Review
Ceritinib (LDK378): A Potent Alternative to Crizotinib for ALK-Rearranged NoneSmall-Cell Lung Cancer Sen Li,1 Xiaolong Qi,2 Yufeng Huang,3 Dingfeng Liu,2 Fangyu Zhou,4 Caicun Zhou4 Abstract The success in identifying the chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) as an oncogenic driver has thoroughly changed the treatment of nonesmall-cell lung cancer. In the past decade, targeted drugs have emerged as an efficient personalized strategy for ALK-rearranged nonesmall-cell lung cancer. The accelerated approval of potent ALK inhibitors, such as crizotinib and more recently ceritinib (LDK378), based on the well designed phase I/II trials has been a landmark success in clinical cancer research and contributes a new era of oncogenic targeted therapy characterized by elegant clinical trial design. In this review, we aim to present the current knowledge on acquired resistance of crizotinib known as a first-in-class ALK inhibitor and potential solutions to improve the cost-effectiveness, and to review the difference between ceritinib and crizotinib; preclinical data and results of the elegant early clinical trial of ceritinib which promoted its accelerated approval, pharmacokinetics, safety profile, and tolerability, the updated results (eg, efficacy on brain metastases), and robust design of ongoing phase II/III trials, and future directions of ceritinib to be a potent alternative to crizotinib for ALK-rearranged nonesmall-cell lung cancer are also presented. Clinical Lung Cancer, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: ALK inhibitor, Clinical trial, Cost-effectiveness, Pharmacokinetics, Resistance
Introduction Lung cancer is the leading cause of cancer deaths worldwide, generally presenting at diagnosis with locally advanced or metastatic diseases. Nonesmall-cell lung cancer (NSCLC) accounts for 85% of lung cancer cases and has usually reached an advanced stage by the time of diagnosis.1,2 As a member of the insulin receptor superfamily, anaplastic lymphoma kinase (ALK) is a transmembrane receptor tyrosine kinase whose gene is initially identified in a subset of individuals Sen Li, Xiaolong Qi, Yufeng Huang and Dingfeng Liu contributed equally to this work. 1
Department of Spine Surgery, the Affiliated Hospital of Luzhou Medical College, Luzhou, China Department of Gastroenterology, Tongji Hospital, Tongji Unversity School of Medicine, Shanghai, China 3 Department of Oncology, Jingjiang People’s Hospital, Jingjiang, China 4 Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China 2
Submitted: Jul 31, 2014; Revised: Sep 26, 2014; Accepted: Sep 30, 2014 Address for correspondence: Sen Li, MD, PhD, Department of Spine Surgery, the Affiliated Hospital of Luzhou Medical College, 25 Taiping St, Luzhou 646000, China Fax: þ8608302292219; e-mail contact: [email protected]
1525-7304/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cllc.2014.09.011
with anaplastic large-cell lymphoma.1,2 Genetic alterations in ALK are implicated in the pathogenesis of several human cancers. ALK can be aberrantly activated by mutation, gene amplification, or chromosomal rearrangement, leading to the expression of a potent oncogenic driver.3 For instance, echinoderm microtubuleassociated protein-like 4 (EML4) ALK fusion was validated as an oncogenic driver in NSCLC. ALK rearrangement occurs in approximately 5% of cases of NSCLC, predominantly in those with adenocarcinoma, who are of younger age and never- or light smokers.1,3 Cytotoxic chemotherapy is regarded as the mainstay of treatment for metastatic NSCLC. However, this “one-size-fits-all” approach has reached an efficacy plateau and been largely supplanted by “personalized” approaches, such as molecularly targeted therapies, which represent the new era of individual treatment for advanced NSCLC.4 Based on the significant advance, targeting treatment with crizotinib was treated as the standard care for advanced ALK-rearranged NSCLC. Unfortunately, most patients, if not all, will develop an acquired resistance to crizotinib within 12 months after initial response.5,6 Therefore, “next-generation” ALK inhibitors with greater effectiveness are urgently needed.
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Ceritinib for ALK-Rearranged NSCLC Approval of Crizotinib Crizotinib (Xalkori, PF-02341066; Pfizer) is an orally active, multitargeted and small-molecule tyrosine kinase inhibitor.2,4,6 When crizotinib was evaluated against a panel of 120 kinases in biochemical assays and 12 cell-based phosphorylation assays, it was nearly 20-fold more selective for ALK and mesenchymal-epithelial transition factor compared with other kinases.4 Therefore, crizotinib is regarded now as the first-in-class ALK inhibitor by competing for the binding to the tyrosine kinase pocket of ALK with adenosine triphosphate (ATP), prohibiting downstream signaling pathway and then showing an anticancer effect.1,2,4 Particularly, crizotinib showed a remarkable effect against ALK-positive NSCLC, demonstrating the dramatic and prolonged responses with low toxicity.2 The adverse events (AEs) were predominantly restricted to the gastrointestinal and visual systems, and generally self-limiting or easily managed.2 Of note, compared with chemotherapy-treated patients, crizotinib recipients reported a significantly greater overall improvement from baseline (P < .01) in global quality of life and in 4 of 5 functional scales of the European Organization for Research and Treatment of Cancer quality of life questionnaire, QLQ-C30.4,7 Besides, consistent with the results of the overall study population, there was a significant improvement of progression-free survival (PFS) (P ¼ .0003), overall response rate (ORR) (P < .0001), and lung cancer symptoms with the treatment of crizotinib.4,7 In the landmark trials of crizotinib PROFILE 1001 and PROFILE 1005, the primary end points in both studies were ORR according to Response Evaluation Criteria in Solid Tumors (RECIST), safety, and tolerability.4 In PROFILE 1005, median PFS of crizotinib treatment was 8.5 months (95% confidence interval [CI], 6.5-9.9) in an analysis performed after 41.8% of PFS events had occurred; furthermore, it was updated to 8.1 months (95% CI, 6.8-9.7) after 65.5% of PFS events had occurred.4 Therefore, crizotinib was approved by the U.S. Food and Drug Administration based on the validated data in 2011 to treat patients with advanced NSCLC harboring ALK rearrangements.8 To compare crizotinib with standard chemotherapy, PROFILE 1007, the first head-to-head phase III study, was conducted at 105 sites in 21 countries, randomly assigned 347 patients with ALK-positive, stage IIIB or IV NSCLC to crizotinib, pemetrexed, or docetaxel.9 According to the results, median PFS was 7.7 months with crizotinib versus 3 months with chemotherapy (P < .0001). Crizotinib tripled the ORR compared with chemotherapy: 65.3% versus 19.3%, respectively (P < .0001).9 Most recently, PROFILE 1014 was another multicenter, randomized open-label phase III study that compared the efficacy and safety of crizotinib versus pemetrexed-cisplatin or pemetrexed-carboplatin in patients with previously untreated advanced ALK-positive NSCLC. Although most patients are still in follow-up and a significant improvement in overall survival has not yet been demonstrated, the crizotinib arm showed significant improvements in PFS and ORR compared with standard chemotherapy at time of data cutoff.10
Acquired Resistance of Crizotinib
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Despite pronounced initial responses to crizotinib for advanced ALK-positive NSCLC, approximately one-third of such patients inevitably develop a relapse within 12 months.6,11 The mechanisms
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of acquired resistance to crizotinib are generally classified into the ALK-dominant and the ALK-nondominant. The ALK kinase domain mutations alone or in combination with ALK copy number gain are considered as ALK-dominant mechanisms because they basically preserve the ALK signaling dominance in the resistant state.2 ALK-dominant mechanisms involve copy number gain of the fusion gene, genetic alteration of the target by secondary mutations, and inadequate local crizotinib penetration to the central nervous system (Figure 1).6 In a series of studies, numerous secondary mutations in ALK kinase domain were identified from clinical samples including G1269A, 1151Tins, L1152R, G1202R, and S1206Y.6 These mutations led to the resistance by either reducing crizotinib binding or increasing ATP affinity which seems to confer degrees of resistance in vitro.2 Moreover, it is observed that the amplification alone was sufficient to result in the resistance to intermediate concentrations (300 nmol/L) of crizotinib.5,12 ALK-nondominant resistance mechanisms include mutations of other oncogenes such as epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog,2 increased autophosphorylation of EGFR,2 amplification of the v-kit HardyZuckerman feline sarcoma viral oncogene homolog,13 and transformation to sarcomatoid carcinoma (Figure 1).6,7,14 In addition, there were also cell lines from ALK-independent resistant patients retaining sensitivity to crizotinib in vitro, which demonstrated that these cells were still sensitive to ALK inhibitors.3,8 Under this circumstance, tumor cells can survive through reactivation of bypass tracks, such as the EGFR pathway. This is the so-called subtherapeutic inhibition of crizotinib to the target.15 Notably, there are always different mechanisms of developed resistance within the same patient. Therefore, the strategy of combined therapy is reasonable and promising to induce the most durable remissions for patients with crizotinib resistance.6
