Elsevier

The Lancet

Volume 389, Issue 10072, 4–10 March 2017, Pages 917-929
The Lancet

Articles
First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study

https://doi.org/10.1016/S0140-6736(17)30123-XGet rights and content

Summary

Background

The efficacy of ceritinib in patients with untreated anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is not known. We assessed the efficacy and safety of ceritinib versus platinum-based chemotherapy in these patients.

Methods

This randomised, open-label, phase 3 study in untreated patients with stage IIIB/IV ALK-rearranged non-squamous NSCLC was done in 134 centres across 28 countries. Eligible patients were assigned via interactive response technology to oral ceritinib 750 mg/day or platinum-based chemotherapy ([cisplatin 75 mg/m2 or carboplatin AUC 5–6 plus pemetrexed 500 mg/m2] every 3 weeks for four cycles followed by maintenance pemetrexed); randomisation was stratified by World Health Organization performance status (0 vs 1–2), previous neoadjuvant or adjuvant chemotherapy, and presence of brain metastases as per investigator's assessment at screening. Investigators and patients were not masked to treatment assignment. The primary endpoint was blinded independent review committee assessed progression-free survival, based on all randomly assigned patients (the full analysis set). Efficacy analyses were done based on the full analysis set. All safety analyses were done based on the safety set, which included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01828099.

Findings

Between Aug 19, 2013, and May 11, 2015, 376 patients were randomly assigned to ceritinib (n=189) or chemotherapy (n=187). Median progression-free survival (as assessed by blinded independent review committee) was 16·6 months (95% CI 12·6–27·2) in the ceritinib group and 8·1 months (5·8–11·1) in the chemotherapy group (hazard ratio 0·55 [95% CI 0·42–0·73]; p<0·00001). The most common adverse events were diarrhoea (in 160 [85%] of 189 patients), nausea (130 [69%]), vomiting (125 [66%]), and an increase in alanine aminotransferase (114 [60%]) in the ceritinib group and nausea (in 97 [55%] of 175 patients), vomiting (63 [36%]), and anaemia (62 [35%]) in the chemotherapy group.

Interpretation

First-line ceritinib showed a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy in patients with advanced ALK-rearranged NSCLC.

Funding

Novartis Pharmaceuticals Corporation.

Introduction

Anaplastic lymphoma kinase (ALK)-rearrangements are oncogenic drivers that occur in 3–7% of patients with non-small-cell lung cancer (NSCLC). Most patients with ALK-rearranged NSCLC are usually younger, are never smokers or have a light smoking history, and have adenocarcinoma histology.1, 2

Crizotinib, an oral small-molecule tyrosine kinase inhibitor of ALK, MET, and ROS1 kinases, was superior to pemetrexed-platinum chemotherapy in patients with untreated advanced ALK-rearranged NSCLC (median progression-free survival was 10·9 months vs 7·0 months, respectively).3 However, most patients treated with crizotinib ultimately progress,4, 5 with the CNS being the common site of progression.6

Ceritinib (LDK378; Novartis, East Hanover, NJ, USA) is a next-generation, selective oral ALK inhibitor with a 20 times greater potency than crizotinib in enzymatic assays.7 It crosses the blood–brain barrier with a brain-to-blood exposure ratio of about 15% in a rat model.8 Results from the phase 1 ASCEND-1 study9, 10 and phase 2 ASCEND-3 study11 demonstrated consistent, high, and durable antitumour efficacy of ceritinib 750 mg/day in ALK inhibitor-naive patients with ALK-rearranged NSCLC who had progressed on multiple lines of chemotherapy (median progression-free survival of 18·4 months for both studies).10, 11

ASCEND-4 is the first randomised, global, phase 3 study to evaluate the efficacy, safety, and patient-reported outcomes of ceritinib versus platinum-pemetrexed doublet followed by pemetrexed maintenance in untreated patients with advanced ALK-rearranged NSCLC. The comparator group, platinum-pemetrexed doublet, was the standard of care in patients with non-squamous NSCLC12, 13 when ASCEND-4 was implemented and pemetrexed maintenance demonstrated additional improvement in progression-free survival and overall survival versus placebo.14, 15, 16

