1. Metastatik Meme Kanserinde Sistemik Tedavi Dr. M. Kadri Altundağ Hacettepe Üniversitesi Onkoloji Enstitüsü Medikal Onkoloji Bilim Dalı 20 Mart 2010, Ankara
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5. MMK de Tedavi Algoritması HER2– Hormon-re s ept ö r – MMK An trasiklinler Ta ksanlar Gem s itabin Capecitabin Vinorelbin Liposomal doxorubi s in Kombinasyon rejimleri Hormonoterapi/kemoterapi + Herceptin HER2+ HER2+ Tamoxifen Aromata z inhibit örü Fulvestrant Over supresyonu HER2– ( Kemoterapi ) Diğer faktörler : Önceki adjuvan tedavi Hastalıksız interval Hastalığın yayılımı Hedefe yönelik tedaviler : Bevacizumab ; lapatinib ; trastuzumab Yeni sitotoksik ajanlar: A braxane,e pothilon lar Hormon-re s ept ö r +
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9. "A small but very important subset of MBC patients, for example, those with a solitary metastatic lesion, can achieve complete remission and a long survival. A more aggressive and multidisciplinary approach should be considered for these selected patients. A clinical trial addressing this specific situation is needed."
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13. MMK de Yeni Tedavilerin Sağkalıma Etkisi Giordano S et al, Cancer 100:44-52, 2004
14. MMK: Genel Sağkalım Kanada Ç al ış mas ı Kohort N Med y an 1 yıl 2 yıl Yeni ajanlar 1991-1992 424 435 gün % 56 % 34 — 1994-1995 561 449 gün % 55 % 33 taksan , vinorelbine 1997-1998 641 562 gün % 64 % 44 docetaxel, aromataz inhibitörü 1999-2001 525 661 gün % 71 % 45 capecitabin, trastuzumab , Chia SKL. ASCO, 2003; Abstract 22. gemsitabin
16. Endokrin T edavi Ş emas ı İ kinci basamak tedavi Üçüncü basamak tedavi D ö rdunc ü basamak tedavi Over Ablasyonu Aromata z İ nhibitor (+/- AI) veya ant iestro j en Aromata z İ nhibitor ü Progestin veya (Eğer postmenopoz ise) SERD Progestin / Androjen Androjen SERM Re kü rren hastal ı k Adjuvan veya 1. Basamak tedavi Premenopozal Postmenopozal Aromataz İ nhibitor veya SERM
18. Hastalar : 576 evre IV meme kanseri T edavi : Haftalık paclitaxel 80 mg/m2 vs 3 haftada bir paclitaxel 175 mg/m2 Sonuçlar Haftalık 3 Haftada Bir RR %40 %28 p=0.017 TTP 9 ay 5 ay p=0.0008 OS 24 ay 16 ay p=0.17 Toksisite (grad 3,4) N ötropeni %5 15% Motor N öropati %8 %4 Sens N öropati %23 %12 Myalgia/Arthralgia %1 %5 Seidman A et al, ASCO 2004, abstract # 512 Metastatik Meme Kanseri Haftalık vs. 3 Haftada Bir Paclitaxel
19. Metastatik Meme Kanserinde AB-paclitaxel (Abraxane) vs. Paclitaxel AB-paclitaxel (Abraxane) 260 mg/m 2 IV 3 haftada bir Standard Premedikasyon Yok Paclitaxel 175 mg/m 2 IV 3 haftada bir Standard Premedi kasyon var Randomiza syon Gradishar W et al, J Clin Oncol 23, 2005
20. Paclitaxel AB-Paclitaxel (175 mg/m2) (260 mg/m2) Sonuçlar RR %11.1 %21.5 p=0.003 TTP 17 hafta 23 hafta p=0.006 To ksisite (grad 3,4) N ötropeni %53 %34 p<0.001 Feb n ötropeni <1% %<1 Sens N ötropeni %2 %10 p<0.001 Metastatik Meme Kanserinde AB-paclitaxel (Abraxane) vs. Paclitaxel Gradishar W et al, J Clin Oncol 23, 2005
