JJCO

Japanese Journal of Clinical Oncology

Japanese Journal of Clinical Oncology, 2017, 1–7 doi: 10.1093/jjco/hyx045 Original Article

Original Article

Ceritinib in patients with advanced, crizotinib-treated, anaplastic lymphoma kinase-rearranged NSCLC: Japanese subset Toyoaki Hida1,*, Miyako Satouchi2, Kazuhiko Nakagawa3, Takashi Seto4, Shingo Matsumoto5, Katsuyuki Kiura6, Hiroshi Nokihara7, Haruyasu Murakami8, Kota Tokushige9, Ben Hatano9, and Makoto Nishio10 1

Department of Thoracic Oncology, Aichi Cancer Center, Nagoya, 2Department of Thoracic Oncology, Hyogo Cancer Center, Akashi, 3Department of Medical Oncology, Kindai University Hospital, Osaka, 4Department of Thoracic Oncology, Kyushu Cancer Center, Fukuoka, 5Division of Thoracic Oncology, National Cancer Center Hospital East, Chiba, 6Department of Allergy and Respiratory Medicine-Thoracic Oncology, Okayama University Hospital, Okayama, 7Department of Thoracic Oncology, National Cancer Center, Tokyo, 8Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, 9Oncology Clinical Development and Medical Affairs Division, Novartis Pharma K.K., Tokyo, and 10Thoracic Center – Thoracic Medical Oncology, The Cancer Institute Hospital of JFCR, Tokyo, Japan *For reprints and all correspondence: Toyoaki Hida, Aichi Cancer Center, Nagoya, Aichi 464-8681, Japan. E-mail: [email protected] Received 20 December 2016; Editorial Decision 10 March 2017; Accepted 23 March 2017

Abstract Introduction: Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer is sensitive to tyrosine kinase inhibitors; however, resistance can develop. Data are presented from the phase II trial (ASCEND-2) evaluating efficacy and safety in a subset of Japanese patients with ALKrearranged non-small cell lung cancer previously treated with platinum-based chemotherapy, who experienced disease progression on crizotinib. Methods: Patients with advanced ALK-rearranged non-small cell lung cancer, including those with asymptomatic or neurologically stable baseline brain metastases, received oral ceritinib 750 mg/day. Whole-body and intracranial responses were assessed by investigator and Blinded Independent Review Committee (RECIST v1.1). Safety and tolerability were also investigated. Results: All 24 Japanese patients had received ≥2 previous treatment regimens, with crizotinib the last therapy received prior to ceritinib. Median duration of ceritinib exposure was 8.1 (range: 0.2–12.5) months. Overall response rate was 45.8% (95% confidence interval: 25.6–67.2). Other efficacy endpoints included disease control rate (79.2% [95% confidence interval: 57.8–92.9]), time to response (median 1.9 months [range: 1.7–3.5]), duration of response (median 9.2 months [95% confidence interval: 4.0–not estimable]) and progression-free survival (median 6.6 months [95% confidence interval: 3.7–9.3]). Of the four patients with active baseline target brain lesions, two achieved an intracranial partial response (50%). The most commonly reported adverse events (majority grade 1/2) were nausea (91.7%), diarrhea (83.3%) and vomiting (83.3%). Conclusions: This study demonstrates the clinical activity and manageable tolerability of ceritinib in a Japanese subset of chemotherapy- and crizotinib-pretreated patients with ALK-rearranged non-small cell lung cancer who progressed on crizotinib, as was shown in the whole ASCEND-2 study population. ClinicalTrials.gov identifier: NCT01685060 © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected].

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Ceritinib in ALK-rearranged NSCLC Japanese patients

Key words: Clinical Trials, interventional therapy, lung medicine, thoracic, thoracic-others