Research in context

Evidence before this study

We searched PubMed on Dec 6, 2016, for reports on clinical trials in advanced untreated anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) using the following search string “(ALK AND NSCLC) AND (naïve OR naive OR untreated OR first-line)”. We did not limit our search by date or language. These searches indicated that the only phase 3 trial published for first-line treatment of ALK-positive NSCLC was for crizotinib (PROFILE 1014) that compared efficacy and safety of crizotinib, an ALK inhibitor with platinum-pemetrexed combination without maintenance treatment. Ceritinib is a next-generation, selective oral ALK inhibitor with 20 times greater potency than crizotinib in enzymatic assays. Results from the phase 1 ASCEND-1 study and phase 2 ASCEND-3 study demonstrated consistent, high, and durable antitumour efficacy of ceritinib 750 mg/day in ALK inhibitor-naive patients with ALK-rearranged NSCLC who had progressed on multiple lines of chemotherapy.

Added value of this study

Ceritinib demonstrated a statistically significant and clinically meaningful improvement in progression-free survival versus pemetrexed-platinum chemotherapy including maintenance pemetrexed in untreated patients with ALK-rearranged NSCLC. The study's primary objective, median progression-free survival as assessed by blinded independent review committee, was 16·6 months (95% CI 12·6–27·2) for ceritinib versus 8·1 months (5·8–11·1) for chemotherapy (with an estimated 45% risk reduction for progression-free survival [HR 0·55, 95% CI 0·42–0·73; p<0·00001]). Improvement in progression-free survival was observed both in patients with or without brain metastases at study entry. The overall response with ceritinib was high, rapid, and prolonged. Additionally, ceritinib had a higher overall intracranial response as compared with chemotherapy. Ceritinib significantly improved the general quality of life and significantly prolonged time to deterioration for lung cancer-specific symptoms compared with chemotherapy. The safety profile of ceritinib was consistent with previous reports.

Implications of all the available evidence

Patients with advanced ALK-rearranged NSCLC treated with first-line ceritinib had a statistically significant and clinically meaningful improvement in progression-free survival compared with chemotherapy. Overall, ceritinib should be considered as a new first-line therapeutic option in patients with ALK-rearranged NSCLC.

Section snippets

Study design and participants

This randomised, open-label, global, phase 3 study was done in 134 sites that randomly assigned at least one patient across 28 countries (Australia, New Zealand, Austria, Brazil, China, Colombia, Denmark, France, Germany, Greece, India, Ireland, Italy, Japan, South Korea, Lebanon, Mexico, Netherlands, Norway, Portugal, Russia, Singapore, Spain, Sweden, Taiwan, Thailand, Turkey, and UK). Adult patients (aged ≥18 years) were eligible if they had histologically or cytologically confirmed locally

Results

Between Aug 19, 2013, and May 11, 2015, 376 patients were randomly assigned to ceritinib (n=189) or chemotherapy (n=187; the full analysis set). All patients assigned to ceritinib were treated. In the chemotherapy group, 175 patients were treated, 87 patients received pemetrexed-cisplatin, and 88 patients received pemetrexed-carboplatin at starting dose (figure 1). None of the patients in the ceritinib group and two patients in the chemotherapy group had protocol deviations that led to

Discussion

In this study, treatment-naive patients with ALK-rearranged NSCLC in the ceritinib group had a statistically significant and clinically meaningful improvement in progression-free survival compared with those in the chemotherapy group that included pemetrexed maintenance. The unprecedented median progression-free survival of 16·6 months in the overall population, 26·3 months in patients without brain metastases and 10·7 months in patients with baseline brain metastases (60% were active brain

References (26)

  • R Katayama et al.

    Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers

    Sci Transl Med

    (2012)
  • GA Otterson et al.

    Clinical characteristics of ALK+ NSCLC patients (pts) treated with crizotinib beyond disease progression (PD): potential implications for management

    J Clin Oncol

    (2012)
  • BJ Solomon et al.

    Intracranial efficacy of crizotinib versus chemotherapy in patients with advanced ALK-positive non-small-cell lung cancer: results from PROFILE 1014

    J Clin Oncol

    (2016)
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