Pfizer Oncology announced that it will initiate a global, phase 3 clinical trial of its investigational oral c-Met and ALK inhibitor, PF-02341066, versus standard of care chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) carrying the ALK (anaplastic lymphoma kinases) fusion gene, who have progressed on one prior treatment with a platinum-based chemotherapy. Updated data from an expansion cohort of a Phase 1 study with PF-02341066 in NSCLC patients with tumours carrying this fusion gene were featured today at the ECCO15/ESMO34 meeting in Berlin, Germany (Abstract #6G).

PF-02341066 is an investigational, selective, ATP-competitive small molecule dual inhibitor of mesenchymal epithelial transition growth factor (c-Met or hepatocyte growth factor) and ALK tyrosine kinases, which are implicated in the progression of several cancers, including NSCLC. A subset of NSCLC patients have been identified whose tumours carry a unique mutation in which the echinoderm microtubule-associated protein-like 4 (EML4) gene is fused to ALK, also known as an EML4-ALK translocation. This fusion/translocation has been reported in 3-7 per cent of all NSCLC patients, with the incidence increasing to 10-20 per cent among NSCLC patients with adenocarcinoma histology and those who have a never-to-light smoking history, and represents one of the newest molecular targets in NSCLC.

"We see this as an extraordinary opportunity for rational drug development. This represents a shift from large trials designed to detect a small benefit in a large group of patients towards looking for a bigger effect in a smaller, better characterized group of patients. By focusing on the subset of patients whose lung cancers carry the EML4-ALK translocation, we will be in the best position to determine the clinical effects of PF-02341066, both good and bad, in comparison to standard chemotherapy," said Dr. Mace Rothenberg, senior vice president of clinical development and medical affairs for Pfizer's Oncology Business Unit.

Lung cancer is the most common cancer worldwide, with NSCLC accounting for approximately 85 per cent of lung cancer cases. Nearly 60 per cent of NSCLC patients are diagnosed late with Stage IIIB/IV advanced disease. For Stage IIIB/IV NSCLC, the five-year survival rate is only 12 percent.

A phase 3 randomized, open-label study of the anti-tumour activity and safety of PF-02341066 versus pemetrexed or docetaxel in patients with measurable NSCLC who have tested positive for the ALK fusion gene and who have progressed on a platinum-based chemotherapy is currently open and enrolling in the United States and will be enrolling globally by the end of 2009. The study is expected to enroll 318 patients.

The primary objective of the study is progression-free survival (PFS), and secondary outcomes include assessment of overall survival, objective response rate, duration of response, disease control rate, and patient-reported outcomes. Patients in the study will be randomized to receive PF-02341066 (250 mg orally BID) or pemetrexed (500 mg/m2 on Day 1 of each 21 day cycle) or docetaxel (75 mg/m2 on Day 1 of each 21 day cycle).

In this study, patients carrying the EML4-ALK translocation were recruited into an expanded cohort at the recommended Phase 2 dose of 250 mg twice daily (BID). To date, 31 NSCLC ALK patients have been evaluated for response.

The overall response rate, to date, is 65 per cent (20/31 patients [95 per cent CI: 45 per cent, 81 per cent]) and disease control rate (DCR) at 8 weeks is 84 percent (26/31 patients [95 percent CI: 66 per cent, 95 per cent]). Median PFS has not yet been reached. The median duration of treatment is 24.5+ weeks.

In the Phase 1 study, the most common adverse events were mild or moderate, and included nausea, vomiting and diarrhea. Treatment-related severe toxicity (elevated liver transaminases) was infrequent and reversible.

"Now that the EML4-ALK translocation has been validated as a therapeutic target in a small, but significant subset of NSCLC patients, we look forward to seeing how our early stage research translates in a larger phase 3 trial," added Rothenberg.

This expansion cohort was part of a dose-escalation study which enrolled 38 advanced cancer patients in the escalation phase, and 57 patients in the expansion cohort, with various tumours, including NSCLC, colorectal, pancreatic, sarcoma and anaplastic large cell lymphoma tumours.