Introduction Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase first discovered in anaplastic large cell lymphoma (1). Activating mutations or translocations of the ALK gene have been identified in several types of cancer, including non-small cell lung cancer (NSCLC) (2), with ALK rearrangement occurring in 2–7% of patients with NSCLC (3). As ALK gene rearrangement can trigger oncogenic signaling pathways, inhibition of ALK by tyrosine kinase inhibitors could lead to suppression of potential oncogenic drivers (4). In patients with advanced ALK-rearranged (ALK+) NSCLC, ALKtargeted therapy has been shown to be superior to standard chemotherapy in both patients who had received prior antineoplastic therapy (5) and in those who were treatment-naïve (6). Crizotinib was the first oral ALK inhibitor (ALKi) approved by the US Food and Drug Administration (FDA) in 2011 for the treatment of patients with advanced ALK+ NSCLC. Although crizotinib has demonstrated superior efficacy compared with standard firstline or second-line chemotherapy in patients with metastatic ALK+ NSCLC (6,7), the development of ALK-dependent crizotinib resistance is a considerable problem for these patients. As the majority of patients show signs of disease progression within the first year of treatment (4,8,9), it is important that next-generation ALKi treatments that demonstrate clinical activity against crizotinib-resistant ALK+ NSCLC are available. As this subset of patients have already failed on multiple prior treatment regimens, there is a clear need for alternative treatments for this patient population. Ceritinib is a selective oral ALKi, with 20-fold greater potency than crizotinib in enzymatic assays (4). It has been demonstrated to cross the blood–brain barrier in rats, with a brain-to-blood exposure [area under the plasma concentration versus time curve from zero to infinity (AUCinf)] ratio of ~15% (10). Clinical data support these findings, with ceritinib achieving intracranial activity (11). The efficacy of ceritinib in ALKi-naïve patients and in patients pretreated with crizotinib was first demonstrated in the global pivotal phase I, dose-escalation/dose-expansion ASCEND-1 study (12). Additionally, a phase I study in Japanese patients with ALK+ malignancies (including NSCLC; NCT01634763) showed a tolerable safety profile and clinical activity similar to that reported for ASCEND-1 following treatment with ceritinib (4). The overall efficacy and safety results for all 140 ALK-rearranged NSCLC patients enrolled in the ASCEND-2 study who were treated with ceritinib 750 mg/day have previously been published (11). Here, we describe the efficacy and safety results for the subpopulation of 24 Japanese patients enrolled in the ASCEND-2 study.

Patients and methods Patient population The Japanese patients were adults with locally advanced or metastatic ALK-rearranged NSCLC confirmed by the FDA-approved fluorescence in-situ hybridization (FISH) assay. Local site confirmation of ALK positivity was acceptable; however, if documentation was unavailable, a confirmatory FISH assay performed at a Novartis-designated central laboratory was required. Further key inclusion criteria for this study included a World Health

Organization (WHO) performance status of 0–2 and measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Additionally, patients must have received prior treatment with 1–3 lines of chemotherapy, which must have included at least one platinum-based chemotherapy regimen, as well as with crizotinib, with crizotinib being the last systemic antineoplastic therapy prior to study entry. All patients must have had disease progression during treatment with crizotinib or within 30 days of last administered dose. First-line treatment with crizotinib followed by cytotoxic chemotherapy and subsequent rechallenge with crizotinib was permitted. Last dose of crizotinib must have been administered ≥1 week before initiation of ceritinib treatment. In addition, any crizotinib-related toxicities must have been resolved to a Common Terminology Criteria for Adverse Events (CTCAE) grade ≤2 before starting ceritinib therapy. Patients with measurable central nervous system disease were included in this study, as long as they were controlled or asymptomatic and did not require increasing doses of steroids within 2 weeks of the study start. Any patient with an impairment of gastrointestinal (GI) function or GI disease that may have significantly altered the absorption of ceritinib was excluded. Further key exclusion criteria included any patient with clinically significant, uncontrolled heart disease and all patients who had undergone any prior therapy with an ALKi other than crizotinib. The protocol was approved by the local institutional review board for each site that participated in the study and written consent was obtained from all patients before screening. This study was conducted in accordance with the principles of the Declaration of Helsinki and the Good Clinical Practice Guidelines of the International Conference on Harmonization.

Study design This was a single-arm, open-label, multicenter, phase II study in patients with ALK-rearranged NSCLC. All patients received ceritinib 750 mg/day on a continuous dosing schedule. The objective of this study was to demonstrate antitumor activity of ceritinib on overall response rate (ORR) as assessed by the investigator. Additional objectives included duration of response (DOR), disease control rate (DCR), time to response (TTR) and overall intracranial response rate (OIRR) as assessed by the investigator and Blinded Independent Review Committee (BIRC), and ORR as assessed by the BIRC. Further secondary objectives were to evaluate progression-free survival (PFS) as assessed by the investigator and the BIRC, overall survival (OS), and to determine the overall tolerability and safety profile of ceritinib 750 mg/day.

