Microsoft PowerPoint - ASCO 1998－2012
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1 Chugai InvestigatorsʼMeeting on Breast Cancer in Chicago 2012 ASCO から学ぶ抗 HER2 療法の進歩 浜松オンコロジーセンター腫瘍内科渡辺亨 Neoadjuvant Adjuvant 1st Line Metastatic 2nd Line Metastatic No HER2 Therapy Anthracycline based then Trastuzumab Taxane + Trastuzumab Chemo + Trastuzumab Trastuzumab Capecitabine + Lapatinib Taxane + Trastuzumab + Pertuzumab? CLEOPATRA TDM-1? EMILIA TDM-1 + Pertuzumab? MARIANNE 1
2 HER タンパクを標的とした薬剤 抗体 T-DM1 ペルツズマブ セツキシマブ パニツムマブ トラスツズマブ P HER2 HER-2 P EGFR HER-1 (EGFR) P P P P 分 薬剤 ラパチニブネラチニブ エルロチニブゲフィチニブ Targeted Therapies for HER2+ Breast Cancer: Trastuzumab, Lapatinib, and T DM1 Antibody: Trastuzumab P P HER2 Cytotoxic: DM1 Stable linker: MCC Emtansine P P P Trastuzumab Lapatinib P T-DM1 Nucleus Spector NL, Blackwell KL. J Clin Oncol 2009; Nelson MH, et al. Ann Pharmacother 2006; Lewis Phillips GD, et al. Cancer Res
3 T DM1: Mechanism of Action HER2 T-DM1 Emtansine release Inhibition of microtubule polymerization Lysosome P P P Internalization Nucleus Adapted from LoRusso PM, et al. Clin Cancer Res ASCO 歴史展望 抗 HER2 療法の巻 IMPACT Author Publication 1998 Trastuzumab single p II MBC Second Line Cobleigh M JCO 17:2639,1999 Trastuzumab p III MBC AC/PTX ± HERCEPTIN Slamon D NEJM 344:783, Trastuzumab single p II MBC First Line Vogel C JCO 20:719, Trastuzumab + Paclitaxel MBC q3w Gelmon K JCO 21:3965,2003 Trastuzumab adjuvant PIII NSABP-B31/NCCTG-N9831 Romand EH NEJM 353:1673, Trastuzumab adjuvant PIII HERA Piccart-Gebhart MJ NEJM 353:1659, Lapatinib+ Capecitabine PIII Geyer CE NEJM 355:2733, Trastuzumab+Taxan vs. Lapatinib+Taxan P III NCIC MA.31 Gelmon K T-DM1 vs Lapatinib + Capecitabine P III Blackwell K 3
4 ASCO 歴史展望 抗 HER2 療法の巻 IMPACT Author Publication 1998 Trastuzumab single p II MBC Second Line Cobleigh M JCO 17:2639,1999 Trastuzumab p III MBC AC/PTX ± HERCEPTIN Slamon D NEJM 344:783, Trastuzumab single p II MBC First Line Vogel C JCO 20:719, Trastuzumab + Paclitaxel MBC q3w Gelmon K JCO 21:3965, Trastuzumab adjuvant PIII NSABP-B31/NCCTG-N9831 Romand EH NEJM 353:1673,2005 Trastuzumab adjuvant PIII HERA Piccart-Gebhart MJ NEJM 353:1659, Lapatinib+ Capecitabine PIII Geyer CE NEJM 355:2733, Trastuzumab+Taxan vs. Lapatinib+Taxan P III NCIC MA.31 Gelmon K T-DM1 vs Lapatinib + Capecitabine P III Blackwell K Efficacy and Safety of Herceptin as a Single Agent in HER2-overexpressing Metastatic Breast Cancer ASCO 1998 Abstract #376 M. Cobleigh, C.L. Vogel, D. Tripathy, N.J. Robert, S. Scholl, L. Fehrenbacher, V. Paton, S. Shak, G. Lieberman, D. Slamon for Genentech, Inc and Herceptin Multinational Clinical Investigators 4
5 Phase II study of Herceptin as a Single Agent Primary Objectives Overall response rateby REC (Response Evaluation Committee) Safety Secondary Duration of response Time to disease progression Survival Quality of Life Phase II study of Herceptin as a Single Agent Design Single arm, open-label Multicenter (54 centers), multinational 222 women enrolled Treatment 4 mg/kg IV loading dose 2 mg/kg weekly maintenance dose 5
6 Objective Response CR PR Population n n % n % Response Evaluation Committee assessment ORR % 95% CI All enrolled, intent-to-treat All treated Investigators' assessment All enrolled, intent-to-treat All treated ASCO 歴史展望 抗 HER2 療法の巻 IMPACT Author Publication 1998 Trastuzumab single p II MBC Second Line Cobleigh M JCO 17:2639,1999 Trastuzumab p III MBC AC/PTX ± HERCEPTIN Slamon D NEJM 344:783, Trastuzumab single p II MBC First Line Vogel C JCO 20:719, Trastuzumab + Paclitaxel MBC q3w Gelmon K JCO 21:3965, Trastuzumab adjuvant PIII NSABP-B31/NCCTG-N9831 Romand EH NEJM 353:1673,2005 Trastuzumab adjuvant PIII HERA Piccart-Gebhart MJ NEJM 353:1659, Lapatinib+ Capecitabine PIII Geyer CE NEJM 355:2733, Trastuzumab+Taxan vs. Lapatinib+Taxan P III NCIC MA.31 Gelmon K T-DM1 vs Lapatinib + Capecitabine P III Blackwell K 6