Cost-Effectiveness of Crizotinib In a phase III, open-label trial that compared crizotinib with chemotherapy in patients with locally advanced or metastatic ALK-positive NSCLC, crizotinib presented an advantage compared with chemotherapy including the median PFS and the ORR.9 However, an interim analysis of overall survival showed no significant improvement with crizotinib. Regardless of acquired resistance after an initial response, the cost-effectiveness of EML4-ALK fusion testing in combination with targeted first-line crizotinib treatment might be another critical challenge to crizotinib.16 Is it reasonable to screen each patient with NSCLC, because only 3% to 5% of the population is ALK-positive, and can we afford to pay for the costly drugs? Djalalov et al conducted a cost-effectiveness analysis using a Markov model in Ontario.17 They suggested that a gain of 0.011 quality-adjusted life-years (QALYs) compared with standard care was acquired via molecular testing with first-line targeted crizotinib treatment. The incremental cost was Canadian $2725 per patient, and the incremental cost-effectiveness ratio (ICER) was $255,970 per QALY gained. Among patients with EML4eALK-positive advanced NSCLC, first-line crizotinib therapy provided 0.379 additional QALYs, cost an additional $95,043 compared with standard care, and produced an ICER of $250,632 per QALY gained.17 In addition, the National Institute for Health and Care
Sen Li et al Figure 1 The Mechanisms of Acquired Resistance to Crizotinib. Anaplastic Lymphoma Kinase (ALK)-Dominant Mechanisms Involve Copy Number Gain of the EML4-ALK Fusion Gene, Genetic Alteration of the Target by Secondary Mutations, and Inadequate Local Crizotinib Penetration to Central Nervous System (CNS). The Secondary Mutations Further Lead to the Resistance by Either Reducing Crizotinib Binding or Increasing Adenosine Triphosphate (ATP) Affinity, Whereas ALK Nondominant Resistance Mechanisms Include Mutations of Other Oncogenes Such as Epidermal Growth Factor Receptor (EGFR) and Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), Increased Autophosphorylation of EGFR, Amplification of V-Kit Hardy-Zuckerman Feline Sarcoma Viral Oncogene Homolog (KIT) and Transformation to Sarcomatoid Carcinoma
Excellence demonstrated that the ICER for crizotinib compared with standard-of-care docetaxel would be more than £100,000 per QALY gained, and for crizotinib compared with best supportive care, would be more than £50,200 per QALY gained.16 Although no one questions the exciting responses obtained with crizotinib, the National Institute for Health and Care Excellence declined approval of crizotinib unfortunately because it could not be considered as a cost-effective use because of the low biomarker frequency and the high drug costs.18,19
Preclinical Study of Ceritinib Ceritinib (LDK378, Zykadia) is a novel, potent and selective small-molecule ATP-competitive second-generation ALK inhibitor, which acts not only in conventional ALK-positive tumors but also in those with the gatekeeper mutation C1156Y and the insulin growth factor-1 receptor.2,6,8,20 Ceritinib is validated as a more potent ALK inhibitor than crizotinib in series of preclinical studies. The representative preclinical evaluation reported by Friboulet et al showed the marked activity in crizotinib-naive models including H2228, H3122, and Ba/F3 cell lines, and MGH006 primary explants in vivo.8 Besides, ceritinib was highly active against common mutations including L1196M, G1269A, S1206Y, and I1171T, however, less active against rare mutations, such as C1156Y, G1202R, 1151T-ins, L1152P, and F1174C.8,21 It resulted as approximately 20-fold more efficient than crizotinib in ALK-rearranged NSCLC cell lines, and showed
more sustained growth inhibition in xenograft models.21 Moreover, a variety of crizotinib-resistant models have also been established to better characterize the activity of ceritinib, including cell lines derived from biopsies of patients resistant to crizotinib. In addition, ceritinib showed potent efficacy against crizotinib-resistant tumors that did not harbor ALK secondary mutations or gene amplification in vitro and in vivo.8
Accelerated Approval of Ceritinib In March 2013, ceritinib was granted accelerated approval by the U.S. Food and Drug Administration, offering an alternative strategy for patients with advanced ALK-positive NSCLC who develop a relapse after crizotinib responses. The accelerated approval was based on a landmark phase I trial that enrolled 163 patients with metastatic ALK-positive NSCLC whose disease progressed during treatment with crizotinib.22 The ORR of ceritinib recipients was 54.6% with a median duration of response of 7.4 months.22 How does ceritinib overcome the resistance to crizotinib and is there any difference between these 2 drugs? The remarkable effect of ceritinib is rooted in its extraordinary chemical structure. For instance, ceritinib can overcome the gatekeeper mutation of L1196M, which leads to the resistance of crizotinib. The polar aromatic amine in the 2-position of the pyridine scaffold of crizotinib might not be ideal to make interactions with a large lipophilic residue at the gatekeeper position, such as methionine.23-25
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Ceritinib for ALK-Rearranged NSCLC However, the chlorine in the 5-position of the pyrimidine of ceritinib could interact more favorably with a methionine gatekeeper.23,24 Therefore, ceritinib can play a better part in interacting with similar large and lipophilic gatekeeper mutants than crizotinib. When it receives favorable interactions with the gatekeeper mutant domain in ALK, ceritinib can suppress the phosphorylation of ALK to a greater extent and compete for the binding with ATP.25-27 In addition, it is noted that interindividual variations of drug levels in plasma might cause insufficient inhibition of the target by crizotinib, which could be less of a problem with ceritinib because it is 20 times as potent as crizotinib.6,23,24 The greater potency of ceritinib might also be sufficient to inhibit the ALK secondary mutations and eventually overcome the resistance.25 Moreover, ceritinib can also decrease cell growth and induce tumor apoptosis by suppressing the phosphorylation of the protein kinase B and extracelluar signal-regulated kinase signaling pathways.16,26,27 Therefore, based on the advantage of the chemical architecture over crizotinib, ceritinib performed better in suppression of phosphorylation of ALK and downstream signaling pathways, resulting in remarkable tumor regression.26,27 Apart from crizotinib, ceritinib is also proposed to overcome the resistance of other next-generation ALK inhibitors, such as alectinib.6,8
Pharmacokinetics of Ceritinib Ceritinib is orally available with a low half maximal inhibitory concentration of a substance of 0.00015 mM and was developed based on the structure of TAE684.28,29 Based on the results of a phase I trial lead by Shaw et al,3 the pharmacokinetic properties of ceritinib were further clarified: first, the maximal plasma concentration (800 205 ng/mL) was achieved approximately 6 hours after the receipt of the established maximum tolerated dose (MTD) over the 3-day pharmacokinetic evaluation period; second, on day 8, the mean SD area under the plasma concentration time curve was 16,500 4750 ng/mL/h during a 24-hour period; third, the mean terminal half-life was approximately 40 hours. Consequently, the steady-state levels of ceritinib were achieved at approximately day 15 after repeated daily dosing based on trough concentrations.3
Tolerability of Ceritinib
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The safety profile of ceritinib was similar but not identical to that of crizotinib. The gastrointestinal AEs during the treatment are similar for both drugs. Besides, both of them are associated with liver function abnormalities, especially an increased level of alanine aminotransferase.3 According to the dose-escalation phase of ceritinib, dose-limiting toxic events included diarrhea, vomiting, dehydration, increased aminotransferase levels, and hypophosphatemia. The most frequent AEs were nausea (59%), vomiting (54%), and diarrhea (48%). The most related AEs were increased alanine aminotransferase levels (21%), increased aspartate aminotransferase levels (11%), diarrhea (7%) and increased lipase levels (7%).3 It is noted that all AEs were reversible with discontinuation of ceritinib therapy, which suggested that these AEs could be effectively administered during the treatment. However, drug-related diarrhea (Grade 3 or 4) was more reported in a ceritinib regimen compared with a crizotinib regimen (7% vs. 0%). Besides, ceritinib had a greater incidence of nausea
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(Grade 3 or 4) than crizotinib (5% vs. 1%).30-32 Therefore, it is essential to clarify the safety profile of ceritinib in the ongoing trials before “pushing” it to the bedside.
