Development of clinical trial for molecular targeted therapy in Breast Cancer Ze-Fei Jiang 军事医学科学院附属医院 江泽飞
Cancer Drug Development: 1945 Present Total No. Approved Drugs 85 75 65 55 Ibritumomab/Tositumomab/Bortezomib Gemtuzumab Trastuzumab Rituximab Topotecan Paclitaxel 45 Carboplatin 35 Etoposide Ifosfamide Doxorubicin 25 Cisplatin Vincristine 15 Fluorouracil Cyclophosphamide 5 0 Nitrogen mustard Years
Targeted Therapies for BC Subtypes HER2 PTEN loss Trastuzumab Lapatinib T-DM1 Pertuzumab MM111 PI3K mutant Anti-PI3K AKT and MTOR Anti-PI3K TNBC Platinum salts Anti-EGFR PARP inhibitors BRCA1 Tamoxifen AI Estrogen degrading FGFR Cabozantinib MM121 HR + FGFR ampl FGR inh BRCA2 PARP inhib Higgins & Baselga; Submitted
NCCN Practice Guidelines in Oncology Widely recognized and applied as the standard of care in the United States in both the academic and community practice settings Used extensively by insurance companies (including Medicare) to set coverage policy
Preferred Therapy Regimens: NCCN guidelines The best management of any cancer patient is in a clinical trial Adapted from NCCN Practice Guidelines in Oncology 2003;v.1
Weekly schedule 3-weekly schedule Phase II Pivotal Study Phase II Phase II No. of patients 46 22 111 105 Prior CT regimens metastatic disease (median) Yes (3) Yes (2) No No Response rate 11% 15% 26% 20% 95% CI 4-24% 11-21% 15-31% 12-28% Median duration of response (months) HERCEPTIN Single-Agent Breast Cancer Phase II Studies 6.6 9.1 8.0 8.3 Median survival 14 13 24.4 NA
Pivotal Phase III Combination Trial (H0468G): Overall Survival In HER2 3+ Patients 1.0 Probability of survival 0.8 0.6 0.4 0.2 Paclitaxel subgroup 40% H + P P 0 18 25 0 5 10 15 20 25 30 35 40 45 50 Time (months) Smith IE. Anticancer Drugs 2001;12:S3 10
HERA TRIAL Primary management (surgery, chemotherapy, radiotherapy) Randomisation Herceptin q3w for 24 months + tamoxifen if ER+ and/or PgR+ Herceptin q3w for 12 months + tamoxifen if ER+ and/or PgR+ Observation + tamoxifen if ER+ and/or PgR+
HERA 无病生存 (2005 年报告 ) % alive and disease free 100 1 year trastuzumab 90 80 70 Observation 60 50 2-yr 40 Events DFS % HR [95% CI] p value 30 20 127 85.8 0.54 [0.43, 0.67] <0.0001 10 220 77.4 0 0 5 10 15 20 25 No. Months from randomization at risk 1694 1472 1067 629 303 102 1693 1428 994 580 280 87
赫赛汀改变了 HER2 阳性转移性乳腺癌的进程 HER2 Negative ( n=1782 ) HER2+ No Herceptin ( n=118 ) HER2+ Herceptin ( n=191 ) Dawood S, et al. J Clin Oncol. 2010; 28:92-98.
HER 信号传导通路 HER2 HER1-4 Phosphorylation RAS PI3K RAC RHO MEKK SEK JNK Raf-1 MEK 1/2 MAPK mtor Akt BAD Cytoskeletal organization Proliferation, Cell cycle progression, gene transcription Cell cycle progressio n Survival Nucleus
帕妥珠单抗联合曲妥珠单抗 显著提高 pcr p = 0.0198 50 p = 0.0141 p = 0.003 pcr, % 95% CI 40 30 20 10 0 45.8 29.0 24.0 16.8 TH THP HP TP Gianni et al. SABCS 2010.
Lapatinib: Mechanism of Action
EGF100151 卡培他滨 + 拉帕替尼 ErbB2+ 局晚或转移性乳腺癌 拉帕替尼 1250 mg 每日口服卡培他滨 2000 mg/m 2 /d 口服连续 2 周休息 1 周为一疗程 既往接受蒽环 紫杉醇类及曲妥珠单抗治疗 随 机 既往未接受卡培他滨治疗 卡培他滨 2500 mg/m2/d 口服连续 2 周休息 1 周为一疗程 N=528 Geyer C, et al. NEJM 2006;355:2733-2743.