7 Addition of Herceptin to First Line Chemotherapy for HER2 Overexpressing Metastatic Breast Cancer Increases Clinical Benefit: A Randomized, Controlled Multinational Phase III ASCO 1998 Abstract #377 D. Slamon, B. Leyland-Jones, S. Shak, V. Paton, A. Bajamonde, T. Fleming, W. Eiemann, J. Wolter, J. Baselga, L. Norton for Genentech, Inc and Herceptin Multinational Clinical Investigators Trastuzumab Combination with Chemotherapy L. Norton, ASCO 1999 Abstract #483 適格例 (n =469) 転移性乳癌 HER2 過剰発現 再発後化学療法未施行 計測可能病変 PS 60% 以上 No adjuvant anthracyclines Adjuvant anthracyclines Trastuzumab + AC (n = 143) AC (n = 138) Trastuzumab + Taxol (n = 92) Taxol (n = 96) 7
8 Overall survival Probability of survival T + CT CT 20.3 mo mo. RR=0.76 p= CT patients treated with Time (months) Trastuzumab after disease 24% 62% 65% progression Herceptin Combination with Chemotherapy Survival Chemotherapy alone Chemotherapy plus HERCEPTIN p =
9 Relationship between Hormone Receptors and HER2 Protein Content in Breast Cancer Tissues ER PgR HER2 protein HER2 protein Toru Watanabe, et al Identification of two breast cancer subtypes type A B nuclear grade low high mitosis few many necrosis low high lymphoid infiltration few many p53 negative positive HER2 negative positive ER positive negative PgR positive negative bcl 2 positive negative 9
10 Identification of four breast cancer subtypes based on hormone receptors and HER2 - HER 2 + ER and/or PgR + - A O AB B 個別化治療のための乳がんの分類 HER2 陰性ホルモン受容体陰性 HER2 陽性ホルモン受容体陰性 HER2 陽性ホルモン受容体陽性 HER2 陰性ホルモン受容体陽性 10
11 ASCO 歴史展望 抗 HER2 療法の巻 IMPACT Author Publication 1998 Trastuzumab single p II MBC Second Line Cobleigh M JCO 17:2639,1999 Trastuzumab p III MBC AC/PTX ± HERCEPTIN Slamon D NEJM 344:783, Trastuzumab single p II MBC First Line Vogel C JCO 20:719, Trastuzumab + Paclitaxel MBC q3w Gelmon K JCO 21:3965,2003 Trastuzumab adjuvant PIII NSABP-B31/NCCTG-N9831 Romand EH NEJM 353:1673, Trastuzumab adjuvant PIII HERA Piccart-Gebhart MJ NEJM 353:1659, Lapatinib+ Capecitabine PIII Geyer CE NEJM 355:2733, Trastuzumab+Taxan vs. Lapatinib+Taxan P III NCIC MA.31 Gelmon K T-DM1 vs Lapatinib + Capecitabine P III Blackwell K Efficacy and Safety of Trastuzumab as a Single Agent in First-Line Treatment of HER2- Overexpressing Metastatic Breast Cancer Subset Objective Response Clinical Benefit * n % n % All patients, n = 111 (95% CI) ( )
12 Herceptin and Paclitaxel Every Three Weeks for Metastatic Breast Cancer Pharmacokinetics Safety Tolerability Gelmon K, et al. ASCO 2001, page 69a, Abstract 271 mayo 23 Modification of CALGB 9840 dose-dense versus standard paclitaxel HER2-positive patients Randomise H H H H H H H H H H paclitaxel H Herceptin H H H H H H H H H H 12
13 Trough Levels - Weekly vs q3w Herceptin (ug/ml) Weekly Administration Week Number H ercep tin ( u g /m L ) Q-3 Weekly Administration Week Number mayo 25 ASCO 歴史展望 抗 HER2 療法の巻 IMPACT Author Publication 1998 Trastuzumab single p II MBC Second Line Cobleigh M JCO 17:2639,1999 Trastuzumab p III MBC AC/PTX ± HERCEPTIN Slamon D NEJM 344:783, Trastuzumab single p II MBC First Line Vogel C JCO 20:719, Trastuzumab + Paclitaxel MBC q3w Gelmon K JCO 21:3965,2003 Trastuzumab adjuvant PIII NSABP-B31/NCCTG-N9831 Romand EH NEJM 353:1673, Trastuzumab adjuvant PIII HERA Piccart-Gebhart MJ NEJM 353:1659, Lapatinib+ Capecitabine PIII Geyer CE NEJM 355:2733, Trastuzumab+Taxan vs. Lapatinib+Taxan P III NCIC MA.31 Gelmon K T-DM1 vs Lapatinib + Capecitabine P III Blackwell K 13
