ASCO 2012 Metastatik Meme Kanseri Prof. Dr. Gül Başaran Acıbadem Üniversitesi Tıp Fakültesi Tıbbi Onkoloji
ASCO 2012 MMK: Faz III çalışmalar Her-2 pozitif MK EMILIA* (plenary) ECOG 1105 (GPS 605)** CLEOPATRA Yan etkiler (GPS 597) QoL (GPS 598) Kardiyak tolerabilite (PDS 533) NCIC CTG MA.31/EGF 108919*: 1. seri Taksan+Trastuzumab vs Taksan+Lapatinib (OAS LBA 671) Her-2 negatif/hr pozitif MMK BOLERO çalışması: güncelleme* (GPS 559) HRQoL (GPS 539) Asyalı hastalar (GPS 540) >65y hastalar (GPS 551) kemik metli hastalarda etki (OAS 9005) Kemoterapi çalışmaları* 1. seri tedavi hft paklitaksel+bev vs hft nab-paklitaksel+bev vs ixabepilone+bev (CALGB 40502)(OAS 1002) İdame tedavi: KGSG-BR 0702: 6XGem+Paklitaksel sonrası GP vs gözlem (0AS 1003) 1. seri tedavi: Gem +Doc vs Gem+Paklitaksel (GPS 1073)**
Daha Önce Trastuzumab ve Bir Taksanla Tedavi Edilen HER2-Pozitif Lokal Olarak İlerlemiş ya da Metastatik Meme Kanserinde Trastuzumab Emtansin (T-DM1) İle Kapesitabin ve Lapatinibin Karşılaştırıldığı Faz 3 Araştırma EMILIA dan Elde Edilen Temel Sonuçlar 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, ABD; 2 Mount Vernon Cancer Center, Northwood, İngiltere; 3 San Raffaele Hospital, Milano, İtalya; 4 Dana-Farber Cancer Institute, Boston, MA, ABD; 5 Medical Office Hematology, Aschaffenburg, Almanya; 6 Massachusetts General Hospital, Boston, MA, ABD; 7 University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, ABD; 8 Seoul National University College of Medicine, Seoul, Kore; 9 Institut Curie, Paris, Fransa; 10 Genentech, Inc, South San Francisco, CA, ABD; 11 Sunnybrook Odette Cancer Center, Toronto, Kanada
HER2+ Meme Kanseri İçin Hedefe Yönelik Tedaviler: Trastuzumab, Lapatinib ve T-DM1 Antikor: Trastuzumab P P HER2 Sitotoksik: DM1 Stabil bağlayıcı: MCC Emtansin P P P Trastuzumab Lapatinib P T-DM1 Nukleus Spector NL, Blackwell KL. J Clin Oncol 2009; Nelson MH, et al. Ann Pharmacother 2006; Lewis Phillips GD, et al. Cancer Res 2008. 4
1 anti-her2 tx alanlarda faz II, ORR: %25.9 (N=112) 1 ve %34.5 (N=110) 2 Daha önce MBCantHer-2 tx almayanlarda faz II randomize n:137 T-DM1 (n=67) vs trastuzumab + dosetaksel (n=70) rand. faz II medyan PFS 9 vs 14 ay (HR=0.59; P=0.035) 3 Daha önce trastuzumab alanlarda randomize faz III Kapesitabin + lapatinib (n=163) vs kapesitabine (n=161) medyan TTP 4.4 vs 8.4 ay (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 2006. T-DM1: Etki Mekanizması HER2 T-DM1 Emtansin salımı Mikrotübül polimerizasyonunun inhibisyonu Lizozom P P P Hücreye giriş Nukleus Adapted from LoRusso PM, et al. Clin Cancer Res 2011. 5
EMILIA Araştırmasının Tasarımı HER2+ (santral) LABC ya da MBC (N=980) T-DM1 3.6 mg/kg q3w IV PD Daha önce taksan ve trastuzumab Metastaz tedavisi sırasında ya da adjuvan tedavi uygulanan 6 ay içinde progresyon 1:1 Kapesitabin 1-14. günler arasında, q3w, oral yolla 1000 mg/m 2 bid + Lapatinib oral yolla 1250 mg/gün qd PD Katmanlandırma faktörleri: Dünyadaki bölge, daha önce MBC ya da rezekte edilemeyen LABC nedeniyle uygulanan kemo rejimlerinin sayısı, viseral hastalık varlığı Birincil sonlanım noktaları: Bağımsız incelemeye göre PFS, OS ve güvenilirlik Önemli ikincil sonlanım noktaları: Araştırmacıya göre PFS, OFF, yanıt süresi, semptom progresyonuna kadar geçen süre 2009-2012