Clinical Trials of Ceritinib Phase I Trial
A phase I trial of ceritinib is generally conducted to determine the MTD and safety profile in patients with advanced ALK-positive NSCLC.1,3 The results of a well-designed study were recently reported by Shaw et al.3 The phase I trial included a dose-escalation phase from 50 to 750 mg once daily, followed by an expansion phase in which all the patients received treatment at the maximum dose (750 mg) established in the dose escalation phase. The ORR was 58% (95% CI, 48-67) among 114 patients who received at least 400 mg ceritinib per day. Among 80 patients previously treated with crizotinib, the ORR was 56% (95% CI, 45-67). The median PFS of these patients was 7.0 months (95% CI, 5.6-9.5).3 Strikingly, the response of ceritinib was independent of whether patients were previously treated with crizotinib. It is noted that among patients who have had a disease relapse during treatment with firstgeneration EGFR inhibitors, the ORR of many “next-generation” drugs are < 10%.22,25,33 A similar phase I/II, multicenter, open-label trial (NCT02040870) is ongoing to determine the pharmacokinetics, safety, and tolerability of ceritinib in adult Chinese patients with advanced ALK-positive NSCLC previously treated with crizotinib. Another ongoing phase Ib, open-label trial (NCT01772797) combined heat shock protein 90 inhibitor AUY922 with ceritinib aims to obtain the incidence rate of dose-limiting toxicities in previously untreated patients, which was proven to be a promising strategy to abrogate the resistance of ALK inhibitors in preclinical studies (Table 1). Brain metastasis is currently one of the biggest challenges in treating ALK-positive NSCLC, especially for patients who are resistant to crizotinib. According to the study by Shaw et al, the median PFS with a daily ceritinib dose 400 mg among 64 patients with brain metastases at baseline was similar to that among 50 patients without brain metastases (6.9 months vs. 7.0 months; P ¼ .37).3 In addition, the results of a phase I, singlearm study of ceritinib were updated by Kim et al at the 2014 American Society of Clinical Oncology Annual Meeting.34 Among 124 patients with initial brain metastases, use of ceritinib (750 mg daily) achieved an ORR of 54.0% (95% CI, 44.9%-63.0%) and a median PFS of 6.9 months (95% CI, 5.4-8.4). Tumor shrinkage was observed in 50.0% of patients (95% CI, 39.7%-60.3%) with brain metastases who had received a previous ALK inhibitor and 69.2% of brain metastases patients (95% CI, 48.2%-85.7%) who had not.34 Although these data are “immature,” the marked response to ceritinib has demonstrated a clinically meaningful effect on brain metastases of ALK-positive NSCLC.
Phase II Trial In a phase II, multicenter, single-arm study of crizotinib-naive adult patients with ALK-activated NSCLC (NCT01685138), participants receive the LDK378 750 mg once daily until the patient experiences unacceptable toxicity that precludes further treatment, discontinues treatment at the discretion of the
Sen Li et al Table 1 Ongoing Trials of Ceritinib (LDK378) in Patients With ALK-Rearranged NoneSmall-Cell Lung Cancer Trial Design
Trial ID
Primary Outcome
Previous Therapy
Assigned Interventions
Phase I/II, Multicenter, Open-Label
NCT02040870
Pharmacokinetics; safety and tolerability
Crizotinib
Arm 1: oral LDK378 once daily in adult Chinese patients
Phase Ib, Open-Label
NCT01772797
Incidence rate of DLT
Untreated
Arm 1: oral LDK378 once daily and I.V. AUY922 weekly
Phase II, Multicenter, Open-Label
NCT01685138
ORR
No previous crizotinib, chemotherapy-naive or pretreated with cytotoxic chemotherapy
Arm 1: oral LDK378 750 mg once daily
Phase II, Multicenter, Open-Label
NCT01685060
ORR
Chemotherapy and crizotinib
Arm 1: oral LDK378 750 mg once daily
Phase III, Multicenter, Randomized, Open-Label
NCT01828099
PFS
Untreated
Arm 1: oral LDK378 750 mg once daily Arm 2: pemetrexed 500 mg/m2 with cisplatin 75 mg/m2 every 21 days for 4 cycles followed by pemetrexed 500 mg/m2 every 21 days Arm 3: pemetrexed 500 mg/m2 with carboplatin AUC 5-6 every 21 days for 4 cycles followed by pemetrexed 500 mg/m2 every 21 days
Phase III, Multicenter, Randomized, Open-Label
NCT01828112
PFS
Chemotherapy (platinum doublet) and crizotinib
Arm 1: oral LDK378 750 mg once daily Arm 2: pemetrexed 500 mg/m2 I.V. every 21 days Arm 3: docetaxel 75 mg/m2 I.V. every 21 days
Abbreviations: AUC ¼ the area under the curve; DLT ¼ dose limiting toxicities; I.V. ¼ intravenous infusion; PFS ¼ progression-free survival.
investigator or patient, starts a new anticancer therapy and/or dies. LDK378 may be continued beyond RECIST-defined progressive disease as assessed by the investigator, if in the judgment of the investigator, there is evidence of clinical benefit. Patients who discontinue the study medication in the absence of progression will continue to be followed for tumor assessment until the time of progressive disease. Besides, another similar phase II trial (NCT01685060) aims to further assess the clinical benefit in ALK-activated NSCLC previously treated with chemotherapy and crizotinib. The ORR was defined as the primary outcome measures for both studies (Table 1).
Phase III Trial An ongoing phase III, multicenter, randomized trial (NCT01828099) aims to compare the antitumor activity of LDK378 versus reference chemotherapy in previously untreated ALK-positive, stage IIIB or IV, nonsquamous NSCLC. LDK378 750 mg is given orally once daily in the experimental arm. Pemetrexed 500 mg/m2 with cisplatin 75 mg/m2 every 21 days for 4 cycles followed by pemetrexed 500 mg/m2 every 21 days or pemetrexed 500 mg/m2 with carboplatin the area under the curve 5 to 6 every 21 days for 4 cycles followed by pemetrexed 500 mg/m2 every 21 days is administrated as an active comparator. Simultaneously, another phase III, multicenter, randomized trial (NCT01828112) is exploring the antitumor activity of LDK378 versus chemotherapy in patients previously treated with chemotherapy (platinum doublet) and crizotinib. Oral LDK378 750 mg once daily is given in the experimental arm and pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 intravenously every 21 days is administrated as an active comparator. The primary outcome measure of both phase III trials is PFS (Table 1).