14 Doxorubicin and Cyclophosphamide Followed by Paclitaxel with or without Trastuzumab as Adjuvant Therapy for Patients with HER-2 Positive Operable Breast Cancer Combined Analysis of NSABP-B31/NCCTG-N9831 Romand EH et al. Disease-Free Survival % AC T N Events AC T AC TH AC TH 87% 75% 85% 67% HR=0.48, 2P=3x10-12 Years From Randomization B31/N
15 B-31/N9831 Survival AC T 94% 92% AC TH 91% 87% N Deaths AC T AC TH HR=0.67, 2P=0.015 Years From Randomization B31/N9831 ASCO, Scientific Session, May 16, 2005 FIRST RESULTS OF THE HERA TRIAL A randomized three-arm multi-centre comparison of: 1 year Herceptin 2 years Herceptin or no Herceptin in women with HER-2 positive primary breast cancer who have completed adjuvant chemotherapy Martine J. Piccart-Gebhart, MD, PhD on behalf of: The Breast International Group (BIG), NON-BIG participating groups, Independent sites, F. Hoffmann La Roche Ltd. 15
![DISEASE-FREE SURVIVAL % alive and disease free 100 90 80 1 year trastuzumab 70 Observation 60 50 2 - yr 40 Events DFS % HR [95% CI] p value 30 20 127](/docs-images/90/104329741/images/16-0.jpg "85.8 0.54 [0.43, 0.67] <0.0001 10 220 77.4 0 0 5 10 15 20 25 No.")
16 DISEASE-FREE SURVIVAL % alive and disease free year trastuzumab 70 Observation yr 40 Events DFS % HR [95% CI] p value [0.43, 0.67] < No. Months from random ization at risk
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18 AC-T vs. AC-T plus trastuzumab hazard ratio, 0.63; P<0.001 AC-T vs. TCH hazard ratio, 0.77; P=0.04 Slamon D, et al N Engl J Med 365: , ASCO 歴史展望 抗 HER2 療法の巻 IMPACT Author Publication 1998 Trastuzumab single p II MBC Second Line Cobleigh M JCO 17:2639,1999 Trastuzumab p III MBC AC/PTX ± HERCEPTIN Slamon D NEJM 344:783, Trastuzumab single p II MBC First Line Vogel C JCO 20:719, Trastuzumab + Paclitaxel MBC q3w Gelmon K JCO 21:3965,2003 Trastuzumab adjuvant PIII NSABP-B31/NCCTG-N9831 Romand EH NEJM 353:1673, Trastuzumab adjuvant PIII HERA Piccart-Gebhart MJ NEJM 353:1659, Lapatinib+ Capecitabine PIII Geyer CE NEJM 355:2733, Trastuzumab+Taxan vs. Lapatinib+Taxan P III NCIC MA.31 Gelmon K T-DM1 vs Lapatinib + Capecitabine P III Blackwell K 18
19 A Phase III Randomized, Open-Label, International Study Comparing Lapatinib and Capecitabine vs. Capecitabine in Women with Refractory Advanced or Metastatic Breast Cancer (EGF100151) C.E. Geyer, D. Cameron, D. Lindquist, S. Chan, T. Pienkowski, C.G. Romieu, A. Jagiello-Gruszfeld, J. Crown, B. Kaufman, A. Chan, J.K. Forster Allegheny General Hospital, Pittsburgh, PA; Western General Hospital, Edinburgh, UK; US Oncolgy Research Network, Houston,TX; Nottingham City Hospital, Nottingham, UK; Cancer Center, Warsaw, Poland; CRCC Val d Aurelle Paul Lamarque, Montpellier, France; ZOZ MSWiA, Olsztyn, Poland; St. Vincent s University Hospital, Dublin, Ireland; Sheba Medical Center, Tel Hashomer, Israel; Mount Medical Centre, Perth, Australia; GlaxoSmithKline, Greenford, UK Study Design Progressive, HER2+ MBC or LABC Previously treated with anthracycline, taxane and trastuzumab* No prior capecitabine Stratification: Disease sites Stage of disease R A N D O M I Z E N=528 Lapatinib 1250 mg po qd continuously + Capecitabine 2000 mg/m 2 /d po days 1-14 q 3 wk Capecitabine 2500 mg/m 2 /d po days 1-14 q 3 wk Patients on treatment until progression or unacceptable toxicity, then followed for survival *Trastuzumab must have been administered for metastatic disease 19
