Clinical activity observed in a phase I dose escalation trial of an oral cMET and ALK inhibitor
Treatment with PF-02341066 demonstrates marked clinical activity against tumors harboring activated ALK gene rearrangements
The EML4-ALK fusion oncogene represents a novel molecular target in a small subset of non-small-cell lung cancers (NSCLC). Patients who harbor this mutation do not benefit from epidermal growth factor receptor (EGFR) tyrosine kinases (TKIs) and should be directed to trials of ALK-targeted agents. First described in 2007, the fusion results from a small inversion within chromosome 2p, which leads to expression of a chimeric tyrosine kinase, in which the N terminal half of echinoderm microtubule-associated protein-like 4 (EML4) is fused to the intracellular kinase domain of anaplastic lymphoma kinase (ALK).
Prof. Jos̩ Baselga discussed results presented first at the ASCO Annual Meeting in Orlando, US, this year and during the Best of 2009 session at the ECCO 15 РESMO 34 Congress in Berlin by Dr Eunice Kwak of the Massachusetts General Hospital Cancer Center, Boston, US. Prof. Baselga said that translocations for decades have been the hallmark of hematologic malignancies and that this represents a new finding in solid tumors. EML4-ALK possesses potent oncogenic activity both in vitro and in vivo. Small molecule inhibitors that target ALK can effectively block this activity. Mesenchymal-epithelial transition (MET) factor is a proto-oncogene that encodes a protein MET, also known as cMET or hepatocyte growth factor receptor (HGFR). Abnormal MET activation in cancer correlates with poor prognosis Рaberrantly active MET triggers tumor growth, formation of new blood vessels, and metastasis. Prof. Baselga went on to say that 2009 will be remembered for the development of PF 02341066, a selective, ATP-competitive, small molecule oral viagra cialis online pharmacy pharmacy of the cMET/HGFR and ALK receptor tyrosine kinases.
Dr Kwak and colleagues conducted first in humans a phase I dose-escalation trial evaluating PF-02341066 as an oral single agent to investigate safety, pharmacokinetics (PK), and pharmacodynamics in patients with advanced cancer (excluding leukemias). PF-02341066 was administered under fasting conditions QD or BID on a continuous schedule to patients in successive dose-escalating cohorts at doses ranging from 50 mg QD to 300 mg BID.
Thirty-seven patients were enrolled into the dose escalation part of the study. Tumor types included colorectal, pancreatic, sarcoma, ALCL, and NSCLC. The maximum tolerated dose (MTD) was 250 mg BID. Three dose-limited toxicities (DLTs) were observed: grade 3 increase in ALT (one patient at 200 mg QD) and grade 3 fatigue (two patients at 300 mg BID). The most common adverse events (AEs) were nausea, emesis, fatigue, and diarrhea. Nausea and emesis were independent of dose or duration of treatment. Mean AUC (30–57% CV) and Cmax (36–69% CV) increased proportionally with dose from 100 mg QD to 300 mg BID. The median terminal half-life was 46 hours. A two- to four-fold increase in the oral midazolam (MDZ) AUC was observed following 28 days of PF-02341066 dosing at 100 mg QD (n = 3) and 300 mg BID (n = 2), respectively, suggesting PF-02341066 to be an inhibitor of CYP3A. Ten patients have entered an enriched RP2D cohort of patients with tumors harboring cMET amplification/gene mutation or ALK fusion genes. There has been one confirmed partial response (PR) in a sarcoma patient with ALK rearrangement (inflammatory myofibroblastic tumor). Among 10 NSCLC patients whose tumors harbor EML4-ALK rearrangement, one patient has had a PR, two patients have achieved unconfirmed PR and four patients have had stable disease (SD). (Three patients experienced reduction in tumor burden by 20% in measurable lesions and one has been treated for 28 weeks.)
The authors concluded that the MTD of PF-02341066 is 250 mg BID. All AEs were manageable and reversible. There was no evidence of non-linear PK at PF 02341066 doses > 100 QD. Future directions in PF-02341066 research for the current phase I clinical trial are to continue to enroll ALK patients in an enriched cohort, to access mature progression-free and overall survival data, to conduct genetic characterization of ALK fusion partners and ALK variants in responders and non-responders, and to continue efforts to identify patients with MET amplifications or mutations. A clinical development has allowed enrollment to begin for a randomized phase III registration trial of PF-02341066 vs. chemotherapy (pemetrexed or docetaxel) in NSCLC patients with ALK rearrangement after failure of first line therapy. This study highlights the importance and feasibility of incorporating prospective molecular genotyping into early-phase clinical trials of novel targeted therapies.