EGF100151 卡培他滨 + 拉帕替尼治疗至疾病进展时间 (TTP)-ITT % 未进展患者的百分比* 100 80 60 40 病例数进展或死亡 中位至疾病进展时间月 风险比 (95% CI) P 值 拉帕替尼 + 卡培他滨 <0.001 卡培他滨 163 161 49 72 8.4 4.4 0.49 (0.34, 0.71) 20 0 0 10 20 30 40 50 60 70 时间 ( 周 ) Geyer C, et al. NEJM 2006;355:2733-2743.
Do we need more Chemo? 194 patients (a) R TP TPC Trastzumab (qwk) Paclitaxel (175 mg/m 2 q3 wks) Trastuzumab (qwk) Paclitaxel (175 mg/m 2 q3 wks) Carboplatin (AUC 6 q3 wks) RR 36% 52% TTP 6.9 m 11.2m Significant benefit 263 patients (b) R TD TDC Trastzumab (q3wk) Docetaxel (75 mg/m 2 q3 wks) Trastuzumab (q3wk) Docetaxel (75 mg/m 2 q3 wks) Carboplatin (AUC 6 q3 wks) 73% 73% 10.5 m 10.5m No significant benefit (a) Robert et al., San Antonio 2002 ; (b) Forbes et al, ASCO 2006
Targeted Therapies for BC Subtypes Trastuzumab Lapatinib T-DM1 Pertuzumab MM111 HER2 PI3K mutant Anti-PI3K AKT and MTOR PTEN loss Anti-PI3K TNBC Platinum salts Anti-EGFR PARP inhibitors BRCA1 Tamoxifen AI Estrogen degrading FGFR Cabozantinib MM121 FGFR ampl FGR inh BRCA2 PARP inhib HER2 - HR + Higgins & Baselga; Submitted
Avastin has transformed the treatment of 5 cancers: A fundamental element of cancer care Metastatic colorectal cancer Superior OS 1 st and 2 nd line Superior PFS 1 st and 2 nd line Metastatic breast cancer Superior PFS in multiple 1 st line trials Superior PFS in 2 nd line Advanced non-small cell lung cancer Superior OS 1 st line Superior PFS 1 st and 2 nd line Metastatic renal cell cancer Superior PFS 1 st line Recurrent glioblastoma Unsurpassed PFS and OS
Avastin Phase III Clinical Trials in Breast Cancer Early breast cancer 1st-line MBC 2nd-line MBC 3rd-line MBC HER2( ) E2100 Paclitaxel +/ Avastin E5103 AC paclitaxel +/ Avastin BEATRICE Chemotherapy +/ Avastin for triple-negative RIBBON-1 (R1) Taxane or Anthracycline +/ Avastin Capecitabine +/ Avastin AVADO Docetaxel +/ Avastin CALGB 40503 Letrozole/Tamoxifen +/ Avastin for HR(+) MBC AVF2119g Capecitabine +/ Avastin RIBBON-2 (R2) Chemotherapy +/ Avastin HER2(+) BETH Chemotherapy/Herceptin +/ Avastin AVEREL Docetaxel/Herceptin +/ Avastin AVF2119g also enrolled a small group of HER2-positive and/or first-line patients.
E2100 中 PFS 获益结果 1.0 IRF 评估 无进展生存评价 0.8 0.6 0.4 0.2 5.9 11.8 Paclitaxel (n=354) Avastin + paclitaxel (n=368) HR 0.60 P<0.001 0 0 6 12 18 24 30 36 Miller, et al. NEJM 2007;357:2666 76
AVADO: 贝伐单抗联合多西紫杉醇延长 PFS Placebo + docetaxel (n=241) Bev 7.5 + docetaxel (n=248) Placebo + docetaxel (n=241) Bev 15 + docetaxel (n=247) HR + 95% CI (unstratified) 0.79 (0.63 0.98) p=0.0318 HR + 95% CI (stratified*) 0.69 (0.54 0.89) p=0.0035 Median 8.0 8.7 HR + 95% CI (unstratified) 0.72 (0.57 0.90) p=0.0099 HR + 95% CI (stratified*) 0.61 (0.48 0.78) p<0.0001 Median 8.0 8.8 1.0 1.0 0.8 0.8 PFS estimate 0.6 0.4 PFS estimate 0.6 0.4 0.2 0.2 0 0 0 6 12 18 0 6 12 18 Months Months *Data censored for non-protocol therapy before PD; mg/kg q3w Miles, et al. ASCO 2008 (Abstract LBA1011)
Avastin Regulatory History in US: 2010 / 07 FDA Recommends Removal of Bevacizumab's Breast Cancer Indication The ODAC vote 12-1 that this indication be removed from bevacizumab s label, reasons: No overall survival advantage High cost Toxicity
NCCN Recommendation Stands Avastin plus Paclitaxel still be recommended as 1 st line option in US http://www.ascopost.com/articles/january-15-2011/fda-recommends-removalof-bevacizumab's-breast-cancer-indication/
Bevacizumab in breast cancer: the current status and future questions What do we know already? the addition of bevacizumab to paclitaxel or Xeloda significantly increases efficacy in first-line mbc What are the open questions? do any patient subgroups derive particular benefit from bevacizumab? for how long should bevacizumab be given? what other data do we expect for bevacizumab?