20 Time to Progession ITT Population % of patients free from progression* Lapatinib + Capecitabine Capecitabine No. of pts Progressed or died* 45 (28%) 69 (43%) Median TTP, wk Hazard ratio (95% CI) 0.51 (0.35, 0.74) P-value (log-rank, 1-sided) Time (weeks) * Censors 4 patients who died due to causes other than breast cancer Disease Progression free Survival Overall Survival Geyer CE et al. N Engl J Med 2006;355:
21 ASCO 歴史展望 抗 HER2 療法の巻 IMPACT Author Publication 1998 Trastuzumab single p II MBC Second Line Cobleigh M JCO 17:2639,1999 Trastuzumab p III MBC AC/PTX ± HERCEPTIN Slamon D NEJM 344:783, Trastuzumab single p II MBC First Line Vogel C JCO 20:719, Trastuzumab + Paclitaxel MBC q3w Gelmon K JCO 21:3965,2003 Trastuzumab adjuvant PIII NSABP-B31/NCCTG-N9831 Romand EH NEJM 353:1673, Trastuzumab adjuvant PIII HERA Piccart-Gebhart MJ NEJM 353:1659, Lapatinib+ Capecitabine PIII Geyer CE NEJM 355:2733, Trastuzumab+Taxan vs. Lapatinib+Taxan P III NCIC MA.31 Gelmon K T-DM1 vs Lapatinib + Capecitabine P III Blackwell K 悲しそうな (-_-;) Karen Gelmon British Columbia Cancer Agency, Vancouver, BC, Canada 21
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33 悲しそうな (-_-;) Karen Gelmon そんな顔するなよ前からわかってたことじゃん 33
34 外科手ASCO から学ぶ抗 HER2 療法の進歩 NPO 法人がん情報局 2012/7/2 GEPAR QUINTO trial (phase III) Germany (Michael Untch) EC(90/600) x 4 DOC(100) x 4 Trastuzumab (8 6) q3w 594 pts R EC(90/600) x 4 DOC(100) x 年 12 月サンアントニオ乳癌シンポジウムでの発表 術pCR 率 (pathological Complete Response) Lapatinib 1,250(1,000) mg/d GEPAR QUINTO trial (phase III) Germany (Michael Untch) EC(90/600) x 4 DOC(100) x 4 Trastuzumab (8 6) q3w pathological CR (%) pts R EC(90/600) x 4 DOC(100) x 4 Lapatinib 1,250(1,000) mg/d 年 12 月サンアントニオ乳癌シンポジウムでの発表 34
35 外科手ASCO から学ぶ抗 HER2 療法の進歩 NPO 法人がん情報局 2012/7/2 neo ALLTO trial (phase II) Spain (Jose Baselga) PAC (80) x 12 Trastuzumab (8/6) q3w 450pts R PAC (80) x 12 Lapatinib 1,250(1,000) mg/d PAC (80) x 12 Trastuzumab (8/6) q3w Lapatinib 1,250(1,000) mg/d 2010 年 12 月サンアントニオ乳癌シンポジウムでの発表 術pCR 率 (pathological Complete Response) neo ALLTO trial (phase II) PAC (80) x 12 Trastuzumab (8/6) q3w pathological CR (%) pts R PAC (80) x 12 Lapatinib 1,250(1,000) mg/d 20.0 PAC (80) x 12 Trastuzumab (8/6) q3w Lapatinib 1,250(1,000) mg/d 年 12 月サンアントニオ乳癌シンポジウムでの発表 35
36 Trastuzumab vs. Lapatinib trastuzumab lapatinib 0 trastuzumab lapatinib EC DOC EC DOC GEPAR QUINTO trial 594 pts PAC PAC neo ALLTO trial 450pts でも使いようによっては役にたつんだぜ 悲しそうな (-_-;) Karen Gelmon 36
37 Trastuzumab vs. Lapatinib vs. Combination trastuzumab lapatinib combination 2010 年 12 月サンアントニオ乳癌シンポジウムでの発表 ASCO 歴史展望 抗 HER2 療法の巻 IMPACT Author Publication 1998 Trastuzumab single p II MBC Second Line Cobleigh M JCO 17:2639,1999 Trastuzumab p III MBC AC/PTX ± HERCEPTIN Slamon D NEJM 344:783, Trastuzumab single p II MBC First Line Vogel C JCO 20:719, Trastuzumab + Paclitaxel MBC q3w Gelmon K JCO 21:3965,2003 Trastuzumab adjuvant PIII NSABP-B31/NCCTG-N9831 Romand EH NEJM 353:1673, Trastuzumab adjuvant PIII HERA Piccart-Gebhart MJ NEJM 353:1659, Lapatinib+ Capecitabine PIII Geyer CE NEJM 355:2733, Trastuzumab+Taxan vs. Lapatinib+Taxan P III NCIC MA.31 Gelmon K T-DM1 vs Lapatinib + Capecitabine P III Blackwell K 37