Hastaların Demografik Özellikleri ve Başlangıçtaki Özellikleri Kap + Lap (n=496) T-DM1 (n=495) Bağımsız incelemeye göre ölçülebilir hastalık, n (%) 389 (78) 397 (80) Metastatik tutulum, n (%) Viseral Viseral olmayan Metastaz alanları, n (%) <3 3 Bilinmeyen 335 (68) 161 (33) 307 (62) 175 (35) 14 (3) 334 (68) 161 (33) 298 (60) 189 (38) 8 (2) ER/PR durumu, n (%) ER+ ve/veya PR+ ER ve PR Bilinmeyen 263 (53) 224 (45) 9 (2) 282 (57) 202 (41) 11 (2)
Daha Önceki Sistemik Tedavi Daha önce uygulanan tedavinin tipi, n (%) Taksanlar Antrasiklinler Endokrin ajanlar Daha önce MBC nedeniyle tedavi, n (%) Evet Hayır Kap + Lap (n=496) 494 (100) 302 (61) 204 (41) 438 (88) 58 (12) T-DM1 (n=495) 493 (100) 303 (61) 205 (41) 435 (88) 60 (12) Daha önce trastuzumab tedavisi, n (%) Yalnızca EBC Trastuzumab tedavisinin süresi, n (%) <1 yıl 1 yıl 495 (100) 77 (16) 212 (43) 284 (57) 495 (100) 78 (16) 210 (42) 285 (58) Son trastuzumab uygulamasından itibaren geçen süre, ay (aralık) 1.5 (0 98) 1.5 (0 63)
Oran (%) Progresyon görülmeyen hasta oranı Ölçülebilir Hastalığı Olan Olgularda Objektif Yanıt Oranı (ORR) ve Yanıt Süresi (DOR) ORR 50 Farklılık: %12.7 (%95 CI, 6.0, 19.4) P=0.0002 %43.6 1.0 Medyan, ay (%95 CI) Kap + Lap 6.5 (5.5, 7.2) T-DM1 12.6 (8.4, 20.8) 40 %30.8 0.8 30 0.6 20 0.4 10 0.2 0 120/389 Kap + Lap 173/397 T-DM1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Risk altındaki hasta sayısı: Kap + Lap 120 105 77 48 32 14 9 8 3 3 1 1 0 0 0 0 0 0 0 T-DM1 173 159 126 84 65 47 42 33 27 19 12 8 2 0 0 0 0 0 0
Progresyon görülmeyen hasta oranı Bağımsız İncelemeye Göre PGS 1.0 0.8 Medyan (ay) Olay sayısı Kap + Lap 6.4 304 T-DM1 9.6 265 Katmanlandırılmış HR=0.650 (%95 CI, 0.55, 0.77) P<0.0001 0.6 0.4 0.2 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Süre (ay) Bağımsız incelemeye göre risk altındaki hasta sayısı: Kap + Lap 496 404 310 176 129 73 53 35 25 14 9 8 5 1 0 0 T-DM1 495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0 Katmanlandırılmamış HR=0.66 (P<0.0001).
Sağkalım oranı Genel Sağkalım: Ara Analiz 1.0 %84.7 Medyan (ay) Olay sayısı Kap + Lap 23.3 129 T-DM1 NR 94 Katmanlandırılmış HR=0.621 (%95 CI, 0.48, 0.81) P=0.0005 Etkinlik durdurma sınırı P=0.0003 ya da HR=0.617 0.8 %77.0 %65.4 0.6 0.4 %47.5 0.2 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Süre (ay) Risk altındaki hasta sayısı: Kap + Lap 496 469 438 364 296 242 195 155 129 97 74 52 31 17 7 3 2 1 0 T-DM1 495 484 461 390 331 277 220 182 149 123 96 67 46 29 16 5 2 0 0 Katmanlandırılmamış HR=0.63 (P=0.0005). NR=ulaşılmamıştır.
Advers Olayların Özeti Kap + Lap (n=488) T-DM1 (n=490) Tüm evrelerdeki AE, n (%) 477 (97.7) 470 (95.9) Evre 3 AE, n (%) 278 (57.0) 200 (40.8) Tedavinin bırakılmasına yol açan AE ler (herhangi bir araştırma ilacı için), n (%) 52 (10.7) 29 (5.9) Tedavi sırasında ölüme yol açan AE ler, n (%) a 5 (1.0) 1 (0.2) LVEF <%50 ve başlangıca göre 15 puan düşüş, % b 7 (1.6) 8 (1.7) a Kap + Lap: CAD, çoğul organ yetersizliği, koma, hidrosefali, ARDS; a T-DM1: metabolik ensefalopati. b Değerlendirilebilen hastalar: 445 (Kap + Lap); 481 (T-DM1).
