Detailed results from an exploratory, randomized Phase II study evaluating the combination of ficlatuzumab (AVEO Oncology), a HGF inhibitory antibody, and gefitinib (Iressa; AstraZeneca) compared to gefitinib monotherapy in previously untreated Asian subjects with non-small cell lung cancer (NSCLC) were presented at the 2012 Congress of the European Society for Medical Oncology(ESMO) in Vienna, Austria, September 28, 2012 – October 2, 2012.

The study did not achieve its primary endpoint. However, the results presented at ESMO suggest that the addition of ficlatuzumab to gefitinib may be effective in select subsets of patients. Commenting on the trial sresults, Tuan Ha-Ngoc, president and chief executive officer, AVEO, noted: ?The insights gleaned from the Phase II study, along with new pharmacodynamic data, show that inhibiting the HGF ligand may be important in the treatment of cancer. We, along with our scientific advisors and clinical investigators, remain encouraged about ficlatuzumab and believe the program warrants further evaluation. Our top priority is the registration and commercialization of tivozanib, and with that in mind, we will be focusing our efforts on further ficlatuzumab development through external collaborations, including with academic institutions and cooperative groups.?

Predictive biomarkers
?This study has identified potential predictive biomarkers for the use of ficlatuzumab in patients with advanced NSCLC,? said Tony Mok, M.D., professor, Department of Clinical Oncology, The Chinese University of Hong Kong, and senior investigator of the study. ?Based on these results, ficlatuzumab merits additional clinical investigation.?

Primary Endpoint

The primary endpoint of the study was overall response rate (ORR); secondary endpoints included progression-free survival (PFS), overall survival (OS) and correlation of biomarkers with clinical activity. In the intent to treat (ITT) population, the addition of ficlatuzumab to gefitinib did not result in statistically significant improved ORR or PFS in Asian treatment-na?ve NSCLC patients. The preliminary OS hazard ratio in the ITT population for ficlatuzumab plus gefitinib versus gefitinib monotherapy was 0.84 (95% CI 0.52, 1.37). Final OS data will be presented once they are mature. The combination was well-tolerated, with no clinically meaningful differences in adverse event rates observed between the two arms. The combination demonstrated a trend for improved ORR and PFS in patients with both EGFRsensitizing mutations and low c-Met biomarker levels (n=19).

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Preliminary results
Preliminary OS results suggest that the addition of ficlatuzumab to gefitinib may have a favorable impact in the subset of patients with high stromal HGF (N=17 patients, HR=0,p=0.03). Trends for OS benefit in other biomarker subsets continue to be evaluated.

Results from a Phase I clinical study evaluating tumor pharmacodynamic changes post ficlatuzumab treatment were also presented at ESMO. In the majority of patients treated, 20 mg/kg of ficlatuzumab (the established Phase 2 dose of ficlatuzumab) resulted in pharmacodynamic modulation in liver metastasis by inhibiting the HGF/c-Met pathway and downstream signaling for cell proliferation, survival, and angiogenesis.

Exploratory Phase II Study
The open-label, two-arm, randomized exploratory Phase II study was designed to compare the combination of ficlatuzumab and gefitinib versus gefitinib monotherapy, in clinically selected Asian subjects with previously untreated advanced NSCLC who have a high likelihood of harboring activating EGFR mutations. Ninety-four (94) patients were randomized to gefitinib and ficlatuzumab/gefitinib arms each; 144 tumor tissue samples were collected for biomarker analysis. Subjects who demonstrated disease control (complete response, partial response, or stable disease for 12 weeks or longer) in the gefitinib arm were eligible to cross-over upon progression to the combination of gefitinib and ficlatuzumab, to assess whether acquired resistance to gefitinib can be overcome with the addition of ficlatuzumab.

HGF/c-Met Pathway
HGF is the sole ligand that binds to and activates a receptor called c-Met. Activation of the HGF/c-Met pathway is believed to be important in normal processes in embryonic development and wound healing, but its dysregulation is believed to play a role in cancer development, metastasis and drug resistance.

HGF/c-Met over-expression is observed in many solid tumors including breast, colorectal, gastric, head and neck, lung and prostate, as well as hematologic malignancies. Additionally, c-Met and EGFR are frequently co-amplified and co-expressed in a variety of tumor types; HGF/c-Met pathway upregulation can render resistance to EGFR-targeted therapies, and vice-versa.

HGF has also been shown to be one of the most potent growth factors that can drive resistance to a panel of anti-cancer therapies. Ficlatuzumab is a humanized IgG1? antibody that binds to the HGF ligand with high affinity and specificity to inhibit the biological activities of the HGF/c-Met pathway. Studies have demonstrated that ficlatuzumab is well tolerated as a single agent as well as in combination with EGFR TKIs.

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