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