Study assessments Efficacy analysis An active target lesion was defined as an investigator- and BIRCassessed measurable lesion, which was either a new untreated metastasis or an existing lesion in progression following local therapy. Assessments of tumor response and progression were performed every 8 weeks. Whole-body (extra- and intracranial sites of disease) and intracranial responses were calculated by the investigator and by the BIRC, according to RECIST 1.1 criteria. Whole-body

Jpn J Clin Oncol, 2017 responses included ORR, DCR, DOR, PFS and TTR. Intracranial responses included OIRR and intracranial disease control rate (IDCR). Safety analysis Safety was monitored at baseline and every subsequent visit throughout the study. Assessments of physical condition, electrocardiogram, performance status and laboratory parameters were performed. All adverse events (AEs) were recorded and graded according to CTCAE 4.03.

Statistical analyses This is a subgroup analysis of all patients in the ASCEND-2 study enrolled from medical institutions situated in Japan. A total of 24 patients, including 1 patient with West Asian ethnicity, were included in this subgroup analysis, and are referred to as ‘Japanese patients’ in this manuscript. All analyses were performed on patients who received at least one dose of ceritinib. ORR was defined as the proportion of patients with a complete response (CR) or partial response (PR), as assessed by whole-body responses; the 95% confidence interval (95% CI) for binomial proportion (including ORR, DCR, OIRR and IDCR) was calculated using the exact Clopper–Pearson methodology. DOR, PFS and OS were estimated using Kaplan–Meier methodology, with associated 95% CI; TTR was summarized using descriptive statistics; DOR and TTR were summarized for patients with a CR or PR. The data cutoff date for this subgroup analysis was 26 February 2014. A complete and detailed description of the overall study design and sample size calculation for the primary endpoint has previously been published (11).

Results Patients Of the 140 ALK-rearranged NSCLC patients enrolled in the ASCEND-2 study and treated with ceritinib 750 mg/day, 24 were Japanese. A full list of demographics for this Japanese subgroup of patients from the ASCEND-2 study can be found in Table 1. The median age of the Japanese patients was 45.5 years and two-thirds (66.7%) of the patients were female (Table 1). All Japanese patients had progressed while receiving crizotinib treatment, which was the last therapy received prior to ceritinib initiation.

Efficacy At the time of data cutoff, treatment was ongoing in 12 patients (50.0%); the remaining 12 patients (50.0%) had discontinued due to disease progression (8/24, 33.3%), AEs (2/24, 8.3%) or subject/ guardian decision (2/24, 8.3%). The outcomes reported in this subgroup analysis focus on investigators’ assessment. At the data cutoff, the median duration of follow-up for all enrolled patients (n = 140) was 8.31 (range: 5.6–14.8) months. In this Japanese patient subgroup, an ORR of 45.8% (95% CI: 25.6–67.2) was achieved (Table 2) with a DCR of 79.2% (95% CI: 57.8–92.9) and a median TTR of 1.9 months (range: 1.7–3.5). The best percentage change in tumor size from baseline following ceritinib treatment for all Japanese patents is shown in Fig. 1. Median DOR and PFS were 9.2 (95% CI: 4.0–NE (non-estimable); 11 patients had a confirmed CR/PR (CR/PR) and 6 of these patients had an event) and 6.6 (95% CI: 3.7–9.3) months, respectively (Table 2; Supplementary Fig. S1). Results according to

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Table 1. Patient and disease characteristics (by investigator) Characteristics

ALK-rearranged NSCLC patients (N = 24)

Age (median), years (range) Sex, n (%) Female Race, n (%) Asian Other WHO/ECOG performance status, n (%) 0 1 2 Tumor histology/cytology, n (%) Adenocarcinoma Adenosquamous cell carcinoma Other Stage at study entry, n (%) IV IVA Site of metastasis, n (%) Brain Bone Lymph nodes Other Pleura Liver Adrenal Lung Kidney Best response to prior crizotinib, n (%) Partial response Stable disease Progressive disease Duration of best response to prior crizotinib, months, median (range) Time since most recent relapse/progression, months, median (range) Number of prior regimens 2 3 >3