Future Directions of Ceritinib Ceritinib is a potent alternative to crizotinib for advanced ALKpositive NSCLC.2-4 The ongoing trials and proposed studies aim to address the question of whether ALK inhibitors, such as ceritinib and crizotinib, could induce a response for patients with earlier stages of NSCLC, including as adjuvant therapy for patients with surgically resected NSCLC.7 However, to clarify the issue, tumors in the early stage have to be tested for EML4-ALK according to ALK fluorescent in situ hybridization at a cost of more than $250 per test.16,17 Besides, high-priced drugs would be heavily consumed. Thus, we have to fully evaluate the health care costs before ceritinib is “rushed” into the trials for the early-stage treatment. The cost-effectiveness of ceritinib, just like crizotinib, is an upcoming critical challenge although its efficacy for advanced ALK-positive NSCLC has been well validated. Greater efficiencies in development of “next-generation” ALK inhibitors, multiplex testing, or testing for several genomic abnormalities in parallel, or selecting patients for testing on the basis of clinical characteristics would make ceritinib more economically feasible.16-18 Moreover, the combined therapy of ceritinib, such as heat shock protein 90 inhibitor (NCT01772797), and EGFR inhibitor, suggests an alternative approach to manage acquired resistance to ALK inhibitors.8,15,35 The immunotherapeutic agents targeting the checkpoint pathway also show the promising results of prolonged clinical responses in patients with NSCLC and suggest a novel combined strategy in the near future.36
Disclosure The authors have stated that they have no conflicts of interest.
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Ceritinib for ALK-Rearranged NSCLC References 1. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin 2014; 64:9-29. 2. Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. J Clin Oncol 2013; 31:1105-11. 3. Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged nonesmall-cell lung cancer. N Engl J Med 2014; 370:1189-97. 4. Frampton JE. Crizotinib: a review of its use in the treatment of anaplastic lymphoma kinase-positive, advanced nonesmall-cell lung cancer. Drugs 2013; 73: 2031-51. 5. Gridelli C, Peters S, Sgambato A, et al. ALK inhibitors in the treatment of advanced NSCLC. Cancer Treat Rev 2014; 40:300-6. 6. Toyokawa G, Seto T. ALK inhibitors: what is the best way to treat patients with ALKþ nonesmall-cell lung cancer? Clin Lung Cancer 2014; 15:313-9. 7. Steuer CE, Ramalingam SS. ALK-positive nonesmall-cell lung cancer: mechanisms of resistance and emerging treatment options. Cancer 2014; 120:2392-402. 8. Friboulet L, Li N, Katayama R, et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in nonesmall-cell lung cancer. Cancer Discov 2014; 4: 662-73. 9. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013; 368:2385-94. 10. Mok T, Kim DW, Wu YL, et al. First-line crizotinib versus pemetrexed-cisplatin or pemetrexed-carboplatin in patients with advanced ALK-positive non-squamous nonesmall-cell lung cancer: results of a phase III study (PROFILE 1014). J Clin Oncol 2014; 32(suppl):5s (abstract 8002). 11. Timm A, Kolesar JM. Crizotinib for the treatment of nonesmall-cell lung cancer. Am J Health Syst Pharm 2013; 70:943-7. 12. Katayama R, Khan TM, Benes C, et al. Therapeutic strategies to overcome crizotinib resistance in nonesmall-cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci U S A 2011; 108:7535-40. 13. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med 2012; 4:120ra17. 14. Kobayashi Y, Sakao Y, Ito S, et al. Transformation to sarcomatoid carcinoma in ALK-rearranged adenocarcinoma, which developed acquired resistance to crizotinib and received subsequent chemotherapies. J Thorac Oncol 2013; 8: e75-8. 15. Rolfo C, Passiglia F, Russo A, et al. Looking for a new panacea in ALK-rearranged NSCLC: may be ceritinib? Expert Opin Ther Targets 2014; 18:983-5. 16. Kelly RJ, Hillner BE, Smith TJ. Cost effectiveness of crizotinib for anaplastic lymphoma kinase-positive, nonesmall-cell lung cancer: who is going to blink at the cost? J Clin Oncol 2014; 32:983-5. 17. Djalalov S, Beca J, Hoch JS, et al. Cost effectiveness of EML4-ALK fusion testing and first-line crizotinib treatment for patients with advanced ALK-positive nonesmall-cell lung cancer. J Clin Oncol 2014; 32:1012-9. 18. Atherly AJ, Camidge DR. The cost-effectiveness of screening lung cancer patients for targeted drug sensitivity markers. Br J Cancer 2012; 106:1100-6. 19. Rawlins MD. NICE: moving onward. N Engl J Med 2013; 369:3-5.
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20. Kantarjian HM, Fojo T, Mathisen M, et al. Cancer drugs in the United States: Justum Pretiumethe just price. J Clin Oncol 2013; 31:3600-4. 21. Ramalingam SS, Khuri FR. Second-generation ALK inhibitors: filling the non “MET” gap. Cancer Discov 2014; 4:634-6. 22. Ceritinib gains FDA approval for lung cancer. Cancer Discov 2014; 4:753-4. 23. Marsilje TH, Pei W, Chen B, et al. Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)N4-(2-(isopropylsulfonyl)phenyl) pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J Med Chem 2013; 56:5675-90. 24. Chen J, Jiang C, Wang S. LDK378: a promising anaplastic lymphoma kinase (ALK) inhibitor. J Med Chem 2013; 56:5673-4. 25. Thomas RK. Overcoming drug resistance in ALK-rearranged lung cancer. N Engl J Med 2014; 370:1250-1. 26. Katayama R, Friboulet L, Koike S, et al. Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib. Clin Cancer Res [e-pud ahead of print]. Accessed September 16, 2014. http://dx.doi.org/10.1158/ 1078-0432.CCR-14-1511. 27. Goldenberg MM. Pharmaceutical approval update. P T 2014; 39:481-520. 28. Chen Z, Akbay E, Mikse O, et al. Co-clinical trials demonstrate superiority of crizotinib to chemotherapy in ALK-rearranged non-small cell lung cancer and predict strategies to overcome resistance. Clin Cancer Res 2014; 20:1204-11. 29. Galkin AV, Melnick JS, Kim S, et al. Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. Proc Natl Acad Sci U S A 2007; 104:270-5. 30. Perez CA, Velez M, Raez LE, et al. Overcoming the resistance to crizotinib in patients with nonesmall-cell lung cancer harboring EML4/ALK translocation. Lung Cancer 2014; 84:110-5. 31. Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic nonesmall-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol 2012; 13:528-38. 32. Sequist LV, Besse B, Lynch TJ, et al. Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced nonsmall-cell lung cancer. J Clin Oncol 2010; 28:3076-83. 33. Campbell A, Reckamp KL, Camidge DR, et al. PF-00299804 patient reported outcomes and efficacy in adenocarcinoma and nonadeno nonesmall-cell lung cancer: a phase II trial in advanced NSCLC after failure of chemotherapy and erlotinib. J Clin Oncol 2010; 28(suppl):15 (abstract 7596). 34. Kim DW, Mehra R, Tan DSW, et al. Ceritinib in advanced anaplastic lymphoma kinase (ALK)-rearranged (ALKþ) nonesmall-cell lung cancer (NSCLC): Results of the ASCEND-1 trial. J Clin Oncol 2014; 32(suppl):5s (abstract 8003). 35. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol 2012; 13:1011-9. 36. Sundar R, Soong R, Cho BC, et al. Immunotherapy in the treatment of nonesmall-cell lung cancer. Lung Cancer 2014; 85:101-9.
