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

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

Phase 3 study of ceritinib vs chemotherapy in ALK-rearranged NSCLC patients previously treated with chemotherapy and crizotinib (ASCEND-5): Japanese subset

“…Other efficacy endpoints (ORR = 54.5% and DCR = 90.9%) were also higher with ceritinib compared to chemotherapy (ORR = 0% and DCR = 33.3%), which was also observed in the ASCEND-5 overall population ( 14 ). The ORR and DCR observed in the ASCEND-5 Japanese patients were consistent with the previously reported Phase 2 (ASCEND-2) Japanese subgroup data in similar patient populations who had previously received crizotinib and chemotherapy ( 13 ). The safety profile of ceritinib in the ASCEND-5 Japanese subgroup was acceptable and consistent with the established safety profile of ceritinib with no new safety signals observed ( 10 , 11 , 13 , 14 ).…”

“…The most common adverse events (AEs) were gastrointestinal related (diarrhea, nausea and vomiting), majority of which were Grade 1 to 2 in severity ( 10 , 11 ). Additionally, Phase 1 (NCT01634763) Japanese study ( 12 ) and Japanese subset in ASCEND-2 study ( 13 ) with ALK + NSCLC patients showed a tolerable safety profile and clinical activity similar to that reported in ASCEND-1 and ASCEND-2 studies. The Phase 1 (NCT01634763) Japanese study also showed that pharmacokinetics and maximum tolerated dose were consistent with the global study ( 9 ).…”

“…The median PFS by BIRC was numerically higher with ceritinib in the Japanese population (9.8 months [95% CI, 4.3–14.0]) than in the overall population (5.4 months [95% CI, 4.1–6.9]), whereas the median PFS with chemotherapy was similar with overlapping CIs between the Japanese patients (1.6 months [95% CI, 1.4–3.0]) and the overall population (1.6 months [95% CI, 1.4–2.8]) ( 14 ). In the ASCEND-2 Japanese population ( N = 24), the median PFS was 6.6 months (95% CI, 3.7–9.3) ( 13 ). This numerical higher PFS in ASCEND-5 Japanese population need to be interpreted with caution because of the small sample size of the Japanese subgroup and overlapping 95% CIs.…”

“…Other reason for better PFS in ASCEND-5 Japanese population may be attributed to the number of prior regimens received. In the ceritinib-treated overall population of ASCEND-5 study ( 14 ), 11% of patients received 2-lines of chemotherapy compared to none in the ASCEND-5 Japanese subgroup, whereas in the ASCEND-2 Japanese population, 54.2% of patients received ≥3 lines of prior regimen (chemotherapy/targeted therapy) ( 13 ). The median OS was similar between both the treatment arms (23.9 months [95% CI: 6.6–NE] for ceritinib vs 22.8 months [95% CI, 8.3–NE] for chemotherapy), which was consistent with the overall population (18.1 months [95% CI, 13.4–23.9] and 20.1 months [95% CI, 11.9–25.1] for ceritinib and chemotherapy, respectively, from the ASCEND-5 overall population) ( 14 ).…”

Phase II study of ceritinib in alectinib‐pretreated patients with anaplastic lymphoma kinase‐rearranged metastatic non‐small‐cell lung cancer in Japan: ASCEND‐9

“…All 20 patients required at least 1 dose adjustment or interruption. Median relative dose intensity in our study with ceritinib 750 mg fasted was 68.6% (range: 30.3-100) which was consistent with that reported in the Japanese population in ASCEND-2 (65.0% [range: 38.5-100.0])26 and ASCEND-5 (71.9% [range: 35.4%-100.0%]) 27. The safety profile of ceritinib was consistent with that previously reported,14,15 with no new or unexpected AE identified.…”