Phase III trial of Avastin plus adjuvant chemotherapy in EBC ( E5103 ) AC x 4 (n~1,000) Paclitaxel x 12 ER-negative or high-risk ER-positive (n=4,950) R AC + Avastin x 4 (n~2,000) Paclitaxel x 12 + Avastin x 4 PI: Kathy Miller AC + Avastin x 4 (n~2,000) Paclitaxel x 12 + Avastin x 4 Avastin x 10 Regimen doxorubicin: 60mg/m 2 q3w cyclophosphamide: 600mg/m 2 q3w Avastin: 15mg/kg q3w paclitaxel: 80mg/m 2 q3w Endpoints primary: DFS secondary: OS, toxicity, short- versus long-term Avastin use
Phase III trial of Avastin plus adjuvant chemotherapy in EBC ( BEATRICE ) Triplenegative EBC (n=2,530) PI: David Cameron R Defined standard chemotherapies Defined standard chemotherapies + Avastin Single-agent Avastin for 1 year Primary endpoint: invasive DFS secondary endpoints: OS, DFS, distant DFS, tolerability and safety Global recruitment
Phase III trial of adjuvant Avastin plus Herceptin in HER2-positive breast cancer ( BETH ) PI: Charles Geyer 6 x (docetaxel 75mg/m 2 q3w + carboplatin AUC 6 q3w) + Herceptin* HER2-positive, node-positive or high-risk node-negative (n = up to 5,400) R 6 x (docetaxel 75mg/m 2 q3w + carboplatin AUC 6 q3w) + Herceptin + Avastin* *Followed by Herceptin + Avastin to a total of 52 weeks 3 x docetaxel 100mg/m 2 q3w + Herceptin + 3 x FEC q3w 3 x docetaxel 100mg/m 2 q3w + Herceptin + Avastin + 3 x FEC q3w Herceptin + Avastin held during FEC therapy, then restarted for 40 weeks IDFS = invasive disease-free survival; RFI = recurrence-free interval; DRFI = distant recurrence-free interval
针对 VEGF 和 VEGFR 系统制剂研发 制剂类型作用主要靶点代表制剂 抗 VEGF 抗体结合和中和游离的 VEGF VEGF 贝伐珠单抗 抗 VEGFR 抗体通过与受体结合阻断 VEGF VEGFR-2 IMC-1121B (Ramucirumab) 可溶性 VEGFR 结合和中和游离的 VEGF VEGF, PIGF, VEGF-B VEGF Trap (AVE0005 or Aflibercept) 小分子 TKIs Ellis, Hicklin. Nat Rev 2008 直接作用于 VEGFR 酪氨酸激酶, 阻断 VEGFR 信号传递 VEGFR-1, VEGFR-2, PDGFR-ß, c-kit, Flt-3 BAY 43-9006 ( 索拉非尼 ) SU11248 ( 舒尼替尼 )
We need to get back to our laboratories to understand more about the disease. We need more biology and a better insight so that we can treat the right patient, at the right time, with the right drug at the right dose." - David J. Kerr 2010 ESMO
生物标志物指导下临床研究 Clinical development All HER2 positive Fishing expedition Exploratory strategy Prospective development Demonstrate benefit in the overall HER2 positive population Retrospective analysis without predefined candidate markers or hypotheses Prospectively defined analysis of candidate markers Prospective patient selection in a Phase III trial Herceptin Pertuzumab and T-DM1 Biomarker research Semi-quantitative approaches Diagnostics Quantitative approaches Current status