Hematolojik Olmayan Advers Olaylar İnsidansı %2 Olan Evre 3 Advers Olaylar Kap + Lap (n=488) T-DM1 (n=490) Advers Olay Tüm Evreler, % Evre 3, % Tüm Evreler, % Evre 3, % Diyare 79.7 20.7 23.3 1.6 El-ayak sendromu 58.0 16.4 1.2 0.0 Kusma 29.3 4.5 19.0 0.8 Hipokalemi 8.6 4.1 8.6 2.2 Yorgunluk 27.9 3.5 35.1 2.4 Bulantı 44.7 2.5 39.2 0.8 Mukoza enflamasyonu 19.1 2.3 6.7 0.2 AST artışı 9.4 0.8 22.4 4.3 ALT artışı 8.8 1.4 16.9 2.9 Kap + Lap (n=488) T-DM1 (n=490) Advers Olay Tüm Evreler, % Evre 3, % Evre 4, % Tüm Evreler, % Evre 3, % Evre 4, % Nötropeni 8.6 3.5 0.8 5.9 1.6 0.4 Febril nötropeni 1.0 0.4 0.6 0.0 0.0 0.0 ALT, alanin aminotransferaz; AST, aspartat aminotransferaz. Anemi 8.0 1.6 0.0 10.4 2.7 0.0
Sonuçlar T-DM1 ile, kapesitabin + lapatinibe kıyasla PFS de üstün: HR=0.650; P<0.0001 Ara genel sağkalım sonuçlarının T-DM1 lehine olduğu, ancak etkinlik durdurma sınıfını geçmediği belirlenmiştir. HR=0.621; P=0.0005 Güvenilirlik ve ikincil etkinlik sonlanım noktalarının T-DM1 lehine olduğu saptanmıştır T-DM1, HER2-pozitif metastatik meme kanseri tedavisinde 2. basamak tedavide önemli bir terapötik seçenek oluşturmalıdır
NEJM 2012 CLEOPATRA
Randomized Controlled Trial Comparing Taxane- Based Chemotherapy with Lapatinib or Trastuzumab as First-Line Therapy for Women with HER2+ Metastatic Breast Cancer: Interim Analysis of NCIC CTG MA.31/GSK EGF 108919 K Gelmon, F Boyle, B Kaufman, D Huntsman, A Manikhas, A Di Leo, M Martin, L Schwartzberg, S Dent, S Ellard, K Tonkin, Y Nagarwala, K Pritchard, T Whelan, D Nomikos, JA Chapman, W Parulekar ClinicalTrials.gov: NCT00667251
MA.31/ EGF108919: Design Taxane (Tax) P 80 mg/m 2 IV weekly (3/4) or D 75 mg/m 2 IV q3 weekly Anti HER2/neu therapy: Lapatinib (L) Plus taxane: 1250 mg po daily Monotherapy 1500 mg po daily EXPERIMENTAL ARM Randomize Centrally Her-2 + Trastuzumab (T) Plus taxane: loading 6 mg/kg IV q3 weekly or 2 mg/kg IV weekly Monotherapy 6 mg/kg IV q3 weekly STANDARD ARM 24 Weeks: Lapatinib plus Taxane Until PD: Lapatinib 24 Weeks: Trastuzumab plus Taxane Until PD: Trastuzumab Primary Outcome: PFS Sample Size: ~ 600 (536 centrally confirmed HER2+ patients)
Purpose of This Presentation MA.31/EGF 108919 has undergone an interim analysis: 4.12An independent DSMC has recommended: these results be released trial conduct be altered Study objectives: Primary To compare the Progression Free Survival (PFS) of taxane therapy plus lapatinib to taxane therapy plus trastuzumab Secondary: Overall survival Adverse events Incidence of CNS metastases (first progression) and time to CNS metastases Objective response rate (ORR), Clinical Benefit response rate(cb), time to response and duration of response QOL Correlative studies
Median PFS TTAX/T = 11.4 months Median PFS LTAX/L = 8.8 months HR = 1.33 (95% CI = 1.06 1.67), P = 0.01 Progression Free Survival Intent to Treat Analysis TTAX/T LTAX/L # TTAX/T # LTAX/L
Progression Free Survival Centrally-confirmed HER2+ Analysis Median PFS TTAX/T= 13.7 months Median PFS LTAX/L = 9.0 months HR = 1.48 (95% CI = 1.15 1.92), P = 0.003 TTAX/T LTAX/L # TTAX/T # LTAX/L
Serious Adverse Events LTAX/L (Total SAE reports = 136) TTAX/T (Total SAE reports = 78) EVENT Total Number* Number post amendment ** EVENT Total Number* Number post amendment ** Diarrhea 32 25 Diarrhea 5 3 Febrile Neutropenia 17 7 Febrile Neutropenia 7 6 * Included as one of the adverse event terms within a single SAE report ** Protocol Amendment after first 189 patients were randomized mandated primary GCSF prophylaxis for patients on docetaxel and lapatinib