38 信にみちた表情のヽ (^o^) Kimberly L. Blackwell Duke University Medical Center, Durham, NC USA Primary Results From EMILIA, a Phase 3 Study of Trastuzumab Emtansine (T DM1) vs Capecitabine and Lapatinib in HER2 Positive Locally Advanced or Metastatic Breast Cancer Previously Treated With Trastuzumab and a Taxane K Blackwell, 1 D Miles, 2 L Gianni, 3 IE Krop, 4 M Welslau, 5 J Baselga, 6 M Pegram, 7 D Y Oh, 8 V Diéras, 9 S Olsen, 10 L Fang, 10, MW Lu, 10 E Guardino, 10 S Verma 11 1 Duke Cancer Institute, Durham, NC, USA; 2 Mount Vernon Cancer Center, Northwood, UK; 3 San Raffaele Hospital, Milan, Italy; 4 Dana Farber Cancer Institute, Boston, MA, USA; 5 Medical Office Hematology, Aschaffenburg, Germany; 6 Massachusetts General Hospital, Boston, MA, USA; 7 University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, USA; 8 Seoul National University College of Medicine, Seoul, Korea; 9 Institut Curie, Paris, France; 10 Genentech, Inc, South San Francisco, CA, USA; 11 Sunnybrook Odette Cancer Center, Toronto, Canada 38
39 Targeted Therapies for HER2+ Breast Cancer: Trastuzumab, Lapatinib, and T DM1 Antibody: Trastuzumab P P HER2 Cytotoxic: DM1 Stable linker: MCC Emtansine P P P Trastuzumab Lapatinib P T-DM1 Nucleus Spector NL, Blackwell KL. J Clin Oncol 2009; Nelson MH, et al. Ann Pharmacother 2006; Lewis Phillips GD, et al. Cancer Res
40 T DM1: Mechanism of Action HER2 T-DM1 Emtansine release Inhibition of microtubule polymerization Lysosome P P P Internalization Nucleus Adapted from LoRusso PM, et al. Clin Cancer Res T DM1 Clinical Rationale for EMILIA Two single arm phase 2 trials in patients who received 1 HER2 directed therapies for MBC ORR: 25.9% (N=112) 1 and 34.5% (N=110) 2 Randomized phase 2 trial in patients without prior HER2 directed therapy for MBC Median PFS longer with T DM1 (n=67) vs. trastuzumab + docetaxel (n=70) 14.2 vs. 9.2 months (HR=0.59; P=0.035) 3 Capecitabine + Lapatinib Randomized phase 3 trial in patients who received prior trastuzumab Median TTP longer with capecitabine + lapatinib (n=163) vs. capecitabine (n=161) 8.4 vs. 4.4 months (HR=0.49; P<0.001) 4 1 Burris HA, et al. J Clin Oncol 2011; 2 Krop I, et al. J Clin Oncol 2012; 3 Hurvitz S, et al. ESMO 2011; 4 Geyer CE, et al. N Engl J Med
41 EMILIA Study Design HER2+ (central) LABC or MBC (N=980) Prior taxane and trastuzumab Progression on metastatic tx or within 6 mos of adjuvant tx 1:1 T-DM1 3.6 mg/kg q3w IV Capecitabine 1000 mg/m 2 orally bid, days 1 14, q3w + Lapatinib 1250 mg/day orally qd PD PD Stratification factors: World region, number of prior chemo regimens for MBC or unresectable LABC, presence of visceral disease Primary end points: PFS by independent review, OS, and safety Key secondary end points: PFS by investigator, ORR, duration of response, time to symptom progression Statistical Considerations for Efficacy End Points Hierarchical statistical analysis: performed in pre-specified sequential order Progression-free Survival (PFS) by Independent Review Final PFS analysis: Targeted number of events: % power to detect HR=0.75; 2-sided alpha 5% Overall Survival Overall Survival (OS) Interim OS analysis: Efficacy stopping boundary determined using Lan-DeMets alpha spending function with O Brien-Fleming boundary and number of death events observed Final OS analysis: Targeted number of events: % power to detect HR=0.80; 2-sided alpha 5% Secondary End Points 41
42 Patient Disposition Cap + Lap T-DM1 Randomized, n Treated, n On treatment at data cutoff date Median follow-up, mos (range) 12.4 (0 35) 12.9 (0 34) First patient in: February 23, 2009 Last patient in: October 13, 2011 Clinical data cutoff: January 14, 2012 Patient Demographics and Baseline Characteristics (1) Cap + Lap (n=496) T-DM1 (n=495) Median age, yrs (range) 53 (24 83) 53 (25 84) Race, n (%) White Asian Black/African American Other Not available World region, n (%) US Western Europe Asia Other ECOG PS, n (%) (75) 86 (17) 21 (4) 10 (2) 5 (1) 136 (27) 160 (32) 76 (15) 124 (25) 312 (64) 176 (36) 358 (72) 94 (19) 29 (6) 7 (1) 7 (1) 134 (27) 157 (32) 82 (17) 122 (25) 299 (61) 194 (39) 42
