Elsevier

The Lancet Oncology

Volume 17, Issue 4, April 2016, Pages 452-463
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(15)00614-2Get rights and content

Summary

Background

ALK-rearranged non-small-cell lung cancer (NSCLC) is sensitive to ALK tyrosine kinase inhibitors (ALK inhibitors) such as crizotinib, but resistance invariably develops, often with progression in the brain. Ceritinib is a more potent ALK inhibitor than crizotinib in vitro, crosses the blood–brain barrier in vivo, and shows clinical responses in patients with crizotinib-resistant disease. We aimed to assess whole-body activity of ceritinib in both ALK inhibitor-pretreated and ALK inhibitor-naive patients with ALK-rearranged NSCLC.

Methods

ASCEND-1 was an open-label, phase 1 trial that recruited patients from 20 academic hospitals or cancer centres in 11 countries in Europe, North America, and Asia-Pacific. Eligible patients were aged 18 years or older with ALK-rearranged locally advanced or metastatic cancer that had progressed despite standard therapy (or for which no effective standard therapy existed), who had at least one measurable lesion at baseline. The primary objective (to determine the maximum tolerated dose) has been reported previously. This updated analysis includes all patients with ALK-rearranged NSCLC given oral ceritinib at the recommended dose of 750 mg/day in the dose-escalation and expansion phases. Here we report the secondary outcomes of overall response, duration of response, and progression-free survival, analysed in all patients who received at least one 750 mg dose of ceritinib. Exploratory analyses included retrospective analysis of intracranial activity by independent neuroradiologists, in patients with untreated or locally treated neurologically stable brain metastases at baseline. Safety was assessed in all patients who received at least one dose of ceritinib. This study is no longer recruiting patients; however, treatment and follow-up are ongoing. This study is registered with ClinicalTrials.gov, number NCT01283516.

Findings

Between Jan 24, 2011, and July 31, 2013, 255 patients were enrolled and received at least one dose of ceritinib 750 mg/day, of whom 246 had ALK-rearranged NSCLC. At data cutoff (April 14, 2014), median follow-up was 11·1 months (IQR 6·7–15·2) and 147 (60%) patients had discontinued treatment, 98 (40%) as a result of disease progression. An overall response was reported in 60 (72% [95% CI 61–82]) of 83 ALK inhibitor-naive patients and 92 (56% [49–64]) of 163 ALK inhibitor-pretreated patients. Median duration of response was 17·0 months (95% CI 11·3–non-estimable [NE]) in ALK inhibitor-naive patients and 8·3 months (6·8–9·7) in ALK inhibitor-pretreated patients. Median progression-free survival was 18·4 months (95% CI 11·1–NE) in ALK inhibitor-naive patients and 6·9 months (5·6–8·7) in ALK inhibitor-pretreated patients. Of 94 patients with retrospectively confirmed brain metastases and at least one post-baseline MRI or CT tumour assessment, intracranial disease control was reported in 15 (79% [95% CI 54–94]) of 19 ALK inhibitor-naive patients and in 49 (65% [54–76]) of 75 ALK inhibitor-pretreated patients. Of these 94 patients, 11 had measurable brain lesions and no previous radiotherapy to the brain, six of whom achieved a partial intracranial response. Serious adverse events were recorded in 117 (48%) of 246 patients. The most common grade 3–4 laboratory abnormalities were increased alanine aminotransferase (73 [30%] patients) and increased aspartate aminotransferase (25 [10%]). The most common grade 3–4 non-laboratory adverse events were diarrhoea and nausea, both of which occurred in 15 (6%) patients. Two on-treatment deaths during the study were deemed to be related to study drug by the investigators, one due to interstitial lung disease and one as a result of multiorgan failure that occurred in the context of infection and ischaemic hepatitis.

Interpretation

The durable whole-body responses reported, together with the intracranial activity, support a clinical benefit for treatment with ceritinib in patients with ALK-rearranged NSCLC who have received crizotinib, or as an alternative to crizotinib. A confirmatory phase 2 clinical trial is ongoing to assess ceritinib activity in patients with ALK-rearranged NSCLC and brain or leptomeningeal metastases.

Funding

Novartis Pharmaceuticals Corporation.

Introduction

Anaplastic lymphoma kinase (ALK) rearrangement is a therapeutically tractable oncogenic driver that occurs in 2–7% of patients with non-small-cell lung cancer (NSCLC).1 So far, three ALK-targeted small-molecule tyrosine kinase inhibitors have been approved by several health authorities.2, 3, 4, 5 The first ALK-targeted therapeutic was crizotinib, which targets cMET, ALK, and ROS1.6, 7 Results of two phase 3 studies comparing crizotinib with chemotherapy in patients with advanced ALK-rearranged NSCLC showed that progression-free survival and response were improved with crizotinib therapy in both second-line and first-line settings.8, 9 However, most responding patients acquire resistance within 1 year, with recurrence generally occurring in the brain or liver.10, 11, 12 In a retrospective analysis11 of patients with ALK-rearranged NSCLC given crizotinib, the site of disease progression was brain in 41% of patients, and liver in 25% of patients. The high incidence of recurrence in the brain might partly be a result of limited blood–brain barrier penetration of crizotinib, which has been described in the clinical setting.13, 14 Crizotinib resistance can result from both ALK-dependent and ALK-independent mechanisms.10, 15, 16 Therefore, treatment options for patients who progress on crizotinib are needed.17