45.5 (29.0−63.0) 16 (66.7) 23 (95.8) 1 (4.2) 7 (29.2) 12 (50.0) 5 (20.8) 22 (91.7) 1 (4.2) 1 (4.2) 23 (95.8) 1 (4.2) 19 (79.2) 12 (50.0) 11 (45.8) 8 (33.3) 7 (29.2) 7 (29.2) 4 (16.7) 3 (12.5) 1 (4.2) 20 (83.3) 3 (12.5) 1 (4.2) 8.0 (2.0–21.0) 1.2 (0.3–15.9)

11 (45.8) 7 (29.2) 6 (25.0)

ALK, anaplastic lymphoma kinase; NSCLC, non-small cell lung cancer; WHO, World Health Organization; ECOG, Eastern Cooperative Oncology Group.

assessment by the BIRC were similar to those from the investigators’ assessment. Intracranial responses in patients with brain metastases at baseline Intracranial responses in patients with active target lesions at study entry were also assessed (Table 2). Of the four Japanese patients who had active target brain lesions, two achieved intracranial PR (50%; Table 2). Both of these patients achieved intracranial PR at the first assessment (days 51 and 56). For these two patients, at time of data cutoff, ceritinib treatment had been ongoing for ~12 months.

Treatment exposure The median duration of ceritinib exposure was 8.1 (range: 0.2–12.5) months, with a median relative dose intensity of 65.0% (range: 38.5–100.0%). A total of 19 (79.2%) patients had at least

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Ceritinib in ALK-rearranged NSCLC Japanese patients

one dose reduction. Of these, six patients (25.0%) had one dose reduction (600 mg), nine patients (37.5%) had two dose reductions (450 mg), three patients (12.5%) had three dose reductions (300 mg) and one patient (4.2%) had their dose reduced more than three times (150 mg). Table 2. Whole-body and intracranial responses based on investigator assessments ALK-rearranged NSCLC patients (N = 24) Best overall response, n (%) CR PR SD PD UNK ORR, n (%) [95% CI] DCR, n (%) [95% CI] DOR, median [95% CI] (months) PFS, median [95% CI] (months)

0 (0.0) 11 (45.8) 8 (33.3) 3 (12.5) 2 (8.3) 11 (45.8) [25.6–67.2] 19 (79.2) [57.8–92.9] 9.2 [4.0–NE] 6.6 [3.7–9.3]

Intracranial responses in patients with measurable brain metastases at study entry Best overall response, n (%) CR 0 (0.0) PR 2 (50.0) SD 0 (0.0) PD 2 (50.0) OIRR, n (%) [95% CI] 2 (50.0) [6.8–93.2] IDCR, n (%) [95% CI] 2 (50.0) [6.8–93.2] CR, complete response; PR, partial response; SD, stable disease; DCR, disease control rate (CR + PR + SD); DOR, duration of response; IDCR, intracranial disease control rate; NE, non-estimable; OIRR, overall intracranial response rate; ORR, overall response rate (CR + PR); CI, confidence interval; PD, progressive disease; PFS, progression-free survival; UNK, unknown.

Safety In total, 100% of patients reported an AE (regardless of study drug relationship), 62.5% of which were grade 3/4. The three most frequently reported AEs were nausea, diarrhea and vomiting (Table 3). Most AEs were manageable following dose reduction and dose interruption, and did not lead to discontinuation of ceritinib treatment. All Japanese patients experienced at least one AE suspected to be drug related (Table 3). AEs leading to treatment discontinuation (fatigue, cancer pain) were seen in two (8.3%) Japanese patients, both of which were grade 3 (Table 3). Grade 3/4 AEs (regardless of study drug relationship) were reported in 15 (62.5%) patients (Table 3). The most common grade 3/4 AEs were gamma-glutamyltransferase (GGT) increased (n = 4, 16.7%), fatigue (n = 3, 12.5%), hepatic function abnormal (n = 3, 12.5%) and hypokalemia (n = 3, 12.5%). Grade 3/4 AEs suspected to be drug related were reported in 13 Japanese patients (54.2%). In total, 22 Japanese patients (91.7%) reported an AE that required a dose reduction or dose interruption. All AEs requiring a dose reduction or dose interruption are listed in Supplementary Table 1. Overall, 19 patients required a dose reduction: 89.5% (n = 17) of these patients required at least one dose reduction due to an AE. Dose interruptions were seen in 20 patients, with AEs being the cause of at least one dose interruption in 90.0% (n = 18) of patients. The most common AEs, regardless of study drug relationship, requiring a dose reduction or dose interruption were nausea (45.8%), diarrhea (37.5%) and vomiting (33.3%). The relationship between ceritinib dosage and treatment duration is illustrated in Supplementary Fig. S2, which also shows the onset of common AEs (hepatic toxicity, nausea/vomiting and diarrhea), regardless of study drug relationship that required dose adjustment. AEs suspected to be study drug related and which required management by dose modification included nausea, vomiting, diarrhea and hepatic toxicity. The median time to first onset of common AEs suspected to be study drug related was nausea, 2 days (range: 1–127 days); vomiting, 2 days (range: 1–37 days); diarrhea, 3 days (range: 1–73 days) and

