[34]Delmar 2017恶性胶质瘤治疗概况

• Primary study objective: determine if dose-intensifying the adjuvant temozolomide improves OS • Secondary objectives:
次要目标：
研究的主要目标：测定增加佐剂替莫唑胺的剂量能否改善总生存期
未治疗的预期寿命=仅数月 手术切除：可行性最大 术后治疗方法
– Untreated life expectancy = months only – Best evidence is 60Gy RT with concomitant temozolomide chemotherapy (RT/TMZ + 6 months adjuvant TMZ) – Decision factors
40
months 月数
months 月数
MGMT Promoter Methylation: Outcomes
(Stupp Lancet Oncol. 2009; Hegi N Engl J Med. 2005)
MGMT启动子甲基化状态：结局
2-yr
2年
Median
中位生存期
3-yr
3年
4-yr
4年
MGMT启动子的甲基化状态是替莫唑胺化疗结局和获益的重要自变量 1,2
RTOG 0525/EORTC 26052-22053
• International randomized phase III clinical trial involving RTOG, EORTC and NCCTG
国际随机化3期临床试验包括RTOG、EORTC和NCCTG
加拿大皇家内科医学院院士、加拿大多伦多神经肿瘤科讲席教授、医学博士詹姆斯R佩里
Prepared for KOL Luncheon, March 9, 2017, Lotte Palace Hotel, New York
供2017年3月9日于纽约乐天皇宫酒店举办的关键舆论领袖午宴使用
Disclosures
病因未明、遗传非唯一病因，病因还有特定职业、手机
Treatment Considerations for Newly Diagnosed Glioblastoma 新确诊多形性胶质母细胞瘤的治疗思路
• Surgical resection: maximum feasible • Post-op Therapy:
The Therapeutic Landscape of Glioblastoma - 2017
2017年恶性胶质瘤治疗概况 James R Perry MD, FRCPC Crolla Professor of Neuro-Oncology University of Toronto, Canada
Overall Survival
70 60 50 40 30 20
TMZ/ RT
替莫唑胺或放疗
TMZ/ RT
替莫唑胺或放疗
40 30 20 10 0
总生存期
RT alone
仅使用放疗
0 4 8 12 16 20 24 28 32 36 40
RT alone
仅适用放疗
10
0
0
5
10
15
20
25
30
35
替莫唑胺与放疗联合用药或作为放疗的佐剂
This trial was restricted to patients 70 years and younger
试验禁招募70岁及青年患者
Retrospective subgroup analysis of MGMT promoter methylation in about half of the patients
2016年5月版WHO脑瘤新分类
胶质瘤病的分子通路
Increasing Incidence of GBM
Hess et al, Cancer 101:2293-9, 2004
FBM发病率增加
Etiology unclear, rarely purely genetic (Li-Fraumeni, Turcots, NF), certain occupations, ? Cell phones
48.9%
23.1%
23.1%
13.8%
RT only
仅放疗
15.3 months
23.9%
7.8%
7.8%
5.2%
• Methylation of MGMT promoter is a strong predictor for outcome and benefit from temozolomide chemotherapy1,2
RT 放疗 TMZ/RT 替莫唑胺或放疗 11.8 12.7 1.9% 13.8%
100 90
甲基状态的 MGMT
TMZ/RT
Median OS, mo: 15.3 21.7 2-yr survival: 22.7% 46.0%
Logrank : p = 0.062
80 70 60 50
Logrank : p = 0.0074
60戈瑞放疗与替莫唑胺联合治疗或放疗辅以佐剂替莫唑胺治疗
Unmethylated MGMT去甲基状态的MGMT
放疗 Randomization: 中位生存期：月数 Median OS, mo: 2年生存期
100 90 80
Methylated MGMT
Randomization: RT
2-yr survival:
Approach to Newly Diagnosed Glioblastoma
新确诊为多形性胶质母细胞瘤的疗法
•Maximal safe resection 最安全的切除术 •60 Gy RT + concomitant/adjuvant temozolomide for appropriate patients
目前医学影像和疗法难以满足疾病增长过度的需求，这存在很大的局 限性
2017: Can’t we do a little better?