21. Metastatik Meme Kanserinde Ab-Paclitaxel (Abraxane) vs Docetaxel Cevap Oranı (%) 300 mg/m 2 100 mg/m 2 150 mg/m 2 docetaxel q3w qw 3/4 qw 3/4 100 mg/m 2 q3w ( A : n = 76) ( B : n = 76) ( C : n = 74) ( D : n = 74) Ab- paclitaxel (Abraxane) Gradishar W et al, ASCO 2007, abstract # 1032
25. Metastatik Meme Kanseri 1. BASAMAK TEDAVİSİ – TAX 306 Nabholtz et al. JCO , 2003 Progresyona Kadar Geçen Süre(ITT): 0 0.2 0.4 0.6 0.8 1 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 AT AC Hasta sayısı 214 215 1 yılda progresyon suz olma % 28 19 Hafta 0 Olasılık Log-Rank Test p = .0153
26. Metastatik Meme Kanseri 1. BASAMAK TEDAVİSİ – TAX 306 Nabholtz et al. JCO 2003 Hematolojik Toksisite: AT AC % hasta % kürler % hasta % kürler Toksisite (n=213) (n=1,354) (n=210) (n=1,312 ) Nötropeni ( Grad 3/4) 96 82 87 69 Febril nötropeni 33 7 10 2 İ nfeksiyon ( Grad 3/4) 7 1 2 <1 Septik ölüm 0 hasta 1 hasta
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28. Metastatik Meme Kanseri 1. BASAMAK TEDAVİ – TAX 307 Tümör Cevabı(ITT): Mackey et. al, ASCO 2002 (abs 137) TAC FAC (n=242) (n=242) Tam Cevap 7% 3% Genel Cevap Oranı 55% 44% P rogresif Hastalık 9% 15% Odds-Ratio ( cevabın ) = 1.5 (95% CI: 1.1-2.2) p = 0.023
29. Metastatik Meme Kanseri 1. BASAMAK TEDAVİSİ – TAX 307 Mackey et. al, ASCO 2002 (abs 137) Progresyona Kadar Geçen Süre(ITT): p = 0.51 (log-rank test) Kümülatif olasılık Hafta Risk sayısı FAC TAC 242 171 102 35 16 10 242 177 100 42 22 10 6 TAC FAC 26.7-31.7 28.3-34.3 95% CI 28.9 31.1 Med y an hf. 76 (31%) 74 (31%) Censored 166 (69%) 168 (69%) Olay FAC TAC TAC FAC 26.7-31.7 28.3-34.3 95% CI 28.9 31.1 Med y an hf. 76 (31%) 74 (31%) Censored 166 (69%) 168 (69%) Olay FAC TAC
30. Kapesitabin’in Enzimatik Aktivasyonu Barsak Karaciğer Kapesitabin 5 ' -DFCR 5 ' -DFUR CyD 5 ' -DFCR 5 ' -DFUR 5-FU T ü m ö r Xeloda CyD CE 5 ' -DFCR = 5 ' -deoxy-5-fluorocytidine; 5 ' -DFUR = 5 ' -deoxy-5-fluorouridine; CE = carboxylesterase; CyD = cytidine deaminase T imidin fosforilaz (TP) Miwa M et al. Eur J Cancer 1998;34:1274-81 Schüller J et al. Cancer Chemother Pharmacol 2000;45:291-7
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34. Antrasiklin ve Taksan tedavisi sonrasında Kapesitabin Monoterapi Çalışmaları ile Elde Edilen İstikrarlı Etkin Sonuçlar Mavroudis (n=47) Kapesitabin Gemsitabin+Vinorelbin 24.1 25.8 5.8 3.7 --- ---
35. MMK de Tek Ajan Gemsitabin Çalışmaları Do z mg/m 2 1,8,15 n Yanıt Oranı % (CR) Med yan TTP ( ay ) Med yan S ağkalım ( ay ) Carmichae l et al J Clin Oncol 1995 800 40 25 (3) NR 11.5 Gerson et al Anti Cancer Drugs 2000 1 25 0 19 42 ( 2) NR NR Blackstein et al Oncology 2002 1200 35 37 (2) 5.1 21.1 Spielmann et al Oncology 2001 1200 41 29 (4) 8.1 18.6 Brodowicz et al Breast 2000 1250 25 2 sıra : 22 3 sıra : 13(1) 5.1 3.5 2 sıra : 12.6 3 sıra : 7.5
39. GT kolu 21- günlük kür R A N D O M İ Z E T kolu 21-günlük kür Gün 1: Gün 1: Pa k lita ksel 175 mg/m 2 Gemsitabin 1250 mg/m 2 Gemsitabin 1250 mg/m 2 Gün 8 : Paklitaksel 175 mg/m 2 n=267 n=262 MMK de Gem sitabin + Paclitaxel v s. Paclitaxel JCO 2008
