A Phase 1, Open-Label, Dose Escalation Study to Evaluate Safety, Pharmacokinetics and Pharmacodynamics of Combined Oral C-Met/ALK Inhibitor (PF-02341066) and Pan-Her Inhibitor (PF-0299804) in Patients With Advanced Non-Small Cell Lung Cancer

BACKGROUND:

• Approximately 85% of lung cancer is defined histologically as NSCLC and the majority of patients present with inoperable locally advanced (Stage IIIB) or metastatic (Stage IV) disease for which no curative treatment is available.
• Patients with disease progression on or after first-line treatment with platinum-based doublets may be candidates for second-line treatment.
• Recent evidence strongly implicates EGFR activating somatic mutations as a mechanism of tumorigenesis and a determinant of sensitivity to EGFR TKIs in NSCLC.
• Despite the dramatic initial response to gefitinib and erlotinib, about 50% of NSCLC tumors develop resistance due to secondary activating mutations in EGFR itself, including the EGFR T790M gatekeeper mutation, and more than 20% of acquired resistance is due to an increase in mesenchymal-epithelial transition factor (c-Met) signaling.
• There is evidence from a limited number of tumors from patients with acquired resistance to EGFR-TKIs that both T790M and cMET resistance mechanisms can occur in the same patient at different metastatic sites and even in different fractions of the same lesion.
• Tumors with acquired resistance to erlotinib and gefitinib might be vulnerable to a combination of PF-00299804 a second generation EGFR TKI which is also an inhibitor of T790M mutation, and PF-02341066 which is an inhibitor of c- Met/Hepatocyte Growth Factor Receptor (HGFR).

OBJECTIVES:

• To define the recommended Phase 2 dose (RP2D) of combined PF-02341066 plus

PF-00299804 in patients with advanced Non-Small Cell Lung Cancer (NSCLC).