LVEF Decrease from Baseline While on Treatment LTAX/L (n = 312) TTAX/T (n = 317) Absolute Decrease (%) Absolute Decrease (%) week n 0 - <20 20 or more n 0- <20 20 or more 12 255 24 199 158 (62) 126 (63) 0 (0) 261 0 (0) 208 36 145 95 (66) 0 (0) 154 180 (69) 142 (68) 106 (69) 0 (0) 3 (1) 3 (2) 48 72 43 (60) 0 (0) 98 77 (79) 2 (2) 60 42 28 (67) 0 (0) 70 50 (71) 0 (0) 72 26 14(54) 0(0) 36 21(58) 1(3)
LV Systolic Dysfunction from Baseline (Acute and delayed) LTAX/L (N = 313) TTAX/T (N = 317) Left Ventricular Systolic Dysfunction Total n (pts) Total Events Grade 1-2 Grade 3-4 Total n (pts) Total Events Grade 1-2 Grade 3-4 Acute 313 8 (2) G1-4 (1) G2-4 (1) 0 317 18 (6) G1-1 (1) G2-16(5) G3 1(1) G4 0 (0) Delayed 164 1 (1) G1 0 (0) G2 1 (1) 0 147 7 (5) G1-1 (1) G2-4 (3) G3 2 (1) G4 0 (0)
Treatment Discontinuations OFF PROTOCOL TREATMENT (n = 382) LTAX/L=202 TTAX/T=180 Reason Number (%) Number (%) Death 5 (2.5) 10 (5.6) Intercurrent Illness 3 (1.5) 3 (1.7) Progressive Disease 143 (70.8) 121 (67.2) Toxicity 36 (17.8) 19 (10.6) Refused Treatment 2 (1.0) 4 (2.2) Symptomatic Progression 4 (2.0) 3 (1.7) Other 9 (4.5) 20 (11.1)
Conclusions In this study comparing LTAX/L to TTAX/T, the PFS was statistically significantly better in the trastuzumab arm with a 2.6 month difference (median PFS) in the ITT population The toxicity pattern of the two arms was different with more rash and diarrhea in the lapatinib containing arm.
HR pozitif/her-2 negatif MMK
BOLERO-2 (Ph III): Everolimus in Advanced BC N = 724 Postmenopausal ER+ Unresectable locally advanced or metastatic BC Recurrence or progression after letrozole or anastrozole R 2:1 EVE 10 mg daily + EXE 25 mg daily (n = 485) Placebo + EXE 25 mg daily (n = 239) Stratification: Sensitivity to prior hormone therapy and presence of visceral metastases Endpoints Primary: PFS (local assessment) Secondary: OS, ORR, QOL, safety, bone markers, PK Abbreviations: BC, breast cancer; ER+, estrogen receptor-positive; EVE, everolimus; EXE, exemestane; ORR, overall response rate; OS, overall survival; PFS, progression-free 31 survival; Ph, phase; PK, pharmacokinetics; QOL, quality of life. Baselga J, et al. N Engl J Med. 2012;366(6):520-529.
BOLERO-2: Baseline Characteristics Were Generally Balanced Between Arms Characteristic Everolimus + Exemestane (N=485), % Placebo + Exemestane (N=239), % Median age (range), years 62 (34, 93) 61 (28, 90) Race Caucasian 74 78 Asian 20 19 Performance status 0 60 59 Liver involvement 33 30 Lung involvement 29 33 Measurable disease a 70 68 32 Adapted from: Baselga J, et al. N Engl J Med. 2012;366(6):520-529. a All other patients had 1 bone lesion.
Therapy 33 BOLERO-2: Prior Therapies Were Balanced Between Treatment Arms Everolimus + Exemestane (N=485), % Placebo + Exemestane (N=239), % Sensitivity to prior hormonal therapy 84 84 Last treatment: LET/ ANA 74 75 Last treatment Adjuvant 21 15 Metastatic 79 85 Prior tamoxifen 47 49 Prior fulvestrant 17 16 Prior chemotherapy for metastatic BC 26 26 Number of prior therapies: 3 54 53 Abbreviations: ANA, anastrozole; LET, letrozole. Adapted from: Baselga J, et al. N Engl J Med. 2012;366(6):520-529.