Ceritinib (LDK378): A Potent Alternative to Crizotinib for ALK-Rearranged NoneSmall-Cell Lung Cancer Sen Li,1 Xiaolong Qi,2 Yufeng Huang,3 Dingfeng Liu,2 Fangyu Zhou,4 Caicun Zhou4 Abstract The success in identifying the chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) as an oncogenic driver has thoroughly changed the treatment of nonesmall-cell lung cancer. In the past decade, targeted drugs have emerged as an efficient personalized strategy for ALK-rearranged nonesmall-cell lung cancer. The accelerated approval of potent ALK inhibitors, such as crizotinib and more recently ceritinib (LDK378), based on the well designed phase I/II trials has been a landmark success in clinical cancer research and contributes a new era of oncogenic targeted therapy characterized by elegant clinical trial design. In this review, we aim to present the current knowledge on acquired resistance of crizotinib known as a first-in-class ALK inhibitor and potential solutions to improve the cost-effectiveness, and to review the difference between ceritinib and crizotinib; preclinical data and results of the elegant early clinical trial of ceritinib which promoted its accelerated approval, pharmacokinetics, safety profile, and tolerability, the updated results (eg, efficacy on brain metastases), and robust design of ongoing phase II/III trials, and future directions of ceritinib to be a potent alternative to crizotinib for ALK-rearranged nonesmall-cell lung cancer are also presented. Clinical Lung Cancer, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: ALK inhibitor, Clinical trial, Cost-effectiveness, Pharmacokinetics, Resistance
Introduction Lung cancer is the leading cause of cancer deaths worldwide, generally presenting at diagnosis with locally advanced or metastatic diseases. Nonesmall-cell lung cancer (NSCLC) accounts for 85% of lung cancer cases and has usually reached an advanced stage by the time of diagnosis.1,2 As a member of the insulin receptor superfamily, anaplastic lymphoma kinase (ALK) is a transmembrane receptor tyrosine kinase whose gene is initially identified in a subset of individuals Sen Li, Xiaolong Qi, Yufeng Huang and Dingfeng Liu contributed equally to this work. 1
Department of Spine Surgery, the Affiliated Hospital of Luzhou Medical College, Luzhou, China Department of Gastroenterology, Tongji Hospital, Tongji Unversity School of Medicine, Shanghai, China 3 Department of Oncology, Jingjiang People’s Hospital, Jingjiang, China 4 Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China 2
Submitted: Jul 31, 2014; Revised: Sep 26, 2014; Accepted: Sep 30, 2014 Address for correspondence: Sen Li, MD, PhD, Department of Spine Surgery, the Affiliated Hospital of Luzhou Medical College, 25 Taiping St, Luzhou 646000, China Fax: þ8608302292219; e-mail contact: [email protected]
1525-7304/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cllc.2014.09.011
with anaplastic large-cell lymphoma.1,2 Genetic alterations in ALK are implicated in the pathogenesis of several human cancers. ALK can be aberrantly activated by mutation, gene amplification, or chromosomal rearrangement, leading to the expression of a potent oncogenic driver.3 For instance, echinoderm microtubuleassociated protein-like 4 (EML4) ALK fusion was validated as an oncogenic driver in NSCLC. ALK rearrangement occurs in approximately 5% of cases of NSCLC, predominantly in those with adenocarcinoma, who are of younger age and never- or light smokers.1,3 Cytotoxic chemotherapy is regarded as the mainstay of treatment for metastatic NSCLC. However, this “one-size-fits-all” approach has reached an efficacy plateau and been largely supplanted by “personalized” approaches, such as molecularly targeted therapies, which represent the new era of individual treatment for advanced NSCLC.4 Based on the significant advance, targeting treatment with crizotinib was treated as the standard care for advanced ALK-rearranged NSCLC. Unfortunately, most patients, if not all, will develop an acquired resistance to crizotinib within 12 months after initial response.5,6 Therefore, “next-generation” ALK inhibitors with greater effectiveness are urgently needed.
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Ceritinib for ALK-Rearranged NSCLC Approval of Crizotinib Crizotinib (Xalkori, PF-02341066; Pfizer) is an orally active, multitargeted and small-molecule tyrosine kinase inhibitor.2,4,6 When crizotinib was evaluated against a panel of 120 kinases in biochemical assays and 12 cell-based phosphorylation assays, it was nearly 20-fold more selective for ALK and mesenchymal-epithelial transition factor compared with other kinases.4 Therefore, crizotinib is regarded now as the first-in-class ALK inhibitor by competing for the binding to the tyrosine kinase pocket of ALK with adenosine triphosphate (ATP), prohibiting downstream signaling pathway and then showing an anticancer effect.1,2,4 Particularly, crizotinib showed a remarkable effect against ALK-positive NSCLC, demonstrating the dramatic and prolonged responses with low toxicity.2 The adverse events (AEs) were predominantly restricted to the gastrointestinal and visual systems, and generally self-limiting or easily managed.2 Of note, compared with chemotherapy-treated patients, crizotinib recipients reported a significantly greater overall improvement from baseline (P < .01) in global quality of life and in 4 of 5 functional scales of the European Organization for Research and Treatment of Cancer quality of life questionnaire, QLQ-C30.4,7 Besides, consistent with the results of the overall study population, there was a significant improvement of progression-free survival (PFS) (P ¼ .0003), overall response rate (ORR) (P < .0001), and lung cancer symptoms with the treatment of crizotinib.4,7 In the landmark trials of crizotinib PROFILE 1001 and PROFILE 1005, the primary end points in both studies were ORR according to Response Evaluation Criteria in Solid Tumors (RECIST), safety, and tolerability.4 In PROFILE 1005, median PFS of crizotinib treatment was 8.5 months (95% confidence interval [CI], 6.5-9.9) in an analysis performed after 41.8% of PFS events had occurred; furthermore, it was updated to 8.1 months (95% CI, 6.8-9.7) after 65.5% of PFS events had occurred.4 Therefore, crizotinib was approved by the U.S. Food and Drug Administration based on the validated data in 2011 to treat patients with advanced NSCLC harboring ALK rearrangements.8 To compare crizotinib with standard chemotherapy, PROFILE 1007, the first head-to-head phase III study, was conducted at 105 sites in 21 countries, randomly assigned 347 patients with ALK-positive, stage IIIB or IV NSCLC to crizotinib, pemetrexed, or docetaxel.9 According to the results, median PFS was 7.7 months with crizotinib versus 3 months with chemotherapy (P < .0001). Crizotinib tripled the ORR compared with chemotherapy: 65.3% versus 19.3%, respectively (P < .0001).9 Most recently, PROFILE 1014 was another multicenter, randomized open-label phase III study that compared the efficacy and safety of crizotinib versus pemetrexed-cisplatin or pemetrexed-carboplatin in patients with previously untreated advanced ALK-positive NSCLC. Although most patients are still in follow-up and a significant improvement in overall survival has not yet been demonstrated, the crizotinib arm showed significant improvements in PFS and ORR compared with standard chemotherapy at time of data cutoff.10
Acquired Resistance of Crizotinib
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Despite pronounced initial responses to crizotinib for advanced ALK-positive NSCLC, approximately one-third of such patients inevitably develop a relapse within 12 months.6,11 The mechanisms
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of acquired resistance to crizotinib are generally classified into the ALK-dominant and the ALK-nondominant. The ALK kinase domain mutations alone or in combination with ALK copy number gain are considered as ALK-dominant mechanisms because they basically preserve the ALK signaling dominance in the resistant state.2 ALK-dominant mechanisms involve copy number gain of the fusion gene, genetic alteration of the target by secondary mutations, and inadequate local crizotinib penetration to the central nervous system (Figure 1).6 In a series of studies, numerous secondary mutations in ALK kinase domain were identified from clinical samples including G1269A, 1151Tins, L1152R, G1202R, and S1206Y.6 These mutations led to the resistance by either reducing crizotinib binding or increasing ATP affinity which seems to confer degrees of resistance in vitro.2 Moreover, it is observed that the amplification alone was sufficient to result in the resistance to intermediate concentrations (300 nmol/L) of crizotinib.5,12 ALK-nondominant resistance mechanisms include mutations of other oncogenes such as epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog,2 increased autophosphorylation of EGFR,2 amplification of the v-kit HardyZuckerman feline sarcoma viral oncogene homolog,13 and transformation to sarcomatoid carcinoma (Figure 1).6,7,14 In addition, there were also cell lines from ALK-independent resistant patients retaining sensitivity to crizotinib in vitro, which demonstrated that these cells were still sensitive to ALK inhibitors.3,8 Under this circumstance, tumor cells can survive through reactivation of bypass tracks, such as the EGFR pathway. This is the so-called subtherapeutic inhibition of crizotinib to the target.15 Notably, there are always different mechanisms of developed resistance within the same patient. Therefore, the strategy of combined therapy is reasonable and promising to induce the most durable remissions for patients with crizotinib resistance.6
