Elsevier

The Lancet Oncology

Volume 13, Issue 10, October 2012, Pages 1011-1019
The Lancet Oncology

Articles
Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study

https://doi.org/10.1016/S1470-2045(12)70344-3Get rights and content

Summary

Background

ALK fusion genes occur in a subset of non-small-cell lung cancers (NSCLCs). We assessed the tolerability and activity of crizotinib in patients with NSCLC who were prospectively identified to have an ALK fusion within the first-in-man phase 1 crizotinib study.

Methods

In this phase 1 study, patients with ALK-positive stage III or IV NSCLC received oral crizotinib 250 mg twice daily in 28-day cycles. Endpoints included tumour responses, duration of response, time to tumour response, progression-free survival (PFS), overall survival at 6 and 12 months, and determination of the safety and tolerability and characterisation of the plasma pharmacokinetic profile of crizotinib after oral administration. Responses were analysed in evaluable patients and PFS and safety were analysed in all patients. This study is registered with ClinicalTrials.gov, number NCT00585195.

Findings

Between Aug 27, 2008, and June 1, 2011, 149 ALK-positive patients were enrolled, 143 of whom were included in the response-evaluable population. 87 of 143 patients had an objective response (60·8%, 95% CI 52·3–68·9), including three complete responses and 84 partial responses. Median time to first documented objective response was 7·9 weeks (range 2·1–39·6) and median duration of response was 49·1 weeks (95% CI 39·3–75·4). The response rate seemed to be largely independent of age, sex, performance status, or line of treatment. Median PFS was 9·7 months (95% CI 7·7–12·8). Median overall survival data are not yet mature, but estimated overall survival at 6 and 12 months was 87·9% (95% CI 81·3–92·3) and 74·8% (66·4–81·5), respectively. 39 patients continued to receive crizotinib for more than 2 weeks after progression because of perceived ongoing clinical benefit from the drug (12 for at least 6 months from the time of their initial investigator-defined disease progression). Overall, 144 (97%) of 149 patients experienced treatment-related adverse events, which were mostly grade 1 or 2. The most common adverse events were visual effects, nausea, diarrhoea, constipation, vomiting, and peripheral oedema. The most common treatment-related grade 3 or 4 adverse events were neutropenia (n=9), raised alanine aminotransferase (n=6), hypophosphataemia (n=6), and lymphopenia (n=6).

Interpretation

Crizotinib is well tolerated with rapid, durable responses in patients with ALK-positive NSCLC. There seems to be potential for ongoing benefit after initial disease progression in this population, but a more formal definition of ongoing benefit in this context is needed.

Funding

Pfizer.

Introduction

Activation of the ALK gene has been described in several human cancers, including non-small-cell lung cancer (NSCLC), inflammatory myofibroblastic tumours, neuroblastomas, and diffuse large B-cell lymphomas, suggesting that ALK-mediated signalling might play a part in the development or progression of these tumours.1, 2, 3 Activation of the ALK gene is usually through chromosomal rearrangement resulting in the placement of one of several different 5′ fusion partners and their associated promoter region upstream of the kinase domain of ALK.

ALK rearrangements in NSCLC were first described in 20074, 5 and have an estimated prevalence of 3–5% in series mostly dominated by adenocarcinoma on histology.6, 7 EML4–ALK is the most common ALK fusion gene in NSCLC and occurs as several variants with different breakpoints in the EML4 gene.8, 9 Other, more rare non-EML4 fusions, including KIF5B–ALK and TFG-ALK, have also been described in lung cancer.5, 9 Their exact frequency and clinical significance remain under investigation but, by analogy with EML4 and other oncogenic ALK fusions,10 they also probably represent targets for therapeutic ALK inhibition in NSCLC. ALK fusions typically occur independently of EGFR and KRAS gene mutations,11, 12, 13, 14, 15 although these aberrations are not mutually exclusive.11, 15, 16 In the recent Lung Cancer Mutation Consortium series,17 8% of ALK-positive adenocarcinomas were also positive for either an EGFR or KRAS mutation.

