinib versus crizotinib just completed accrual, and its results might better define the impact of these second-generation ALK inhibitors as front-line treatment of ALK-positive NSCLC.
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Brigatinib Brigatinib (AP26113) is an orally active kinase inhibitor that potently inhibits mutant activated forms of ALK and EGFR in cell culture models. Preclinical data showed that this agent had a 100-fold selectivity for ALK-positive versus ALK-negative cell lines. In addition, brigatinib was active against several ALK mutations, including the L1196M gatekeeper mutation.[52] In a recent phase I/II study including 79 NSCLC patients with ALK translocation and pretreated with crizotinib, brigatinib showed an impressive RR of 72% with a median PFS of 56 weeks. Of note, 6 of 12 patients with measurable brain lesions at baseline obtained a PR, demonstrating the CNS penetration of the agent. The most common AEs were fatigue (36%), nausea (45%), and diarrhea (36%), which were generally grade 1 or 2 in severity. Early onset (