43 Patient Demographics and Baseline Characteristics (2) Cap + Lap (n=496) T-DM1 (n=495) Measurable disease by independent review, n (%) 389 (78) 397 (80) Metastatic involvement, n (%) Visceral Non-visceral Metastatic sites, n (%) <3 3 Unknown ER/PR status, n (%) ER+ and/or PR+ ER and PR Unknown 335 (68) 161 (33) 307 (62) 175 (35) 14 (3) 263 (53) 224 (45) 9 (2) 334 (68) 161 (33) 298 (60) 189 (38) 8 (2) 282 (57) 202 (41) 11 (2) Prior treatment type, n (%) Taxanes Anthracyclines Endocrine agents Prior therapy for MBC, n (%) Yes No Prior trastuzumab treatment, n (%) EBC only Duration of trastuzumab treatment, n (%) <1 yr 1 yr Prior Systemic Treatment Cap + Lap (n=496) 494 (100) 302 (61) 204 (41) 438 (88) 58 (12) 495 (100) 77 (16) 212 (43) 284 (57) T-DM1 (n=495) 493 (100) 303 (61) 205 (41) 435 (88) 60 (12) 495 (100) 78 (16) 210 (42) 285 (58) Median time since last trastuzumab, mos (range) 1.5 (0 98) 1.5 (0 63) 43
44 Drug Exposure Cap (n=487) Lap (n=488) T-DM1 (n=490) Median dose intensity, % Pts with dose reduction, n (%) 260 (53.4) 133 (27.3) 80 (16.3) T-DM1 decreased to 3.0 mg/kg, n (%) 58 (11.8) T-DM1 decreased to 2.4 mg/kg, n (%) 22 (4.5) Now I will present the efficacy results. Progression Free Survival by Independent Review Proportion progression-free Median (mos) No. events Cap + Lap T-DM Stratified HR=0.650 (95% CI, 0.55, 0.77) P< Time (mos) No. at risk by independent review: Cap + Lap T-DM Unstratified HR=0.66 (P<0.0001). 44
45 Progression Free Survival by Independent (IRC) and Investigator (INV) Review 1.0 IRC Cap + Lap T DM1 HR=0.650 (95% CI, 0.55, 0.77) P< Proportion progression-free INV Cap + Lap T DM1 HR=0.658 (95% CI, 0.56, 0.77) P< Time (mos) No. at risk by independent review: Cap + Lap T-DM Unstratified HR by independent review=0.66 (P<0.0001). Progression Free Survival Subgroup Analyses Pre specified Stratification Factors Baseline characteristic All pts Total n 991 Cap + Lap Median, mos 6.4 T-DM1 Median, mos HR (95% CI) (0.56, 0.78) T-DM1 better Cap + Lap better World region US Western Europe Other (0.51, 0.98) 0.56 (0.41, 0.74) 0.73 (0.56, 0.94) Number prior chemo regimens for MBC or unresectable LABC 0 1 >1 HRs from unstratified analysis Presence of visceral disease Yes No (0.55, 0.85) 0.63 (0.49, 0.82) 0.55 (0.45, 0.67) 0.96 (0.71, 1.30) Hazard ratio
46 Progression Free Survival Subgroup Analyses Baseline characteristic Total n Cap + Lap Median, mos T-DM1 Median, mos HR (95% CI) T-DM1 better Cap + Lap better All pts (0.56, 0.78) Age <65 yrs 65 yrs (0.52, 0.74) 1.06 (0.68, 1.66) ER and PR status ER+ and/or PR+ ER and PR (0.58, 0.91) 0.56 (0.44, 0.72) Line of therapy a First Second Third (0.30, 0.85) 0.69 (0.53, 0.91) 0.69 (0.55, 0.86) Hazard ratio HRs were from unstratified analysis. a Defined as any systemic therapy, including endocrine or chemotherapy. Overall Survival: Interim Analysis Proportion surviving % 77.0% 65.4% Median (mos) No. events Cap + Lap T-DM1 NR 94 Stratified HR=0.621 (95% CI, 0.48, 0.81) P= Efficacy stopping boundary P= or HR= % No. at risk: Time (mos) Cap + Lap T-DM Unstratified HR=0.63 (P=0.0005). NR=not reached. 46