2017年：如何能再创佳绩？
New WHO Classification of Brain Tumors, May 2016 Based upon biomarkers moreso than histology
不可逆失活
MGMT Gene MGMT基因
MGMT Enzyme
MGMT酶
MGMT Gene
MGMT基因 MGMT启动子区
MGMT Promoter Region
Decreased response to TMZ treatment
Turned On
对替莫唑胺的治疗反应 减弱
X
MGMT Gene
MGMT基因
Learning Objectives
学习目标 To understand current treatment standards in GBM 掌握现行多形性胶质瘤细胞治疗标准 To review the major pillars of therapy and the failures of the past 回顾核心疗法与总结失败经验
回顾VAL-083临床应用的机遇
A huge limitation is that the disease grows beyond the margins of current imaging and current therapy
Glioma: Beyond the Margins 神经胶质瘤：疾病过度增加
信息披露
•
• •
•
• •
•
MSD Oncology (speaking honoraria) 演讲酬金赞助 Roche (advisory) 顾问 DelMar Pharma (advisory) 顾问 Vascular Biogenics (advisory) 顾问 Orbus Therapeutics (advisory, reviewer) 顾问、评审 Leadiant Biosciences (Sigma Tau) (advisory) 顾问 Midatech (UK) (advisory) 顾问
Temozolomide (Temodal, Temodar) 替莫唑胺 • • • • Well tolerated oral alkylating chemotherapy 耐受性良好的口服烷化剂化疗制剂 Mild non-cumulative myelotoxicity 非累积发生的中度骨髓抑制 Flexible schedules 灵活的方案 Level 1 evidence supporting concurrent chemoradiation and adjuvant treatment 第一级临床证据支持 放化疗与佐剂联合治疗 • Might be a radiation sensitizer 可充当放疗增敏剂 • Effective essentially only in cells harboring MGMT promoter methylation (low MGMT repair enzyme presence) – 40% of GBM
决策因素 年龄：各种放疗方案
临床证据是放疗剂量60戈瑞联合替莫唑胺化学治疗（放疗/替莫唑胺联合6个月替莫唑胺佐剂）
• Age: different RT schedules • Neurological status • MGMT promoter methylation status
MGMT启动子甲基化状态 神经系统状态
5-yr
5年
MGMT 去甲基状态的MGMT 12.6 unmethylated months RT/TMZ 放疗或替莫唑胺治疗
14.8%
11.1%
11.1%
8.3%
RT only
仅使用放疗
11.8 months
1.8%
0%
0%
0%
MGMT 甲基化状态MGMT 23.4 methylated months RT/TMZ 放疗或替莫唑胺治疗
Increased response to TMZ treatment
Turned Off
- Methylated 甲基化
对替莫唑胺的治疗反应增 强
RT + TMZ in newly diagnosed glioblastoma
放疗联合替莫唑胺治疗新确诊多形性胶质母细胞瘤
RT + concomitant and adjuvant TMZ became a new standard of care (Stupp et al. ASCO 2004, New Engl J Med 2005)
•
• •
Targeted therapy, antiangiogenic therapy, immunotherapy, novel approaches 靶向疗法、抗血管生成疗法、免疫疗法、新型疗法
•
•
To understand the limitations of current alkylator treatment and the urgent need in unmethylated GBM 掌握现用烷化剂疗法的局限性与去甲基化GBM的迫切需求 To review the opportunity for VAL-083 in clinical practice
达的MGMT修复酶）—40%的GBM
仅对携带甲基化状态的MGMT启动子的细胞具有根本疗效（存在低表
MGMT Removes Methyl Groups from DNA MGMT去除DNA的甲基
O N N N
CH3
NH N NH2 HS CH 2 CH CO
NH2
Active MGMT
COOH
dR
活化的MGMT
Guanine methylated by Temodal
repair by MGMT
通过MGMT修复
NH S CH 2 CH CO
由替莫唑胺甲基化的鸟嘌呤
O N N dR N NH NH 2
NH2
Inactive MGMT
失活MGMT
COOH
Normal Guanine
正常鸟嘌呤
Irreversible inaBaidu Nhomakorabeativation
近半数患者的MGMT启动子甲基化的回顾性亚 组分析 Probability of overall survival (%): 总生存率（%） Radiotherapy plus temozolomide:放疗与替莫唑胺联合治疗 Months:月份 Radiotherapy：放疗 Treatment:治疗 OS：总生存期