Crizotinib (PF-02341066) is a potent, orally available, ATP-competitive, small-molecule inhibitor of ALK and c-Met receptor tyrosine kinase, with half maximum inhibitory concentration values of 5–25 nmol/L.18, 19 Preclinical testing against over 120 kinases showed crizotinib to be highly (>20 times) selective for these targets.18

The first-in-man crizotinib study began in 2006 with a dose-escalation phase undertaken in patients with solid tumours, which was followed by protocol-defined patient prescreening for evidence of ALK or MET activation in specific tumour types. Patients with ALK-positive or MET-positive tumours were enrolled into a series of molecularly defined expansion cohorts at the proposed recommended phase 2 dose (250 mg twice daily in 28-day cycles).

After the discovery of ALK gene rearrangements in NSCLC and promising results in two patients with ALK-positive NSCLC enrolled during the dose-escalation phase of the study,20, 21 the protocol was amended and an additional ALK-positive NSCLC expanded cohort was instigated in 2008. Response data from the first 19 evaluable patients with ALK-positive NSCLC within the cohort revealed a high proportion of objective responses (53%).20 Subsequent data from the first 82 patients confirmed these findings (57%).21

Here, we present an updated analysis of patients with ALK-positive NSCLC who were treated with crizotinib in the first-in-man single-arm crizotinib study before the data cutoff of June 1, 2011.

Section snippets

Patients

The design, methods, and objectives of this phase 1 single-arm study have been described previously21 and are briefly summarised here. Patients aged 18 years or older with measurable ALK-positive stage III or IV NSCLC (defined by a break-apart fluorescence in-situ hybridisation assay), adequate organ function, and an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1 were eligible for enrolment. Patients with an ECOG PS score of 2 were eligible on investigator and

Results

The first patient in the ALK-positive NSCLC cohort was enrolled on Aug 27, 2008, and received their first dose on Aug 28, 2008, and the last patient was enrolled on May 29, 2011, and received their first dose on June 1, 2011. The data cutoff for this study was June 1, 2011. Table 1 lists the baseline clinicopathological characteristics for the 149 patients enrolled before the data cutoff. At the data cutoff, the median duration of treatment was 43·1 weeks (range 0·1–138·6) and treatment was

Discussion

In this updated analysis, crizotinib was well tolerated and resulted in rapid and durable responses in patients with ALK-positive advanced NSCLC (panel), with more than 60% of patients having an objective response and median PFS of almost 10 months.

Clinical and demographic details from the 149 patients revealed many of the features now thought to be characteristic of patients with ALK-positive lung cancer.11, 12 The median age was young (52 years), although the age range was wide. Although some

References (45)

  • AJ Weickhardt et al.

    The therapeutic potential of anaplastic lymphoma kinase inhibitors in lung cancer: rationale and clinical evidence

    Clin Invest

    (2011)
  • YL Choi et al.

    Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer

    Cancer Res

    (2008)
  • K Takeuchi et al.

    KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer

    Clin Cancer Res

    (2009)
  • JE Butrynski et al.

    Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor

    N Engl J Med

    (2010)
  • DR Camidge et al.

    Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment

    Clin Cancer Res

    (2010)
  • AT Shaw et al.

    Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK

    J Clin Oncol

    (2009)
  • T Takahashi et al.

    Clinicopathologic features of non-small-cell lung cancer with EML4-ALK fusion gene

    Ann Surg Oncol

    (2010)
  • DW Wong et al.

    The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS

    Cancer

    (2009)
  • X Zhang et al.

    Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression

    Mol Cancer

    (2010)
  • M Varella-Garcia et al.

    ALK gene rearrangement in unselected Caucasians with non-small cell lung cancer (NSCLC)

    Proc Am Soc Clin Oncol

    (2010)
  • MG Kris et al.

    Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: the NCI's Lung Cancer Mutation Consortium (LCMC)

    Proc Am Soc Clin Oncol

    (2011)
  • JG Christensen et al.

    Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma

    Mol Cancer Ther

    (2007)
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