Figure 1. Best percentage change in tumor size from baseline with ceritinib in Japanese patients (N = 21/24) (per investigator assessment). Only patients with measurable disease at baseline and at least one valid post-baseline assessment were included. Best percentage change from baseline >0 (n = 0); best percentage change from baseline 10% of patients at all grades and at grade 3/4 ALK-rearranged NSCLC patients (N = 24) Preferred term

All grades, n (%)

Summary of AEs Total number of patients experiencing 24 (100.0) at least 1 AE AEs suspected to be drug related 24 (100.0) SAEs 7 (29.2) SAEs suspected to be drug related 7 (29.2) 9 (37.5) Deatha On-treatment death 1 (4.2) Summary of AEs occurring in >10% of patients Nausea 22 (91.7) Vomiting 20 (83.3) Diarrhea 20 (83.3) Decreased appetite 16 (66.7) Fatigue 10 (41.7) Alanine aminotransferase increased 10 (41.7) Aspartate aminotransferase increased 10 (41.7) Weight decreased 8 (33.3) Blood alkaline phosphate increased 7 (29.2) Gamma-glutamyltransferase increased 6 (25.0) Abdominal pain 6 (25.0) Dermatitis acneiform 6 (25.0) Constipation 5 (20.8) Anemia 5 (20.8) Headache 5 (20.8) Insomnia 5 (20.8) Rash 5 (20.8) Hepatic function abnormal 4 (16.7) Hypokalemia 4 (16.7) Abdominal pain, upper 4 (16.7) Dysgeusia 4 (16.7) Edema peripheral 4 (16.7) Electrocardiogram QT prolongation 4 (16.7) Hyperuricemia 4 (16.7) Neck pain 4 (16.7) Non-cardiac chest pain 4 (16.7) Cancer pain 3 (12.5) Hypoalbuminemia 3 (12.5) Blood creatine increased 3 (12.5) Dry skin 3 (12.5) Musculoskeletal pain 3 (12.5) Nasopharyngitis 3 (12.5) Pyrexia 3 (12.5) Stomatitis 3 (12.5) White blood cell count decreased 3 (12.5)

Grade 3/4, n (%)

15 (62.5) 13 (54.2) 6 (25.0) 6 (25.0) NA NA 1 (4.2) 1 (4.2) 0 (0.0) 1 (4.2) 3 (12.5) 2 (8.3) 0 (0.0) 0 (0.0) 1 (4.2) 4 (16.7) 0 (0.0) 0 (0.0) 2 (8.3) 1 (4.2) 0 (0.0) 0 (0.0) 0 (0.0) 3 (12.5) 3 (12.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (4.2) 1 (4.2) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

NA, not applicable; SAEs, serious adverse events. Only AEs occurring during treatment or within 30 days of the last dose of ceritinib were reported. a Including those >30 days after the last dose of ceritinib.

hepatic toxicity, 26 days (range: 7–29 days). The median duration of time to first dose interruption and time to first dose reduction was both within 1 month from beginning ceritinib treatment (1.0 [0.1, 4.2] month and 1.0 [0.2, 2.3] month, respectively). For the one patient who had their dose reduced more than three times (150 mg); each dose reduction period lasted 1 day and the subject returned to a ceritinib dose of 600 mg following each reduction; each dose reduction was marked as subject/guardian decision.

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Serious AEs (SAEs) were reported in seven (29.2%) patients; all were considered to be drug related. Pericarditis was the most commonly reported SAE (regardless of study drug relationship) and was reported in two Japanese patients (8.3%). No patients reported interstitial lung disease. There were no discontinuations in this patient subset due to an SAE. In addition, there were no patient deaths attributable to ceritinib in this subset of Japanese patients [one patient died during the study; cause of death was determined to be underlying disease (NSCLC)].

