Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial

Abstract

SUMMARY Background ALK-rearranged non-small-cell lung cancer (NSCLC) is sensitive to ALK tyrosine kinase inhibitors (ALKi) such as crizotinib, but resistance invariably develops, often with progression in the brain. Ceritinib is a more potent ALKi than crizotinib in vitro, crosses the blood-brain barrier in vivo and shows clinical responses in crizotinib-resistant disease. Here, we assessed whole-body and intracranial activity of ceritinib in both ALK-pretreated and ALKi-naïve patients with ALK-rearranged NSCLC. Methods The primary objective (to determine the maximum tolerated dose of ceritinib) of this first-in-human, phase I, open-label ASCEND-1 trial has been reported previously. In the analysis reported here, antitumour efficacy of ceritinib was evaluated in all patients with ALK-rearranged NSCLC (n=246) treated with ceritinib at the recommended dose of 750 mg/day. Additionally, as patients with untreated or locally treated neurologically stable brain metastases at baseline were permitted in this study, intracranial efficacy was retrospectively confirmed by independent neuroradiologists for 94 patients with baseline brain metastases and at least one post-baseline MRI/CT tumour assessment. This study is no longer recruiting patients; however, treatment and follow-up are ongoing. This study is registered with ClinicalTrials.gov, number NCT01283516. Findings Median follow-up at the time of this report was 11 1 months (interquartile range 6·7–15·2). Patients were mainly heavily pretreated (105/246 [42·7%] at least three prior regimens). The overall response rate was 72·3% (60/83; 95% confidence interval [CI] 61·4–81·6) for ALKi-naïve (n=83) and 56·4% (92/163; 95% CI 48·5–64·2) for ALKi-pretreated (n=163) patients. Median progression-free survival in ALKi-naïve and ALKi-pretreated patients was 18·4 (95% CI 11·1-non-estimable) and 6·9 (95% CI 5·6–8·7) months, respectively. Brain metastases by investigator assessment were reported at study entry in 124 patients. Of these, 94 (n=19 ALKi-naïve and n=75 ALKi-pretreated) were included in the retrospective analysis; intracranial disease control rate was 78·9% (15/19; 95% CI 54·4– 93·9) in ALKi-naïve patients and 65·3% (49/75; 95% CI 53·5–76·0) in ALKi-pretreated patients. Of the 94 patients included in the retrospective analysis, 11 had measurable brain lesions and no prior radiotherapy to the brain: 6 of these achieved a partial intracranial response. Safety was evaluated for all 246 patients with ALK-rearranged NSCLC. Serious adverse events were recorded for 117 (47·6%) patients. The most common grade 3/4 laboratory abnormalities were increased alanine aminotransferase and increased aspartate aminotransferase, occurring in 73 (29·7%) and 25 (10·2%) patients, respectively. The most common grade 3/4 non-laboratory adverse events were diarrhoea and nausea, both of which occurred in 15 (6.1%) patients. Two on-treatment deaths in the study were considered to be related to study drug by the investigators, one due to interstitial lung disease and one as a result of mult...

Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

“…Of 124 ALKpositive NSCLC patients with brain metastases at baseline, 94 had brain scans evaluated by central review. In ALK-TKI naive (n=19) and ALK-TKI pre-treated patients (n=75), disease-control rate (DCR) was 79% and 65%, respectively; whole body disease-control rate and duration were similar to what observed in the overall population (70). The median time required to achieve intracranial responses (6.1 weeks) overlapped with what observed for extracranial disease.…”

“…Importantly, all the 19 cases for whom tumor material was available at crizotinib progression responded to ceritinib, regardless of the respective mechanism of acquired resistance, also when the precise molecular explanation was not uncovered (81). The updated analysis of this trial at median duration of follow-up of 11.1 months, showed a median PFS of 18.4 and of 6.9 months in ALK inhibitor naive and pre-treated patients that received ceritinib at the recommended 750 mg/day dose (70).…”

“…Considering the results obtained by ceritinib in crizotinib-naïve patients (70), current trials evaluating ceritinib treatment in ALK-TKI-naive patients (ASCEND 3 and 4) should aim to confirm the latter data and to reach a comprehensive duration of disease control at least Although preclinical and clinical research mainly focuses on acquired resistance to crizotinib, absolute lack of response to the inhibitor can be distinctly observed in 5% to 7% of ALK-positive patients (11,13,63). Albeit most of the primary resistance cases can be attributed to misdiagnoses of ALKrearrangements (48), "true" biological de novo resistance can be driven by co-occurring K-RAS mutations (83) or by unknown mechanisms (17).…”

“…With respect to ceritinib, in the expansion cohort of the phase I trial (ASCEND-1) the most frequent all-grade toxicity was diarrhea, which occurred in 213 out of 255 patients (86%); nausea was reported in 205 cases (83%) (70). The most common grade 3-4 laboratory abnormalities were increased alanine aminotransferase [73 (30%) patients] and increased aspartate aminotransferase [25 (10%)] (70).…”

“…The most common grade 3-4 laboratory abnormalities were increased alanine aminotransferase [73 (30%) patients] and increased aspartate aminotransferase [25 (10%)] (70). Concerning the phase II study ASCEND-2, conducted in patients who underwent chemotherapy and crizotinib, the most common all-grade toxicity was nausea, occurring in 114 patients (81.4%); increased ALT (24 patients, 17.1%), nausea (9 patients, 6.4%), diarrhea (9 patients, 6.4%), fatigue (9 patients, 6.4%), dyspnea (8 patients, 5.7%), and AST elevation (7 patients, 5%) were the most frequent grade 3-4 events (70). Diarrhea (102 patients, 82.3%) was the most common all-grade toxicity in the phase II study ASCEND-3, conducted in patients naive from ALK inhibitors; in this trial, elevated gamma-glutamyltranspeptidase (gamma-GT, 23 patients, 18.5%), ALT (19 patients, 15.3%) and AST (9 patients, 7.3%) were the most frequent grade 3-4 events (72).…”