Intracranial and whole-body response of ceritinib in ALK inhibitor-naïve and previously ALK inhibitor-treated patients with ALK-rearranged non-small-cell lung cancer (NSCLC): updated results from the phase 1, multicentre, open-label ASCEND-1 trial

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 multi-organ failure that occurred in the context of infection and ischaemic hepatitis. INTERPRETATION: This study demonstrated clinically meaningful and durable responses in mainly heavily pretreated patients with ALK-rearranged NSCLC (ALKi-naïve and ALKi-pretreated) receiving ceritinib 750 mg/day. Treatment with ceritinib also achieved both whole-body and intracranial efficacy in patients with brain metastases at baseline, a common site of disease progression in patients with NSCLC. The durable whole-body responses reported, together with the intracranial efficacy, support a clinical benefit for treatment with ceritinib in patients post-crizotinib, or as an alternative to crizotinib in patients with ALK-rearranged NSCLC. FUNDING: Sponsored by Novartis Pharmaceuticals Corporation.