Cost-Effectiveness of Crizotinib In a phase III, open-label trial that compared crizotinib with chemotherapy in patients with locally advanced or metastatic ALK-positive NSCLC, crizotinib presented an advantage compared with chemotherapy including the median PFS and the ORR.9 However, an interim analysis of overall survival showed no significant improvement with crizotinib. Regardless of acquired resistance after an initial response, the cost-effectiveness of EML4-ALK fusion testing in combination with targeted first-line crizotinib treatment might be another critical challenge to crizotinib.16 Is it reasonable to screen each patient with NSCLC, because only 3% to 5% of the population is ALK-positive, and can we afford to pay for the costly drugs? Djalalov et al conducted a cost-effectiveness analysis using a Markov model in Ontario.17 They suggested that a gain of 0.011 quality-adjusted life-years (QALYs) compared with standard care was acquired via molecular testing with first-line targeted crizotinib treatment. The incremental cost was Canadian $2725 per patient, and the incremental cost-effectiveness ratio (ICER) was $255,970 per QALY gained. Among patients with EML4eALK-positive advanced NSCLC, first-line crizotinib therapy provided 0.379 additional QALYs, cost an additional $95,043 compared with standard care, and produced an ICER of $250,632 per QALY gained.17 In addition, the National Institute for Health and Care
Sen Li et al Figure 1 The Mechanisms of Acquired Resistance to Crizotinib. Anaplastic Lymphoma Kinase (ALK)-Dominant Mechanisms Involve Copy Number Gain of the EML4-ALK Fusion Gene, Genetic Alteration of the Target by Secondary Mutations, and Inadequate Local Crizotinib Penetration to Central Nervous System (CNS). The Secondary Mutations Further Lead to the Resistance by Either Reducing Crizotinib Binding or Increasing Adenosine Triphosphate (ATP) Affinity, Whereas ALK Nondominant Resistance Mechanisms Include Mutations of Other Oncogenes Such as Epidermal Growth Factor Receptor (EGFR) and Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), Increased Autophosphorylation of EGFR, Amplification of V-Kit Hardy-Zuckerman Feline Sarcoma Viral Oncogene Homolog (KIT) and Transformation to Sarcomatoid Carcinoma
Excellence demonstrated that the ICER for crizotinib compared with standard-of-care docetaxel would be more than £100,000 per QALY gained, and for crizotinib compared with best supportive care, would be more than £50,200 per QALY gained.16 Although no one questions the exciting responses obtained with crizotinib, the National Institute for Health and Care Excellence declined approval of crizotinib unfortunately because it could not be considered as a cost-effective use because of the low biomarker frequency and the high drug costs.18,19
Preclinical Study of Ceritinib Ceritinib (LDK378, Zykadia) is a novel, potent and selective small-molecule ATP-competitive second-generation ALK inhibitor, which acts not only in conventional ALK-positive tumors but also in those with the gatekeeper mutation C1156Y and the insulin growth factor-1 receptor.2,6,8,20 Ceritinib is validated as a more potent ALK inhibitor than crizotinib in series of preclinical studies. The representative preclinical evaluation reported by Friboulet et al showed the marked activity in crizotinib-naive models including H2228, H3122, and Ba/F3 cell lines, and MGH006 primary explants in vivo.8 Besides, ceritinib was highly active against common mutations including L1196M, G1269A, S1206Y, and I1171T, however, less active against rare mutations, such as C1156Y, G1202R, 1151T-ins, L1152P, and F1174C.8,21 It resulted as approximately 20-fold more efficient than crizotinib in ALK-rearranged NSCLC cell lines, and showed
more sustained growth inhibition in xenograft models.21 Moreover, a variety of crizotinib-resistant models have also been established to better characterize the activity of ceritinib, including cell lines derived from biopsies of patients resistant to crizotinib. In addition, ceritinib showed potent efficacy against crizotinib-resistant tumors that did not harbor ALK secondary mutations or gene amplification in vitro and in vivo.8
Accelerated Approval of Ceritinib In March 2013, ceritinib was granted accelerated approval by the U.S. Food and Drug Administration, offering an alternative strategy for patients with advanced ALK-positive NSCLC who develop a relapse after crizotinib responses. The accelerated approval was based on a landmark phase I trial that enrolled 163 patients with metastatic ALK-positive NSCLC whose disease progressed during treatment with crizotinib.22 The ORR of ceritinib recipients was 54.6% with a median duration of response of 7.4 months.22 How does ceritinib overcome the resistance to crizotinib and is there any difference between these 2 drugs? The remarkable effect of ceritinib is rooted in its extraordinary chemical structure. For instance, ceritinib can overcome the gatekeeper mutation of L1196M, which leads to the resistance of crizotinib. The polar aromatic amine in the 2-position of the pyridine scaffold of crizotinib might not be ideal to make interactions with a large lipophilic residue at the gatekeeper position, such as methionine.23-25
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Ceritinib for ALK-Rearranged NSCLC However, the chlorine in the 5-position of the pyrimidine of ceritinib could interact more favorably with a methionine gatekeeper.23,24 Therefore, ceritinib can play a better part in interacting with similar large and lipophilic gatekeeper mutants than crizotinib. When it receives favorable interactions with the gatekeeper mutant domain in ALK, ceritinib can suppress the phosphorylation of ALK to a greater extent and compete for the binding with ATP.25-27 In addition, it is noted that interindividual variations of drug levels in plasma might cause insufficient inhibition of the target by crizotinib, which could be less of a problem with ceritinib because it is 20 times as potent as crizotinib.6,23,24 The greater potency of ceritinib might also be sufficient to inhibit the ALK secondary mutations and eventually overcome the resistance.25 Moreover, ceritinib can also decrease cell growth and induce tumor apoptosis by suppressing the phosphorylation of the protein kinase B and extracelluar signal-regulated kinase signaling pathways.16,26,27 Therefore, based on the advantage of the chemical architecture over crizotinib, ceritinib performed better in suppression of phosphorylation of ALK and downstream signaling pathways, resulting in remarkable tumor regression.26,27 Apart from crizotinib, ceritinib is also proposed to overcome the resistance of other next-generation ALK inhibitors, such as alectinib.6,8
Pharmacokinetics of Ceritinib Ceritinib is orally available with a low half maximal inhibitory concentration of a substance of 0.00015 mM and was developed based on the structure of TAE684.28,29 Based on the results of a phase I trial lead by Shaw et al,3 the pharmacokinetic properties of ceritinib were further clarified: first, the maximal plasma concentration (800 205 ng/mL) was achieved approximately 6 hours after the receipt of the established maximum tolerated dose (MTD) over the 3-day pharmacokinetic evaluation period; second, on day 8, the mean SD area under the plasma concentration time curve was 16,500 4750 ng/mL/h during a 24-hour period; third, the mean terminal half-life was approximately 40 hours. Consequently, the steady-state levels of ceritinib were achieved at approximately day 15 after repeated daily dosing based on trough concentrations.3
Tolerability of Ceritinib
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The safety profile of ceritinib was similar but not identical to that of crizotinib. The gastrointestinal AEs during the treatment are similar for both drugs. Besides, both of them are associated with liver function abnormalities, especially an increased level of alanine aminotransferase.3 According to the dose-escalation phase of ceritinib, dose-limiting toxic events included diarrhea, vomiting, dehydration, increased aminotransferase levels, and hypophosphatemia. The most frequent AEs were nausea (59%), vomiting (54%), and diarrhea (48%). The most related AEs were increased alanine aminotransferase levels (21%), increased aspartate aminotransferase levels (11%), diarrhea (7%) and increased lipase levels (7%).3 It is noted that all AEs were reversible with discontinuation of ceritinib therapy, which suggested that these AEs could be effectively administered during the treatment. However, drug-related diarrhea (Grade 3 or 4) was more reported in a ceritinib regimen compared with a crizotinib regimen (7% vs. 0%). Besides, ceritinib had a greater incidence of nausea
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(Grade 3 or 4) than crizotinib (5% vs. 1%).30-32 Therefore, it is essential to clarify the safety profile of ceritinib in the ongoing trials before “pushing” it to the bedside.