Probability (%) of Event PFS Based on Local Assessment at 18-mo Follow-up in BOLERO-2 Confirms Earlier Reports 100 80 60 HR = 0.45 (95% CI: 0.38-0.54) Log-rank P value: <.0001 Kaplan-Meier medians EVE 10 mg + EXE: 7.8 months PBO + EXE: 3.2 months 40 20 0 Censoring times EVE 10 mg EXE (n/n = 310/485) PBO + EXE (n/n = 200/239) Number of patients still at risk EVE 10 mg + EXE PBO + EXE 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 Time (week) 485 436 366 304 257 221 185 158 124 91 66 50 35 24 22 13 10 8 2 1 0 239 190 132 96 67 50 39 30 21 15 10 8 5 3 1 1 1 0 0 0 0 Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo. Piccart M, et al. ASCO 2012; abstract 559 (poster). 34
Probability (%) of Event PFS Based on Central Review at 18-mo Follow-up in BOLERO-2 Confirms Earlier Reports and Local Assessment 100 80 60 HR = 0.38 (95% CI: 0.31-0.48) Log-rank P value: <.0001 Kaplan-Meier medians EVE 10 mg + EXE: 11.0 months PBO + EXE: 4.1 months 40 20 0 Censoring times EVE 10 mg + EXE (n/n = 188/485) PBO + EXE (n/n = 132/239) Number of patients still at risk EVE 10 mg + EXE PBO + EXE 35 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 Time (week) 485427359292239211166140108 77 239179114 76 56 39 31 27 16 13 Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo Piccart M, et al. ASCO 2012; abstract 559 (poster). 62 9 48 6 32 4 21 1 18 0 11 0 10 0 5 0 0 0
Percent BOLERO-2 (18 mo f/up): Response Rates & Clinical Benefit Were Significantly Higher in the Everolimus Arm P < 0.0001 P < 0.0001 36 Piccart M, et al. ASCO 2012; abstract 559 (poster).
BOLERO-2 (18 mo f/up): Overall Survival Was Numerically Better With Everolimus PFS Interim 1 (7 mo follow-up) PFS Update 2 (12 mo follow-up) PFS Final 3 (18 mo update) Cut-off Date 11-Feb-2011 8-Jul-2011 15-Dec-2011 OS events (EVE vs PBO%) 83 (10.6 vs 13.0%) 137 (17.3 vs 22.7%) 200 (25.4 vs 32.2%) Δ OS events 2.4% 5.4% 6.8% Abbreviations: EVE, everolimus; mo, month; OS, overall survival; PBO, placebo; PFS, progression-free survival; vs, versus. 1. Baselga J, et al. N Engl J Med. 2012;366(6):520-529. 2. Hortobagyi 37 G, et al. SABCS 2011; abstract S3-7 (oral). 3. Piccart M, et al. ASCO 2012; abstract 559 (poster).
BOLERO-2 (18 mo f/up): Common Adverse Events Were Consistent With the Established Safety Profile of Everolimus Everolimus + Exemestane (N=482), % Grade Placebo + Exemestane (N=238), % Grade All 1 2 3 4 All 1 2 3 4 Total 100 7 40 44 9 91 26 36 23 5 Stomatitis 59 29 22 8 0 12 9 2 <1 0 Rash 39 29 9 1 0 7 5 2 0 0 Fatigue 37 18 14 4 <1 27 16 10 1 0 Diarrhea 34 26 6 2 <1 19 14 4 <1 0 Nausea 31 21 9 <1 <1 29 21 7 1 0 Appetite decreased Non-infectious pneumonitis* 31 19 10 1 0 13 8 4 1 0 16 7 6 3 0 0 0 0 0 0 Hyperglycemia* 14 4 5 5 <1 2 1 1 <1 0 *Adverse Events of clinical interest. Piccart M, et al. ASCO 2012; abstract 559 (poster). 38
PFS Benefits Were Consistent in All Subgroups Median PFS, months HR EVE + EXE PBO + EXE All N = 724 Age group < 65 449 65 275 Region Asia 137 Europe 275 North America 274 Other 38 Japanese patients Japan 106 Non-Japan 618 Race Asian 143 Caucasian 547 Other 34 Baseline ECOG performance status 0 435 1, 2 274 PgR status Negative 184 Positive 523 0.45 7.82 3.19 0.38 8.31 2.92 0.59 6.83 4.01 0.60 8.48 4.14 0.45 7.16 2.83 0.38 8.41 2.96 0.40 4.53 1.48 0.58 8.54 4.17 0.42 7.16 2.83 0.62 8.48 4.14 0.42 7.36 2.96 0.25 6.93 1.41 0.48 8.25 4.11 0.39 6.93 2.76 0.51 6.93 2.83 0.41 8.08 3.32 Abbreviations: EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival.; PgR, progesterone receptor. Favors EVE + EXE Favors PBO + EXE Piccart M, et al. ASCO 2012; abstract 559 (poster). 39
