ArticlesCH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1–2 study
Introduction
A fusion tyrosine kinase gene comprising the EML4 gene and the ALK gene has been identified in non-small-cell lung cancer (NSCLC) with inversion of chromosome 2p. Mouse 3T3 fibroblasts expressing EML4-ALK had increased transforming activity and tumorigenicity.1 Transgenic mice expressing EML4-ALK fusion gene in lung alveolar epithelial cells were generated and exhibited development of adenocarcinoma in lungs shortly after birth,2 suggesting that the EML4-ALK fusion gene could be a driver mutation for NSCLC and serve as a promising candidate for a therapeutic target.1, 3 Therefore, the introduction of new ALK inhibitors is expected to improve the treatment of patients with ALK-rearranged NSCLC.3
So far, crizotinib, a multi-targeted receptor tyrosine kinase inhibitor of ALK, MET, and ROS1 oncogene,4, 5 is the only agent that has been approved for ALK-rearranged NSCLC in the USA, European Union, Japan, and other countries. In the phase 1 trial of crizotinib in patients with ALK-rearranged NSCLC, 87 of 143 evaluable patients had an objective response (60·8%, 95% CI 52·3–68·9). Median progression-free survival (PFS) was 9·7 months.6 In a retrospective study7 comparing survival outcomes in crizotinib-treated patients enrolled in the phase 1 trial and crizotinib-naive controls screened during the same period, crizotinib therapy was associated with better survival. However, resistance to crizotinib occurs by a number of mechanisms, including ALK gene alterations, such as ALK point mutations and copy number gain, and activation of bypass signalling through activation of other oncogenes.8, 9 Additionally, poor penetration of crizotinib across the blood–brain barrier is thought to be associated with a higher incidence of brain involvement if relapse occurs.10 In the crizotinib phase 2 trial, the most common site for single organ disease progression was the brain.11
CH5424802 (RO5424802; Chugai Pharmaceutical Co, Ltd, Tokyo, Japan) is a novel, highly selective oral ALK inhibitor. In-vitro kinase assays showed that this compound selectively inhibits ALK. CH5424802 also shows high anti-tumour activity both in vitro and in vivo against tumour cell lines with some type of ALK gene alteration, such as NSCLC and anaplastic large-cell lymphoma lines harbouring an ALK fusion gene and a neuroblastoma line harbouring amplified ALK gene. More importantly, CH5424802 yielded potential anti-tumour activity against the gatekeeper Leu1196Met mutation in EML4-ALK,12 which has been identified in tumour cells refractory to crizotinib.13
We report the results of a phase 1–2 study of CH5424802 (AF-001JP study) that was designed to identify the maximum tolerated dose (MTD) and pharmacokinetic parameters of the drug, and subsequently to assess its activity and safety in ALK inhibitor-naive patients with ALK-rearranged NSCLC.
Section snippets
Study design and patients
This study was a multicentre, single-arm, open-label, phase 1–2 trial (AF-001JP). Patients were eligible if they were aged 20 years or older; had histologically or cytologically confirmed advanced or metastatic ALK-rearranged stage IIIB, IV, or recurrent NSCLC; had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; had measurable lesions as defined by Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) (for the phase 2 portion only); received two or
Results
The first patient identified with ALK-positive NSCLC was enrolled on Sept 10, 2010, and received their first dose on Sept 14, 2010. The last patient was enrolled on April 18, 2012, and received their first dose on April 18, 2012. Data cutoff for this report was July 31, 2012.
For both the phase 1 and phase 2 parts of this study, 436 patients were screened for ALK and 135 (31%) patients were identified as ALK-positive. 70 patients were enrolled and treated in either the phase 1 (24 patients) or
Discussion
The results of this phase 1–2 study showed that CH5424802, given at a dose of 300 mg twice daily, is safe and active in patients with ALK-rearranged NSCLC. Almost 94% of patients achieved an objective response, and early reductions in tumour size of at least 30% were noted in most patients within the first 6 weeks. The proportion of patients who achieved an objective response noted here for CH5424802 is substantially higher than that of crizotinib (60·8% and 53%) in two separate early phase
References (29)
- et al.
Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study
Lancet Oncol
(2012) - et al.
Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis
Lancet Oncol
(2011) - et al.
CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant
Cancer Cell
(2011) - et al.
Clinical activity observed in a phase I dose escalation trial of an oral c-MET and ALK inhibitor, PF-02341066
Eur J Cancer
(2009) - et al.
Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer
Nature
(2007) - et al.
A mouse model for EML4-ALK-positive lung cancer
Proc Natl Acad Sci
(2008) - et al.
Anaplastic lymphoma kinase: role in cancer pathogenesis and small-molecule inhibitor development for therapy
Expert Rev Anticancer Ther
(2009) - 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) - et al.
ROS1 rearrangements define a unique molecular class of lung cancers
J Clin Oncol
(2012) - et al.
Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers
Sci Transl Med
(2012)