Clinical Trials of Ceritinib Phase I Trial
A phase I trial of ceritinib is generally conducted to determine the MTD and safety profile in patients with advanced ALK-positive NSCLC.1,3 The results of a well-designed study were recently reported by Shaw et al.3 The phase I trial included a dose-escalation phase from 50 to 750 mg once daily, followed by an expansion phase in which all the patients received treatment at the maximum dose (750 mg) established in the dose escalation phase. The ORR was 58% (95% CI, 48-67) among 114 patients who received at least 400 mg ceritinib per day. Among 80 patients previously treated with crizotinib, the ORR was 56% (95% CI, 45-67). The median PFS of these patients was 7.0 months (95% CI, 5.6-9.5).3 Strikingly, the response of ceritinib was independent of whether patients were previously treated with crizotinib. It is noted that among patients who have had a disease relapse during treatment with firstgeneration EGFR inhibitors, the ORR of many “next-generation” drugs are < 10%.22,25,33 A similar phase I/II, multicenter, open-label trial (NCT02040870) is ongoing to determine the pharmacokinetics, safety, and tolerability of ceritinib in adult Chinese patients with advanced ALK-positive NSCLC previously treated with crizotinib. Another ongoing phase Ib, open-label trial (NCT01772797) combined heat shock protein 90 inhibitor AUY922 with ceritinib aims to obtain the incidence rate of dose-limiting toxicities in previously untreated patients, which was proven to be a promising strategy to abrogate the resistance of ALK inhibitors in preclinical studies (Table 1). Brain metastasis is currently one of the biggest challenges in treating ALK-positive NSCLC, especially for patients who are resistant to crizotinib. According to the study by Shaw et al, the median PFS with a daily ceritinib dose 400 mg among 64 patients with brain metastases at baseline was similar to that among 50 patients without brain metastases (6.9 months vs. 7.0 months; P ¼ .37).3 In addition, the results of a phase I, singlearm study of ceritinib were updated by Kim et al at the 2014 American Society of Clinical Oncology Annual Meeting.34 Among 124 patients with initial brain metastases, use of ceritinib (750 mg daily) achieved an ORR of 54.0% (95% CI, 44.9%-63.0%) and a median PFS of 6.9 months (95% CI, 5.4-8.4). Tumor shrinkage was observed in 50.0% of patients (95% CI, 39.7%-60.3%) with brain metastases who had received a previous ALK inhibitor and 69.2% of brain metastases patients (95% CI, 48.2%-85.7%) who had not.34 Although these data are “immature,” the marked response to ceritinib has demonstrated a clinically meaningful effect on brain metastases of ALK-positive NSCLC.
Phase II Trial In a phase II, multicenter, single-arm study of crizotinib-naive adult patients with ALK-activated NSCLC (NCT01685138), participants receive the LDK378 750 mg once daily until the patient experiences unacceptable toxicity that precludes further treatment, discontinues treatment at the discretion of the
Sen Li et al Table 1 Ongoing Trials of Ceritinib (LDK378) in Patients With ALK-Rearranged NoneSmall-Cell Lung Cancer Trial Design
Trial ID
Primary Outcome
Previous Therapy
Assigned Interventions
Phase I/II, Multicenter, Open-Label
NCT02040870
Pharmacokinetics; safety and tolerability
Crizotinib
Arm 1: oral LDK378 once daily in adult Chinese patients
Phase Ib, Open-Label
NCT01772797
Incidence rate of DLT
Untreated
Arm 1: oral LDK378 once daily and I.V. AUY922 weekly
Phase II, Multicenter, Open-Label
NCT01685138
ORR
No previous crizotinib, chemotherapy-naive or pretreated with cytotoxic chemotherapy
Arm 1: oral LDK378 750 mg once daily
Phase II, Multicenter, Open-Label
NCT01685060
ORR
Chemotherapy and crizotinib
Arm 1: oral LDK378 750 mg once daily
Phase III, Multicenter, Randomized, Open-Label
NCT01828099
PFS
Untreated
Arm 1: oral LDK378 750 mg once daily Arm 2: pemetrexed 500 mg/m2 with cisplatin 75 mg/m2 every 21 days for 4 cycles followed by pemetrexed 500 mg/m2 every 21 days Arm 3: pemetrexed 500 mg/m2 with carboplatin AUC 5-6 every 21 days for 4 cycles followed by pemetrexed 500 mg/m2 every 21 days
Phase III, Multicenter, Randomized, Open-Label
NCT01828112
PFS
Chemotherapy (platinum doublet) and crizotinib
Arm 1: oral LDK378 750 mg once daily Arm 2: pemetrexed 500 mg/m2 I.V. every 21 days Arm 3: docetaxel 75 mg/m2 I.V. every 21 days
Abbreviations: AUC ¼ the area under the curve; DLT ¼ dose limiting toxicities; I.V. ¼ intravenous infusion; PFS ¼ progression-free survival.
investigator or patient, starts a new anticancer therapy and/or dies. LDK378 may be continued beyond RECIST-defined progressive disease as assessed by the investigator, if in the judgment of the investigator, there is evidence of clinical benefit. Patients who discontinue the study medication in the absence of progression will continue to be followed for tumor assessment until the time of progressive disease. Besides, another similar phase II trial (NCT01685060) aims to further assess the clinical benefit in ALK-activated NSCLC previously treated with chemotherapy and crizotinib. The ORR was defined as the primary outcome measures for both studies (Table 1).
Phase III Trial An ongoing phase III, multicenter, randomized trial (NCT01828099) aims to compare the antitumor activity of LDK378 versus reference chemotherapy in previously untreated ALK-positive, stage IIIB or IV, nonsquamous NSCLC. LDK378 750 mg is given orally once daily in the experimental arm. Pemetrexed 500 mg/m2 with cisplatin 75 mg/m2 every 21 days for 4 cycles followed by pemetrexed 500 mg/m2 every 21 days or pemetrexed 500 mg/m2 with carboplatin the area under the curve 5 to 6 every 21 days for 4 cycles followed by pemetrexed 500 mg/m2 every 21 days is administrated as an active comparator. Simultaneously, another phase III, multicenter, randomized trial (NCT01828112) is exploring the antitumor activity of LDK378 versus chemotherapy in patients previously treated with chemotherapy (platinum doublet) and crizotinib. Oral LDK378 750 mg once daily is given in the experimental arm and pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 intravenously every 21 days is administrated as an active comparator. The primary outcome measure of both phase III trials is PFS (Table 1).