PFS Benefits Were Consistent in All Subgroups Median PFS, months HR EVE + EXE PBO + EXE All N = 724 Number of organs involved 1 219 2 232 3 271 Presence of visceral metastasis No 318 Yes 406 Bone only lesions at baseline No 573 Yes 151 Number of prior therapies 1 118 2 217 3 389 Prior chemotherapy No 231 Yes 493 Prior use of hormonal therapy other than NSAI No 326 Yes 398 0.45 7.82 3.19 0.40 11.50 4.37 0.52 6.70 3.45 0.41 6.93 2.56 0.41 9.86 4.21 0.47 6.83 2.76 0.48 6.90 2.83 0.33 12.88 5.29 0.60 8.05 4.37 0.45 6.93 2.96 0.41 8.18 2.96 0.53 6.97 3.45 0.41 8.18 3.19 0.52 7.00 4.11 0.39 8.11 2.76 Abbreviation: EVE, everolimus; EXE, exemestane; HR, hazard ratio; NSAI, nonsteroidal aromatase inhibitor; PBO, placebo; PFS, progression-free survival. Piccart M, et al. ASCO 2012; abstract 559 (poster). Favors EVE + EXE 40 Favors PBO + EXE
1 PFS Benefits Were Comparable in Elderly vs Younger Patients Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival; wk, weeks. Pritchard, KI, et al. ASCO 2012; abstract 551 (poster). 41
2 PFS Benefits Were Comparable In Asian and Non-Asian Patients Abbreviations: EVE, everolimus ; EXE, exemestane; PBO, placebo; PFS, progression-free survival; wk, weeks. Noguchi S, et al. ASCO 2012; abstract 540 (poster). 42
EVE Disease Progression in Bone: BOLERO-2 Overall Population Figure 3. Everolimus decreases disease PD in bone in the overall population (N = 724). a Cumulative incidence of disease progression was determined using the competing risk method; exploratory P =.036 by Gray s test. Abbreviations: EVE, everolimus; EXE, exemestane; PBO, placebo; PFS, progression-free survival. Gnant M, et al. ASCO 2012, Abstract 512 43
3 EVE Disease Progression in Bone: Patients With Bone Metastases at Baseline Figure 4. Everolimus decreases disease progression in bone in subgroup of patients with bone metastases at baseline a (n Cumulative = 556) incidence of disease progression was determined using the competing risk method ; exploratory P =.0165 by Gray s test. 44
4
KEMOTERAPİ ÇALIŞMALARI
CALGB 40502/NCCTG N063H Randomized Phase III Trial of Weekly Paclitaxel compared to Weekly Nanoparticle Albumin Bound Nab-Paclitaxel or Ixabepilone +/- Bevacizumab as First-Line Therapy for Locally Recurrent or Metastatic Breast Cancer HS Rugo, WT Barry, A Moreno-Aspitia, A Lyss, C Cirrincione, D Toppmeyer, E Mayer, M Naughton, RM Layman, LA Carey, RA Somer, EA Perez, C Hudis, E Winer
CALGB 40502 - NCCTG N063H - CTSU 40502 An Open Label Phase III Trial of Firstline Therapy - - for Locally Recurrent or Metastatic Breast Cancer N = 900 (planned) Strata: Adj taxanes ER/PR status Exp 1 Control Exp 2 nab-paclitaxel 150 mg/m 2 weekly + bevacizumab 10 mg/kg q 2 wks 2 paclitaxel 90 mg/m 2 weekly + bevacizumab 10 mg/kg q 2 wks 1 ixabepilone 16 mg/m 2 weekly + bevacizumab 10 mg/kg q 2 wks 3 Restage q 2 cycles until disease progression All chemotherapy was given on a 3 week on, one week off schedule Patients could discontinue chemotherapy - and continue bevacizumab alone after 6 cycles if stable or responding disease 1. Miller et al, N Engl J Med, 2007 2. Gradishar et al, J Clin Oncol, 2009 3. Dickson et al, Proc ASCO 2006.