Research in context

Evidence before this study

We searched PubMed, ClinicalTrials.gov, and conference abstracts for reports published in English with terms related to ALK and NSCLC, with no data limits. These searches, which were done before finalisation of the protocol (August, 2010), indicated that the standard of care for most patients with advanced non-small-cell lung cancer (NSCLC) is cytotoxic chemotherapy. However, the identification of oncogenic drivers has led to the development of targeted therapeutics that have become the first-line treatment in suitable patients. The success of this targeted approach has highlighted the need to identify genotype-specific subsets of patients who might benefit from targeted therapies. ALK rearrangement occurs in 2–7% of patients with NSCLC, in which it acts as a potent oncogenic driver. ALK is one of the newer molecular targets, and at the time of study design (2010) no ALK-targeted therapeutic was available for patients with ALK-rearranged NSCLC. The first-in-class ALK-targeted therapeutic, crizotinib, which was originally synthesised as an inhibitor of cMET, was in the early stages of efficacy assessment in this patient population. More recent searches using terms related to crizotinib, resistance, and brain metastases, which were done throughout the study duration and, most recently, before submission of the manuscript (October, 2015), have indicated that crizotinib is more effective than chemotherapy in patients with ALK-rearranged NSCLC in both first-line and second-line settings. However, patients invariably develop resistance within a year, with frequent disease progression in the brain. Consequently, this population of patients is in need of effective alternative therapeutics.

Added value of this study

This updated analysis of the ASCEND-1 phase 1 study builds upon early reports of 130 patients who received the second-generation ALK inhibitor, ceritinib, at 50–750 mg/day. Here, notable antitumour activity and a high proportion of durable responses are reported in 246 patients with advanced metastatic ALK-rearranged NSCLC who received ceritinib at the recommended dose of 750 mg/day. Tumour responses were noted in patients who were ALK-inhibitor naive and in patients who had previously received ALK inhibitors. Moreover, durable whole-body responses were reported for patients with brain metastases at study entry. A retrospective analysis by independent neuroradiologists of intracranial responses in these patients with brain metastases at baseline and at least one post-baseline tumour assessment found a high proportion of patients with intracranial disease control.

Implications of all the available evidence

Clinical activity of ceritinib was noted in patients with ALK-rearranged NSCLC who had progressed on previous treatment with crizotinib, providing a therapeutic option for patients who might otherwise have limited choices. Moreover, in patients with brain metastases at study entry, both whole-body and intracranial responses were reported, suggesting the potential for ceritinib to effectively treat this patient population and the possibility that ceritinib could be an alternative therapeutic approach to local ablative therapy in patients with ALK-rearranged NSCLC and brain metastases. Our results raise the possibility that ceritinib might also have a role as an alternative to crizotinib in patients with ALK-rearranged NSCLC.

Ceritinib (LDK378) is a potent and selective oral tyrosine kinase inhibitor of ALK.18 In vitro, ceritinib inhibits ALK with a potency that is 20 times greater than that of crizotinib, and has nanomolar potency against patient-derived crizotinib-resistant tumour cell lines.19 In preclinical xenograft studies, immediate tumour regrowth was reported after completion of crizotinib treatment, whereas regrowth upon stopping ceritinib treatment was notably delayed.19 Further, in a tissue distribution study using a rat model, ceritinib crossed the blood–brain barrier with a brain-to-blood exposure ratio of about 15%.20 Consistent with these preclinical observations, ceritinib has shown activity against crizotinib-resistant tumours in patients with ALK-rearranged NSCLC, including brain metastases.18

Preliminary activity and safety data from the dose-escalation phase of the ASCEND-1 study have been reported previously.18 The objective of the analyses reported here was to investigate the antitumour activity of ceritinib in a larger cohort of patients with ALK-rearranged NSCLC, including both ALK inhibitor-naive and ALK inhibitor-pretreated patients, given the recommended dose of 750 mg/day, with a longer median duration of follow-up than reported previously. Additionally, we report the results from a retrospective review of brain MRI and CT scans to assess intracranial activity of ceritinib in patients with treated and untreated neurologically stable brain metastases at study entry.

Section snippets

Study design and participants

The study methods for the multicentre, open-label, phase 1, ASCEND-1 study have been published previously.18 Briefly, patients were recruited from 20 academic hospitals, or cancer centres associated with academic hospitals, in 11 countries across Europe, North America, and Asia-Pacific (appendix p 1). Patients were eligible if they had ALK-rearranged NSCLC, were aged 18 years or older, had locally advanced or metastatic NSCLC that had progressed (by physician assessment) despite standard

Results

We enrolled 255 patients between Jan 24, 2011, and July 31, 2013, who received at least one dose of ceritinib at the 750 mg/day recommended dose. Of these, 246 (96%) had ALK-rearranged NSCLC, of whom 83 (34%) patients were ALK inhibitor-naive and 163 (66%) were ALK inhibitor-pretreated (figure 1). Of the 163 ALK inhibitor-pretreated patients, 149 (91%) had progressive disease on (or within 2 weeks of the last dose of) the previous ALK inhibitor. All ALK inhibitor-pretreated patients had

Discussion

In the updated analysis of this phase 1 study, ceritinib treatment resulted in clinically meaningful, rapid, and durable antitumour responses in both ALK inhibitor-naive and ALK inhibitor-pretreated patients with ALK-rearranged NSCLC, most of whom had received several previous lines of antineoplastic therapy. Additionally, ceritinib antitumour activity was shown in patients who had asymptomatic or controlled brain metastases at baseline, with both extracranial and intracranial responses noted.

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