Future Directions of Ceritinib Ceritinib is a potent alternative to crizotinib for advanced ALKpositive NSCLC.2-4 The ongoing trials and proposed studies aim to address the question of whether ALK inhibitors, such as ceritinib and crizotinib, could induce a response for patients with earlier stages of NSCLC, including as adjuvant therapy for patients with surgically resected NSCLC.7 However, to clarify the issue, tumors in the early stage have to be tested for EML4-ALK according to ALK fluorescent in situ hybridization at a cost of more than $250 per test.16,17 Besides, high-priced drugs would be heavily consumed. Thus, we have to fully evaluate the health care costs before ceritinib is “rushed” into the trials for the early-stage treatment. The cost-effectiveness of ceritinib, just like crizotinib, is an upcoming critical challenge although its efficacy for advanced ALK-positive NSCLC has been well validated. Greater efficiencies in development of “next-generation” ALK inhibitors, multiplex testing, or testing for several genomic abnormalities in parallel, or selecting patients for testing on the basis of clinical characteristics would make ceritinib more economically feasible.16-18 Moreover, the combined therapy of ceritinib, such as heat shock protein 90 inhibitor (NCT01772797), and EGFR inhibitor, suggests an alternative approach to manage acquired resistance to ALK inhibitors.8,15,35 The immunotherapeutic agents targeting the checkpoint pathway also show the promising results of prolonged clinical responses in patients with NSCLC and suggest a novel combined strategy in the near future.36
Disclosure The authors have stated that they have no conflicts of interest.
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Ceritinib for ALK-Rearranged NSCLC References 1. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin 2014; 64:9-29. 2. Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. J Clin Oncol 2013; 31:1105-11. 3. Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged nonesmall-cell lung cancer. N Engl J Med 2014; 370:1189-97. 4. Frampton JE. Crizotinib: a review of its use in the treatment of anaplastic lymphoma kinase-positive, advanced nonesmall-cell lung cancer. Drugs 2013; 73: 2031-51. 5. Gridelli C, Peters S, Sgambato A, et al. ALK inhibitors in the treatment of advanced NSCLC. Cancer Treat Rev 2014; 40:300-6. 6. Toyokawa G, Seto T. ALK inhibitors: what is the best way to treat patients with ALKþ nonesmall-cell lung cancer? Clin Lung Cancer 2014; 15:313-9. 7. Steuer CE, Ramalingam SS. ALK-positive nonesmall-cell lung cancer: mechanisms of resistance and emerging treatment options. Cancer 2014; 120:2392-402. 8. Friboulet L, Li N, Katayama R, et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in nonesmall-cell lung cancer. Cancer Discov 2014; 4: 662-73. 9. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013; 368:2385-94. 10. Mok T, Kim DW, Wu YL, et al. First-line crizotinib versus pemetrexed-cisplatin or pemetrexed-carboplatin in patients with advanced ALK-positive non-squamous nonesmall-cell lung cancer: results of a phase III study (PROFILE 1014). J Clin Oncol 2014; 32(suppl):5s (abstract 8002). 11. Timm A, Kolesar JM. Crizotinib for the treatment of nonesmall-cell lung cancer. Am J Health Syst Pharm 2013; 70:943-7. 12. Katayama R, Khan TM, Benes C, et al. Therapeutic strategies to overcome crizotinib resistance in nonesmall-cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci U S A 2011; 108:7535-40. 13. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med 2012; 4:120ra17. 14. Kobayashi Y, Sakao Y, Ito S, et al. Transformation to sarcomatoid carcinoma in ALK-rearranged adenocarcinoma, which developed acquired resistance to crizotinib and received subsequent chemotherapies. J Thorac Oncol 2013; 8: e75-8. 15. Rolfo C, Passiglia F, Russo A, et al. Looking for a new panacea in ALK-rearranged NSCLC: may be ceritinib? Expert Opin Ther Targets 2014; 18:983-5. 16. Kelly RJ, Hillner BE, Smith TJ. Cost effectiveness of crizotinib for anaplastic lymphoma kinase-positive, nonesmall-cell lung cancer: who is going to blink at the cost? J Clin Oncol 2014; 32:983-5. 17. Djalalov S, Beca J, Hoch JS, et al. Cost effectiveness of EML4-ALK fusion testing and first-line crizotinib treatment for patients with advanced ALK-positive nonesmall-cell lung cancer. J Clin Oncol 2014; 32:1012-9. 18. Atherly AJ, Camidge DR. The cost-effectiveness of screening lung cancer patients for targeted drug sensitivity markers. Br J Cancer 2012; 106:1100-6. 19. Rawlins MD. NICE: moving onward. N Engl J Med 2013; 369:3-5.
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20. Kantarjian HM, Fojo T, Mathisen M, et al. Cancer drugs in the United States: Justum Pretiumethe just price. J Clin Oncol 2013; 31:3600-4. 21. Ramalingam SS, Khuri FR. Second-generation ALK inhibitors: filling the non “MET” gap. Cancer Discov 2014; 4:634-6. 22. Ceritinib gains FDA approval for lung cancer. Cancer Discov 2014; 4:753-4. 23. Marsilje TH, Pei W, Chen B, et al. Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)N4-(2-(isopropylsulfonyl)phenyl) pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J Med Chem 2013; 56:5675-90. 24. Chen J, Jiang C, Wang S. LDK378: a promising anaplastic lymphoma kinase (ALK) inhibitor. J Med Chem 2013; 56:5673-4. 25. Thomas RK. Overcoming drug resistance in ALK-rearranged lung cancer. N Engl J Med 2014; 370:1250-1. 26. Katayama R, Friboulet L, Koike S, et al. Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib. Clin Cancer Res [e-pud ahead of print]. Accessed September 16, 2014. http://dx.doi.org/10.1158/ 1078-0432.CCR-14-1511. 27. Goldenberg MM. Pharmaceutical approval update. P T 2014; 39:481-520. 28. Chen Z, Akbay E, Mikse O, et al. Co-clinical trials demonstrate superiority of crizotinib to chemotherapy in ALK-rearranged non-small cell lung cancer and predict strategies to overcome resistance. Clin Cancer Res 2014; 20:1204-11. 29. Galkin AV, Melnick JS, Kim S, et al. Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. Proc Natl Acad Sci U S A 2007; 104:270-5. 30. Perez CA, Velez M, Raez LE, et al. Overcoming the resistance to crizotinib in patients with nonesmall-cell lung cancer harboring EML4/ALK translocation. Lung Cancer 2014; 84:110-5. 31. Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic nonesmall-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol 2012; 13:528-38. 32. Sequist LV, Besse B, Lynch TJ, et al. Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced nonsmall-cell lung cancer. J Clin Oncol 2010; 28:3076-83. 33. Campbell A, Reckamp KL, Camidge DR, et al. PF-00299804 patient reported outcomes and efficacy in adenocarcinoma and nonadeno nonesmall-cell lung cancer: a phase II trial in advanced NSCLC after failure of chemotherapy and erlotinib. J Clin Oncol 2010; 28(suppl):15 (abstract 7596). 34. Kim DW, Mehra R, Tan DSW, et al. Ceritinib in advanced anaplastic lymphoma kinase (ALK)-rearranged (ALKþ) nonesmall-cell lung cancer (NSCLC): Results of the ASCEND-1 trial. J Clin Oncol 2014; 32(suppl):5s (abstract 8003). 35. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol 2012; 13:1011-9. 36. Sundar R, Soong R, Cho BC, et al. Immunotherapy in the treatment of nonesmall-cell lung cancer. Lung Cancer 2014; 85:101-9.