Discussion The results from this single-arm, open-label, multicenter, phase II study have demonstrated the clinical activity of ceritinib 750 mg once-daily in Japanese patients with ALK+ NSCLC who progressed on crizotinib. The efficacy results from the Japanese patient subset of the ASCEND-2 study were similar to those observed in the whole study population (11), with an ORR that was in line with, and numerically higher than, that observed in the overall ASCEND-2 patient population (45.8% vs 38.6%, respectively) (11). In this Japanese patient subgroup, a DCR of 79.2% was achieved, which is comparable to that observed in the overall patient population of the ASCEND-2 study (77.1%) (11). Furthermore, in patients achieving a response, the median DOR was similar to that reported for crizotinib-pretreated patients in the whole study population (9.2 [95% CI: 4.0–NE] and 9.7 months [95% CI: 7.1–11.1] for Japanese patients and all patients from the ASCEND-2 study, respectively) (11). Median PFS was also similar to that reported in the entire patient population of the ASCEND-2 study (6.6 [95% CI: 3.7–9.3] and 5.7 months [95% CI: 5.4–7.6], for Japanese patients and all patients from the ASCEND-2 study, respectively) (11). Collectively, the results from the key supporting secondary endpoints investigated show that ceritinib demonstrated efficacy in 24 Japanese patients previously treated with crizotinib, providing further evidence for ceritinib activity following progression on crizotinib in patients with ALK+ NSCLC in this patient population. A recent study presented data suggesting intracranial activity in patients with ALK+ NSCLC and brain metastases following crizotinib therapy (13). In this study, an OIRR of 18% from data of 22 patients with previously untreated measurable lesions in the brain was demonstrated. As the brain is a common site of progression following treatment with crizotinib, intracranial responses in patients with active brain metastases at study entry were also investigated in the ASCEND-2 study. Ceritinib has been shown to penetrate the blood–brain barrier in a rat model, with an AUCinf ratio of ~15% (10). Overall, four Japanese patients presented with measurable brain metastases at study entry: two of these patients (50%) achieved a PR. Additionally, both patients achieved an OIRR and IDCR by the cutoff date. Although the patient numbers are low, these results are encouraging and suggest ceritinib may provide a treatment approach for managing brain metastasis in Japanese patients. Costa et al. (13) also presented data illustrating intracranial responses in patients treated with crizotinib who had not received prior therapy with an ALKi. These findings suggest that intracranial responses may be achieved following first-line ALKi therapy in this population of patients. The safety profile of ceritinib in Japanese patients was acceptable and generally consistent with the known safety profile of ALKi. When briefly compared with the overall safety analysis of the ASCEND-2 study, the incidence of nausea, vomiting, fatigue, aspartate aminotransferase increased, GGT increased, anemia and blood alkaline

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phosphatase increased were numerically higher in the Japanese subgroup. However, overall, the incidence and type of AEs among patients in this subgroup analysis was generally consistent with those reported for the whole population of the ASCEND-2 study (11). Furthermore, AEs suspected of being treatment-related and that occurred at a high frequency within the Japanese subgroup were manageable through dose modification (11). No new or unexpected SAEs were reported GI-related AEs requiring dose reduction or dose interruption generally occurred within the first week of ceritinib treatment, and hepatic toxicity within the first month. Consistent with this, the median duration of time to first dose interruption and time to first dose reduction was both within 1 month of beginning ceritinib treatment. The median duration of exposure to ceritinib was 8.1 months, and AEs leading to treatment discontinuation were seen in only two (8.3%) patients; neither were related to the GI system. Taken together, these results suggest that appropriate management of GIrelated AEs through dose interruptions and dose reductions can support the continuation of ceritinib treatment. The most frequently reported AEs were GI-related; however, the majority of these were classed as grade 1 or 2 in severity. GI-related AEs are also known and common (40–60%) AEs reported by patients following crizotinib treatment (7). Of note, no patients in this Japanese subgroup reported interstitial lung disease, a known AE associated with crizotinib therapy (7). Collectively, the results from the analyses of this subgroup demonstrate that ceritinib has efficacy in Japanese patients with advanced ALK+ NSCLC who have previously been treated with crizotinib. With favorable response rates observed following treatment, the antitumor activity of ceritinib was evident in this patient population, as was also observed in the full ASCEND-2 study patient population. Furthermore, safety analyses are consistent with those reported previously. These results support the positive benefit–risk profile of ceritinib in Japanese patients with ALK+ NSCLC who have progressed on crizotinib.