47 Objective Response Rate (ORR) and Duration of Response (DOR) in Patients with Measurable Disease Percent ORR Difference: 12.7% (95% CI, 6.0, 19.4) P= % 120/389 Cap + Lap 43.6% 173/397 T-DM1 Proportion progression-free DOR Median, mos (95% CI) Cap + Lap 6.5 (5.5, 7.2) T-DM (8.4, 20.8) No. at risk Cap + Lap T-DM Patient Reported Outcomes Time to Symptom Progression The FACT-Breast Trial Outcome Index 1 evaluates Physical Well-Being Functional Well-Being Breast Cancer-Specific Symptoms Symptom progression defined as 5-point decrease from baseline Cap + Lap T-DM1 Time to symptom progression (n=445) (n=450) Median, mos HR (95% CI) P value 0.80 (0.67, 0.95) Brady MJ, et al. J Clin Oncol
48 Overview of Adverse Events Cap + Lap (n=488) T-DM1 (n=490) All-grade AE, n (%) 477 (97.7) 470 (95.9) Grade 3 AE, n (%) 278 (57.0) 200 (40.8) AEs leading to treatment discontinuation (for any study drug), n (%) 52 (10.7) 29 (5.9) AEs leading to death on treatment, n (%) a 5 (1.0) 1 (0.2) LVEF <50% and 15-point decrease from baseline, % b 7 (1.6) 8 (1.7) a Cap + Lap: CAD, multiorgan failure, coma, hydrocephalus, ARDS; a T-DM1: metabolic encephalopathy. b Evaluable pts: 445 (Cap + Lap); 481 (T-DM1). Non Hematologic Adverse Events Grade 3 AEs With Incidence 2% Cap + Lap (n=488) T-DM1 (n=490) Adverse Event All Grades, % Grade 3, % All Grades, % Grade 3, % Diarrhea Hand-foot syndrome Vomiting Hypokalemia Fatigue Nausea Mucosal inflammation Increased AST Increased ALT ALT, alanine aminotransferase; AST, aspartate aminotransferase. 48
49 Hematologic Adverse Events Adverse Event All Grade, % Cap + Lap (n=488) Grade 3, % Grade 4, % All Grade, % T-DM1 (n=490) Grade 3, % Grade 4, % Neutropenia Febrile neutropenia Anemia Thrombocytopenia Conclusions T DM1 demonstrated improved efficacy over capecitabine + lapatinib T DM1 demonstrated a significant improvement in PFS HR=0.650; P< Interim overall survival favored T DM1 but did not cross the efficacy stopping boundary HR=0.621; P= Safety and secondary efficacy end points favored T DM1 T DM1 should offer an important therapeutic option in the treatment of HER2 positive metastatic breast cancer 49
50 Thanks To all of the patients who participated in the trial and their families To the investigators, clinicians and research staff at the 213 sites in 26 countries 99 SABCS 歴史展望 抗 HER2 療法の巻 IMPACT Author Publication 1998 Trastuzumab single p II MBC Second Line Cobleigh M JCO 17:2639,1999 Trastuzumab p III MBC AC/PTX ± HERCEPTIN Slamon D NEJM 344:783, Trastuzumab single p II MBC First Line Vogel C JCO 20:719, Trastuzumab + Paclitaxel MBC q3w Gelmon K JCO 21:3965,2003 Trastuzumab adjuvant PIII NSABP-B31/NCCTG-N9831 Romand EH NEJM 353:1673, Trastuzumab adjuvant PIII HERA NEJM 353:1659, Lapatinib+ Capecitabine PIII Geyer CE NEJM 355:2733, Trastuzumab vs Lapatinib vs, combination in neoadjuvant Pertuzumab vs Trastuzumab+Pertuzumab in neoajuvant Trastuzumab + DTX vs. Trastuzumab+Perutuzumab + DTX (CLEOPATRA) Trastuzumab+Taxan vs. Lapatinib+Taxan P III NCIC MA.31 T-DM1 vs Lapatinib + Capecitabine P III Untch M Gianni L Lancet Oncol 13: 135,2012 Lancet Oncol 13: 25,2012 Baselga H NEJM 366: 109,2012 Gelmon K Blackwell K 50
51 HER2 二量体形成とシグナル伝達 HER2 HER3 Ferguson et al. Mol Cell. 2003;11: Olayioye et al. EMBO J. 2000;19: Hynes et al. Nat Rev Cancer. 2005;5: Rowinsky. Annu Rev Med. 2004;55: Ligand activated HER2:HER3 dimer P P P P チロシンキナーゼのリン酸化 トラスツズマブとペルズズマブは HER2 タンパクの異なる部位に結合する トラスツズマブ HER2 ペルツズマブ HER3 Subdomain IV of HER2 Trastuzumab disrupts ligand-independent HER2-HER3-PI3K complex Trastuzumab prevents HER2 receptor shedding Blocks HER2 signaling and flags cells for destruction by the immune system via ADCC Dimerization domain of HER2 Pertuzumab prevents ligand-induced HER2:HER3 dimerization Pertuzumab does not prevent HER2 receptor shedding Flags cells for destruction by the immune system via ADCC Junttila et al. Cancer Cell. 2009;15: ; Hynes et al. Nat Rev Cancer 2005;5: Rowinsky. Annu Rev Med. 2004;55:
