Abstract A227: Antitumor activities of ASP3026 against EML4-ALK-dependent tumor models.

Abstract

EML4-ALK is an oncogenic fusion kinase, which was first identified in non-small cell lung cancer (NSCLC), and is regarded as an attractive therapeutic target for treating a subpopulation of NSCLC patients. Crizotinib, which is inhibitor for MET and ALK, was recently approved by FDA (26 August 2011) for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. We synthesized and screened chemical compounds utilizing an ALK kinase inhibition assay aimed at the EML4-ALK target for drug discovery, and found ASP3026, a novel and selective inhibitor for the ALK kinase. ASP3026 potently inhibited ALK kinase activity and was more selective than crizotinib in a Tyr-kinase panel. In an anchorage independent in vitro cell growth assay, ASP3026 inhibited the growth of NCI-H2228, a human NSCLC tumor cell line endogenously expressing EML4-ALK variant 3 and that of 3T3 cells expressing EML4-ALK variant 1, 2 and 3. The plasma and tumor concentrations of ASP3026 in mice xenografted with NCI-H2228 tumor were determined using high-performance liquid chromatography-tandem mass spectrometry. Significant tumor penetration was observed. The antitumor activities were evaluated using mice bearing subcutaneous NCI-H2228 tumor xenografts. ASP3026, (daily oral dosing for 14 days) induced dose dependent anti-tumor effects starting at 1 mg/kg with marked regression at 10, 30 and 100 mg/kg. Body weights were unaffected. Crizotinib, (twice daily oral dosing) was less potent, with growth inhibition at 10 mg/kg, and tumor regression at 30 mg/kg. A dose of 100 mg/kg of crizotinib was poorly tolerated. Resistance mutations in ALK kinase domain against crizotinib were reported following sequence analysis of tumor cells derived from crizotinib-relapsed patients. The position of the mutation is the so-called gatekeeper mutation and is thought to be one of the causes of crizotinib relapse. In an EML4-ALK driven tumor model with gatekeeper mutation, ASP3026 showed potent anti-tumor effects while crizotinib was ineffective even at 100 mg/gk qd. In summary, ASP3026 has a broad safety margin and inhibitory activity at the gatekeeper mutation. Therefore, ASP3026 may still effective in EML4-ALK fusion positive NSCLC patients, that have relapsed to crizotinib. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A227.

Crizotinib-Resistant NPM-ALK Mutants Confer Differential Sensitivity to Unrelated Alk Inhibitors

“…This is not surprising, as already shown by clinical experience with other tyrosine kinase inhibitors, such as imatinib in chronic myeloid leukaemia (31). Second generation ALK inhibitors are currently under clinical investigation, for example, AP26113 developed by ARIAD (32), currently in phase I/II clinical trial (NCT01449461), LDK378 by NOVARTIS (33) now in phase I clinical trial (NCT01283516), and ASP3026 by ASTELLAS PHARMA (34), structurally related to NVP-TAE684, which is also in phase I trials (NCT01284192 and NCT01401504). As expected, interest in new drugs that may be able to overcome crizotinib resistance is growing fast.…”

Personalized treatment of EGFR mutant and ALK-positive patients in NSCLC

“…It showed even more potency when binding to crizotinibresistant protein where crizotinib had failed. It also had safe dosing profile in mouse models [95].…”

Anaplastic lymphoma kinase rearrangement in lung Cancer: Its biological and clinical significance

“…Based on the dose-limiting toxicities, such as diarrhea, vomiting, dehydration, elevated aminostransferase levels and hypophosphatemia, the maximum tolerated dose of ceritinib was set as 750 mg per day. Among 114 patients who received over 400 mg per day, the overall response rate was 58% (95% CI [48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67], while the median PFS of these patients was 7.0 months (95% CI 5.6-9.5). Similar to alectinib, ceritinib was also found to be effective against crizotinibresistant disease, i.e., the overall response rate was 56% (95% CI .…”

“…Other ALK inhibitors, such as ASP3026 [65] and X-396 [66], are also currently under clinical evaluation (Table 2). Although it is not clear at present whether crizotinib or second-generation ALK inhibitors will be the superior treatment, a head-to-head study comparing crizotinib with the second-generation ALK inhibitors would clarify this point.…”