Supplementary data Supplementary data are available at Japanese Journal of Clinical Oncology online.

Funding The study was sponsored/funded by Novartis Pharmaceuticals Corporation and this publication is funded by Novartis Pharma K.K.

Acknowledgements The authors thank the participating patients, their families, all study coinvestigators and research coordinators. Medical writing support was provided by Rachel Cicchelli, PhD, QXV Comms (an Ashfield business, part of UDG Healthcare plc), Macclesfield, UK, and was fully funded by Novartis Pharma K.K.

Conflict of interest statement None declared.

Disclosure statement Dr Hida has received honoraria from Novartis Pharma, Chugai Pharmaceutical and Pfizer. Dr Satouchi has received honoraria from

Novartis Pharma, Chugai Pharmaceutical and Pfizer Japan. Dr Nakagawa has received research funding from Chugai Pharmaceutical Co. Ltd, MSD K.K., Ono Pharmaceutical Co. Ltd, EPS Associates Co. Ltd, Quintiles Inc., Daiichi Sankyo Co. Ltd, Japan Clinical Research Operations, Eisai Co. Ltd, PPD-SNBL K.K., Pfizer Japan Inc., Takeda Pharmaceutical Co., Nippon Boehringer Ingelheim Co. Ltd, Taiho Pharmaceutical Co. Ltd and Bristol-Myers Squibb Company, and has received honoraria from Astellas Pharmaceuticals Inc., AstraZeneca K.K., EPS Holdings Inc., Ono Pharmaceutical Co. Ltd, Kyowa Hakko Kirin Co. Ltd, Showa Yakuhin Kako Co. Ltd, SymBio Pharmaceuticals Limited, Daiichi Sankyo Co. Ltd, Chugai Pharmaceutical Co. Ltd, Nippon Boehringer Ingelheim Co. Ltd, Eli Lilly Japan K.K., Pfizer Japan Inc. and Bristol-Myers Squibb Company. Dr Seto has received consulting fees, honoraria, speaking fees or expert testimony fees from AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Eli Lilly, Fuji Pharmaceutical, Hisamitsu Pharmaceutical, Kyowa Hakko Kirin, Mochida Pharmaceutical, Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, Roche Diagnostics, Sanofi, Showa Yakuhin Kako, Sumitomo Dainippon Pharma, Taiho Pharmaceutical and Takeda Pharmaceutical. Dr Matsumoto has no involvement that might raise the question of bias in the work reported or in the conclusions, implications, or opinions stated. Dr Kiura has received consulting fees, honoraria, speaking fees or expert testimony fees from Taiho Pharmaceutical Co. Ltd, Eli Lily Japan, AstraZeneca Co. Ltd, Nippon Boehringer Ingelheim Co. Ltd, Daiichi Sankyo Pharmaceutical Co. Ltd and Shionogi Co. Ltd. Dr Nokihara has received honoraria from Ono Pharmaceutical, Chugai Pharma, Bristol-Myers Squibb, Eli Lilly, AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim and Sanofi. Dr Murakami has received honoraria from Novartis Pharma K.K., Chugai Pharmaceutical Co. Ltd and Pfizer Inc. Mr Tokushige and Mr Hatano are both current employees of Novartis Pharma K.K. Dr Nishio has received consulting fees, honoraria, speaking fees or expert testimony fees from Pfizer, Bristol-Myers Squibb, Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, Novartis and Boehringer Ingelheim.

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ALK-rearranged non-small-cell lung cancer previously treated with chemotherapy and crizotinib: results from ASCEND-2. J Clin Oncol 2016;34:2866–73. 12. Shaw AT, Mehra R, Tan DS, et al. Evaluation of ceritinib-treated patients with anaplastic lymphoma kinase rearranged (ALK+) non-small cell lung cancer (NSCLC) and brain metastases in the ASCEND-1 study. Ann Oncol 2014;25:iv455–56. ; Abstr # 1293 P. 13. Costa DB, Shaw AT, Ou SH, et al. Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases. J Clin Oncol 2015;33:1881–8.

Ceritinib in patients with advanced, crizotinib-treated, anaplastic lymphoma kinase-rearranged NSCLC: Japanese subset.

Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer is sensitive to tyrosine kinase inhibitors; however, resistance can develop. Da...
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