52 外科手ASCO から学ぶ抗 HER2 療法の進歩 NPO 法人がん情報局 2012/7/2 NeoSphere trial (phase II) Italy (Luca Geanni) 417 pts R DOC(100) x 4 Trastuzumab (8/6) q3w DOC(100) x 4 Trastuzumab (8/6) q3w Pertuzumab (8/6) q3w Trastuzumab (8/6) q3w Pertuzumab (8/6) q3w DOC(100) x 4 Pertuzumab (8/6) q3w 術pCR 率 (pathological Complete Response) NeoSphere trial (phase II) DOC(100) x 4 Trastuzumab (8/6) q3w DOC(100) x 4 Trastuzumab (8/6) q3w Pertuzumab (8/6) q3w pts R Trastuzumab (8/6) q3w Pertuzumab (8/6) q3w DOC(100) x 4 Pertuzumab (8/6) q3w pathological CR (%)
53 Trastuzumab vs. Pertuzumab vs. Combination trastuzumab pertuzumab combination 2010 年 12 月サンアントニオ乳癌シンポジウムでの発表
54 SABCS 2011 A Phase III, Randomized, Double-Blind, Placebo-Controlled Registration Trial to Evaluate the Efficacy and Safety of Placebo + Trastuzumab + Docetaxel vs. Pertuzumab + Trastuzumab + Docetaxel in Patients with Previously Untreated HER2-Positive Metastatic Breast Cancer (CLEOPATRA) J Baselga, J Cortés, S-B Kim, S-A Im, R Hegg, Y-H Im, L Roman, J L Pedrini, T Pienkowski, A Knott, E Clark, M C. Benyunes, G Ross, and S M Swain 1. Baselga et al. N Engl J Med 2011 Study design Patients with HER2-positive MBC centrally confirmed (N=808) 1:1 n=406 Placebo + trastuzumab Docetaxel* 6 cycles recommended Pertuzumab + trastuzumab PD PD n=402 Docetaxel* 6 cycles recommended Randomization was stratified by geographic region and prior treatment status (neo/adjuvant chemotherapy received or not) Study dosing q3w: - Pertuzumab/Placebo: 840 mg loading dose, 420 mg maintenance - Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance - Docetaxel: 75 mg/m 2, escalating to 100 mg/m 2 if tolerated *<6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at investigator discretion MBC, metastatic breast cancer; PD, progressive disease
55 Primary endpoint: Independently assessed PFS Median follow-up: 19.3 months Progression-free survival (%) Ptz + T + D: median 18.5 months Pla + T + D: median 12.4 months Time (months) n at risk Ptz + T + D Pla + T + D = 6.1 months HR = % CI p< D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab Stratified by prior treatment status and region 109 Overall survival: Pre-defined interim analysis Median follow-up: 19.3 months, n = 165 OS events Overall survival (%) Ptz + T + D: 69 events Pla + T + D: 96 events HR = 0.64* 95% CI p = * n at risk Time (months) Ptz + T + D Pla + T + D * The interim overall survival analysis did not cross the pre-specified OʼBrien-Fleming stopping boundary (HR 0.603; p ) D, docetaxel; OS, overall survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab
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19CRC/2009.8.8-9 T0 T1 T2 T3 T4 M0 N0 M1 19CRC 2009.8.8 1 2 N1 N2 N3 Stage 0 Stage I Stage IIA Stage IIB Stage IIIA Stage IIIB Stage IIIC Stage IV Tis 3 4 5 6 1 19CRC/2009.8.8-9 7 8 Subtype of Breast Cancer
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2) Dolphin, A., Jenner, P., Marsden, C,D., Pycock, C. and Tarsy, D. : Pharmacological evidence for cerebral dopamine receptor blockade by metoclopramide in rodents, Psychopharmacologia, 41 : 133, 1975.
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1) Michaelis L. Biochem Z., 59, 78, 1914. 2) Ferris H. C. Dent. Cosmos Phila., 63, 10, 93, 1921. 3) Bloomfield A. L. Bull Johns Hopk. Hosp. Bait., 31, 118, 1920. 4) Starr H. C. J. Biol. Chem. Bait., 54,