O-0004 Updated Analysis of Phase II Study of the Anti-IGF-1R Antibody MK-0646 with Gemcitabine +/- Erlotinib for Advanced Pancreatic Cancer (APC)

Abstract

ABSTRACT Introduction IGF-1R activation results in the phosphorylation of IRS-1 and downstream effector proteins of the PI3-Kinase/ Akt, mTOR and S6 kinase pathways that are important in cellular proliferation, survival, and drug resistance in pancreatic cancer. The monoclonal antibody MK-0646 (dalotozumab) blocks the ligand-receptor interaction, internalizes the receptor, and causes its degradation. Receptor cross-talk between IGF-1R and EGFR and enhanced IGF-1R-induced activation of the PI3-kinase/Akt pathways mediate resistance to anti-EGFR agents. Prior phase I established the MTD of MK-0646 as 10 mg/kg with G and 5 mg/kg with G + E. Methods Patients with stage IV, previously untreated APC, ECOG performance status (PS) 0-1, adequate hematologic and organ function were enrolled. Uncontrolled hyperglycemia or cardio-respiratory conditions were exclusions. Phase II study uses adaptive randomized design with Arm A (G + MK-0646), Arm B (G + E + MK-0646) and Arm C (G + E). G was administered as 1000 mg/m2 over 100 min, weekly x 3, MK-0646 over 60 min, weekly x 4 and E 100 mg daily. Cycles repeated q 4 weeks. Study endpoints: Overall survival (OS), progression-free survival (PFS), response rate and toxicity. Results 72 pts were enrolled (68 evaluable; A = 24, B = 28, C = 16 pts). Median PFS of arms A, B and C were 5.5 months (95% CI: 3.9 – NA), 3.0 months (95% CI: 1.8 – 5.6) and 2.0 months (95% CI: 1.8 – NA), respectively (log-rank test; p-value = 0.17). Median OS of A was 11.3 months (95% CI: 8.9 – NA), B- 8.9 months (95% CI: 5.3 – NA) and C- 5.7 months (95% CI: 2.0 – NA) (log-rank test; p-value = 0.44). 35 archival core biopsies were analyzed, 21 had adequate tissue for analysis. Biomarker analysis with available blood and tissue samples is ongoing and preliminary data will be presented at ASCO 2012. Conclusion The combination of G + M may be a promising combination for APC. Biomarker analysis may help identify those patients who would benefit from anti-IGF-1R therapy.