Objectives Primary: To compare progression-free survival, in the setting of bevacizumab use, between: nab-paclitaxel and paclitaxel Ixabepilone and paclitaxel Secondary: Time to treatment failure Overall survival Toxicity (including grade 3/4 peripheral neuropathy) Eligibilty No prior chemotherapy for advanced disease At least 12 months from adjuvant taxanes Measurable disease Adequate organ function Peripheral neuropathy < grade 1 Treated and stable brain metastases allowed ECOG PS < 1
Patient Characteristics (2) nab pac ixa Site of metastases N=262* N=274* N=241* Any visceral 73% 76% 82% Any soft tissue 67% 70% 67% Any bone 60% 57% 66% Tumor subtype HER2 positive 2% 3% 2% ER/PgR Status ER/PgR Positive 72% 71% 73% Disease-free interval De novo 12% 12% 13% < 1 year 22% 21% 17% > 1 year 66% 67% 70% Disease characteristics were missing for 22 of 799 patients: (9 Nab, 9 Pac, and 4 Ixa)
Proportion Progression-Free 0.0 0.2 0.4 0.6 0.8 1 CALGB 40502 Progression-Free Survival By Treatment Arm Comparison HR P-value 95% CI Pac Nab Ixa nab vs. pac 1.19 0.12 0.96-1.49 ixa vs. pac 1.53 < 0.0001 1.24-1.90 paclitaxel nab-paclitaxel ixabepilone 0 10 20 30 Months From Study Entry Agent N Median PFS paclitaxel 283 10.6 nab-paclitaxel 271 9.2 ixabepilone 245 7.6
Proportion Alive Proportion Progression Free 0.0 0.2 0.4 0.6 0.8 1 Proportion Alive Proportion Progression Free 0.0 0.2 0.4 0.6 0.8 1 Unplanned Subset Analysis of PFS : No Differences ER+ Disease ER+ Disease Triple Triple Negative Disease paclitaxel Pac nab-paclitaxel Nab Ixa ixabepilone Pac Nab Ixa 0 10 20 30 Months From Study Entry 0 5 10 15 20 25 30 Months From Study Entry Comparison HR P-value 95% CI Comparison HR P-value 95% CI nab vs. pac 1.38 0.0194 1.05 1.81 nab vs. pac 0.93 0.7354 0.62 1.40 ixa vs. pac 1.60 0.0006 1.22 2.08 ixa vs. pac 1.46 0.0647 0.98 2.18
Percent Dose Reductions by Cycle 3 uction 45% 29190001900r2l All Cause Cumulative Discontinuation by Cycle 19190001900r2l 9190001900r2l paclitaxel nab-paclitaxel ixabepilone 30190001900r1l 15% 15% 20190001900r1l 10190001900r1l nab Pac pac ixa Ixa Cycle 3 0190001900r1l 1 2 3 4 5 Cycle number
Proportion on Treatment Proportion Alive 0.0 0.2 0.4 0.6 0.8 1 CALGB 40502 Time to Treatment Failure Comparison HR P-value 95% CI Pac Nab Ixa nab vs. pac 1.40 0.0005 1.16-1.70 ixa vs. pac 1.37 0.0014 1.13-1.67 paclitaxel nab-paclitaxel ixabepilone 0 5 10 15 20 25 30 Months From Study Entry Agent N Median TTF paclitaxel 283 7.1 nab-paclitaxel 271 5.4 ixabepilone 245 5.1
Proportion Alive 0.0 0.2 0.4 0.6 0.8 1 CALGB 40502 Overall Survival paclitaxel Pac nab-paclitaxel Nab ixabepilone Ixa Comparison HR P-value 95% CI nab vs. pac 1.02 0.92 0.75-1.38 ixa vs. pac 1.28 0.10 0.95-1.72 0 10 20 30 Months From Study Entry Agent N Median OS paclitaxel 283 26 nab-paclitaxel 271 27 ixabepilone 245 21
Grade 3+ Adverse Events nab (N = 258) pac (N = 262) ixa (N = 237) Hematologic 51% p < 0.0001 21% 12% p = 0.004 Non- Hematologic 60% p = 0.0002 44% 56% p = 0.005 Any AE (Hem or Non-Hem) 79% 55% 59%
Arm Grade 2 3 4 Grade 3+ nab (N = 258) 27% 24% 1% 25% p=0.012 Sensory Neuropathy pac (N = 262) 27% 16% <1% 16% ixa (N = 237) 22% 22% 3% 25% p=0.022 nab (N = 258) pac (N = 262) ixa (N = 237) Other AEs Grade 3+ Leukopenia Neutropenia 17% p = 0.0004 47% p = 0.0001 7% 18% 3% p = 0.042 7% p = 0.0002 Hypertension 7% 8% 11% Fatigue 16% p = 0.010 9% 15% p = 0.036 Pain 10% p = 0.010 4% 4% Motor neuropathy 10% p = 0.0003 2% 6% p = 0.021
Summary In patients with chemotherapy naïve advanced breast cancer receiving bevacizumab, this NCI-supported, cooperative group trial shows that: Neither weekly nab-paclitaxel or ixabepilone are superior to weekly paclitaxel Weekly paclitaxel appears to offer better progression-free survival than ixabepilone Hematologic toxicity was greater with nabpaclitaxel; sensory neuropathy was greater in both experimental arms compared to paclitaxel
