恶性黑色素瘤药物发展

恶性黑色素瘤 药物发展 Alexander M.M. Eggermont, MD, PhD ErasmusMC-Daniel den Hoed Cancer Center Rotterdam Shanghai, CSCO, 2008 黑色素瘤治疗靶点 全身治疗 化疗 细胞因子 抗体型疫苗 新的分子靶向药物 促凋亡剂 抗BRAF 抗VEGFR2 EGFR, MEK, ERK 抗整合素 抗血管生成制剂 转移潜能 无限增值 血管生成 自主生长信号 肿瘤抑制缺失阻断 凋亡 (Hanahan 100:8372-8377. 一例进展期黑色素瘤患者Ipilimumab相关性皮疹 Ipilimumab 刺激黑色 素细细胞免疫识别识别 (A) 网状红红斑样样皮疹 (B) 血管周围围淋巴细细胞 浸润润突破表皮 (C) CD4+ T细细胞临临近 死亡的黑色素细细胞 (D) CD8+ T细细胞临临近 死亡的黑色素细细胞 1. Hodi SF, et al. Proc Natl Acad Sci. 2003;100:4712-4717. 1. Attia P, et al. J Clin Oncol. 2005;23:6043-6053. 2. Beck K, et al. J Clin Oncol. 2006;24:2283-2289. Overview of Gastrointestinal (GI) irAEs Diarrhea is a frequent irAEs1,2 Most cases are mild or moderate Watery to frank blood Biopsy usually demonstrates inflammatory colitis Management algorithm established Most cases respond to either symptomatic treatment or steroids Can rarely lead to GI perforation ( 6 months = 63% N=54 9 months = 40% N=50 12 months = 22% N=41 Flaherty et al, 2007 BAY 43-9006 is well tolerated with full doses of carboplatin & paclitaxel No evidence of additive toxicities or PK interactions Antitumor activity in metastatic melanoma patients Durable partial responses, all lasting 6+ months 63% of patients on study for more than 6 months Antitumor activity was independent of BRAF mutational status BAY 43-9006, carboplatin & paclitaxel Summary BAY 43-9006 +Carbo + Taxol vs Carbo + Taxol ECOG/SWOG/EORTC PHASE III TRIAL IN 800 PATIENTS 1ST LINE BAY 43-9006 +Carbo + Taxol vs Carbo + Taxol PRISM Trial in 250 PTS DTIC/TMZ FAILURES 2ND LINE FAILED BAY 43-9006, carboplatin & paclitaxel PHASE III TRIALS Metastatic potential Immortalization Angiogenesi s Growth signal independence Loss of tumor suppression Blocked apoptosis (Hanahan & Weinberg, 2000) Acquired Characteristics of Cancer Cells OBLIMERSEN Oblimersen + DTIC vs DTIC 1.1 x Upper Limit of Normal Median HR P Genasense/ DTIC 4.6 DTIC 1.11 0.412 4.7 55% improvement N = 508 Relationship Between LDH and Survival 0.8 1.1 2.0 5.0 N 274 234 157 76 19 LDH Kaplan-Meier survival curves at 24-month minimum follow- up by LDH category: Study GM301 (overall p 0.0001) Survival curves at 24-month minimum follow-up among patients with baseline LDH value 0.8 x ULN AGENDA TRIAL DTIC vs DTIC + Oblimersen in stage IV melanoma LDH 1mm 2 yrs PEG-IFN vs OBSERVATION 1000 pts ULCERATION BIOLOGY THANK YOU FOR YOUR ATTENTION OBLIMERSEN Oblimersen + DTIC vs DTIC 0.8 UNL LDH STA-4783 ST-4783 + Taxol vs Taxol Up to 2x UNL LDH ABRAXANE Abraxane vs DTIC Up to 2x UNLLDH THYMOSIN-alpha THYMOSIN + DTIC vs DTIC Up to 1.2 UNL LDH AVASTIN Stage IV ? Phase III in stage IIB-III VA