N:241 MMK 1.seri D75 d1 G1000 d1/8 3hft P175 G1250 d17d8 3hft D30G800 d1,8,15 P80 G800 d1,8,15 Erken kapanmış TTP ler benzer Hft daha az grad3/4 toksisite 3hft daha iyi YO GPS 23/abst :
36 vs 28 ay 12 vs 8 ay
ZOOM Study Design Endpoints: Primary: Skeletal morbidity rate (SMR) (non-inferiority) ZOOM: A Prospective, Randomized Trial of ZA for Long-term Treatment in Patients With Bone-Metastatic BC After 1 yr of Standard ZA Treatment Secondary: Proportion of patients experiencing SREs (overall and by event), time to first SRE, SMR by event, bone pain, use of analgesics, bone marker levels, safety N = 420 (Planned) Key eligibility criteria BC stage IV Confirmed bone metastasis Prior zoledronic acid treatment (4 mg q 4 wk) 9-12 infusions R 1:1 Arm 1: Zoledronic acid (4 mg q 12 wk) Arm 2: Zoledronic acid (4 mg q 4 wk) Treatment duration 1 year Accrual: February 2006 - February 2010 Abbreviations: q, every; R, randomization; SRE, skeletal-related event. http://www.clinicaltrials.gov. Identifier NCT00375427.
Primary Efficacy Analysis SMR ZOL q 12 wk (Arm 1) ZOL q 4 wk (Arm 2) N (ITT population) 209 216 Mean SMR (95% CI) 0.26 (0.15, 0.37) 0.22 (0.14, 0.29) 95% CI -0.09 to 0.17 The upper limit of the CI ( 0.17) was less than the recalculated non-inferiority margin of 0.19. This result indicates that the efficacy of the q 12 wk arm was not inferior to the q 4 wk arm. a 95% CI of LS mean difference was 0.09, +0.17. Abbreviations: CI, confidence interval; ITT, intent to treat; LS, least squares; q, every; SMR, skeletal morbidity rate; ZOL, zoledronic acid.
Change in NTX vs Baseline, % (median with interquartile range) Change in NTX Levels On-Study * * * *P <.05 by Wilcoxon test comparing arms Abbreviations: NTX, N-telopeptide of type I collagen; q, every; ZOL, zoledronic acid.
ZOOM: Summary ZOOM is the first trial to compare quarterly vs monthly ZOL in BC patients after ~1 y of standard ZOL therapy Primary endpoint of SMR was met: q 12 wk ZOL was non-inferior to q 4 wk ZOL Safety profiles of the 2 treatment schedules were similar No meaningful differences in renal AEs or ONJ event rates Exploratory analyses of median NTX levels showed an increase from baseline in the q 12 wk arm, but almost no change in the q 4 wk arm Open-label design Study limitataions Different clinic visit frequencies between arms No prespecified imaging frequency Single-country study Abbreviations: AE, adverse event; BC, breast cancer; NTX, N-telopeptide of type I collagen; ONJ, osteonecrosis of the jaw; q, every; SMR, skeletal morbidity rate; ZOL, zoledronic acid.
ASC0 2012 MMK: Diğer Bisfosfonatlar: Kemik metli MK: Marker-directed vs std şema ZA (PDS 511) Everolimusun etkisi (PDS 512) ZOOM çalışması: 1yıl ZA sonrası 4 vs 12 hft bir ZA ile devam (OAS 9005) Prognoz:Her-2 + hastalıkta beyin metastazlarını predikte eden 13-gen imzası (OAS 505) Anti-Her-2 tedavi alan hastalarda Her-2 + MMK hastalarda adj T almanın klinik seyire etkisi (PDS 527) Metaanaliz: Primer tm ve metastaz arasında reseptör diskordansı (GPS 546) 42çlş. discordance: ER 20% Pr 33% Her-2 9%; poz den neg:24/44/14 % neg den poz:12/15/6 % Primer ve metastatik dokuda kantitatif Her-2 bakılması ve PI3K mutasyon profili (GPS 614) MMK nin kanser gen profili (PDS1015) NGS Toksisite:Bazal CGA yapmanın tek ajan KT alan yaşlı MMK hastalarında toksisiteyi predikte etmede rolü (Dutch OMEGA study) (GPS 1080) Evre IV hastalıkta cerrahinin rolü: PDS 1032, GPS 1113,1114,1115 (senkron kemik met)
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