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41. 18.5 ay 15.8 ay Gem sitabin + Paclitaxel v s. Paclitaxel Genel sağkalım JCO 2008 0 .0 0.2 0.4 0.6 0.8 1.0 Zaman ( Ay ) 0 6 12 18 24 30 36 42 Genel Sağkalım Olasılığı GT T Log rank p=0.018 Hazard Ratio 0.78 (0.63, 0.96)
42. Gem sitabin + Paclitaxel v s. Paclitaxel Grad 3 / 4 Hematolojik Toksisite % Hasta G + P (n=262) Grad 3 Grad4 P (n=259) Grad3 Grad4 Anemi 6 1 2 < 1 L ökopeni 10 1 2 0 N ötropeni 31 17 4 7 T rombositopeni 5 1 0 0 Febril nötropeni 5 2 İlaca Bağlı Ölüm 1 hasta 1 hasta
43. Daha Önceden Antrasiklin Almış Metastatik Meme Kanserinin Tedavisinde Gemcitabine plus Docetaxel (GD) v s Capecitabine plus Docetaxel (CD) Faz III çalışma S Chan, G Romieu, J Huober, T Delozier, M Tubiana-Hulin, A Lluch, A Schneeweiss, A Llombart, E Carrasco, P Fumoleau JCO 2008
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45. GD Kolu RANDOM İ Z ASYON Do s eta kse l 75 mg/m 2 G 1 Ge msitabin 1000 mg/m 2 G 1, 8 – 21 günde bir Do s eta kse l 75 mg/m 2 G 1 K ape s itabin 1250 mg/m 2 bid G 1-14 21- günde bir CD Kolu İlk veya ikinci basamak Hastalar tedaviye progresyona kadar devam etmişlerdir. Hastalık değerlendirilmesi her üç kürden sonra JCO 2008
46. Sağkalım Dağılım Fonksiyonu 0.00 0.25 0.50 0.75 1.00 Haftalar 0 20 40 60 80 100 120 P=0.2886 (log-rank) CD kolu GD kolu 208 114 43 16 3 Riskli hastalar JCO 2008 MMK de Gemsitabin+Docetaxel vs Capecitabin+Docetaxel Progres yonsuz Sağkalım
49. Araştırmacı Do z Basamak n Cevap Oranı Ruiz G 1200 (1,8) 1 3 1 %81 C 75 (1) q21 Shaharyar G 1250 (1,8) 2 21 %62 C 75 ( 2 ) q21 Galvez G 1 2 00 (1,8 ,15 ) 2 41 %49 C 50 ( 1 ) q2 8 Xu G 1200 (1,8) 2 43 %44 C 30 ( 1 )q2 1 MMK de Gemsitabin + Cisplatin Birinci gün Cisplatin Uygulaması ile
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52. TNMK de Güncel Hedefler Arslan C, Dizdar O, Altundag K. Expert Opin Pharmacother 2009 Hedef R asyonel Tedavi DNA DNA aberra syonları (BRCA1 muta syonu ) , DNA onarım mekanizmasındaki bozuklukluklar Kemoterapi - Double strand DNA kırıkları , platin analogları , topoi zomeraz I ve II inhibit örleri PARP1 BRCA1 disfonksiyonu PARP inhibit örleri EGFR Artmış ekspresyon (%50 – %70) Cetuximab, erlotinib c-kit Artmış ekspresyon (%31) İ matinib Src Artmış ekspresyon , dasatinib ’e hassasiyet Dasatinib
53. Addition of PARP1 Inhibitor BSI-201 to Gemcitabine/Carboplatin Improves Outcomes in Metastatic TNBC O’Shaughnessy J, et al. ASCO 2009. Abstract 3. Restaging every 2 Cycles 21-day cycle *Patients randomized to gem/carbo alone could crossover to receive gem/carbo + BSI-201 at disease progression. BSI-201 5.6 mg/kg IV on Days 1, 4, 8, 11 + Gem 1000 mg/m 2 IV on Days 1, 8 + Carbo AUC 2 IV on Days 1, 8 Metastatic TNBC (N = 120) RANDOMIZE BSI-201: S mall molecule PARP inhibitor Gem* 1000 mg/m 2 IV on Days 1, 8 + Carbo AUC 2 IV on Days 1, 8
54. Addition of PARP1 Inhibitor BSI-201 to Gemcitabine/Carboplatin Improves Outcomes in Metastatic TNBC O'Shaughnessy et al. ASCO 2009 Abstract 3 Survival, mos Gemcitabin/ Carboplatin (n = 59) BSI-201 + Gemcitabin/ Carboplatin (n = 57) HR (95% CI) P Value Median PFS 3.3 6.9 0.342 (0.200-0.584) < .0001 Median OS 5.7 9.2 0.348 (0.189-0.649) .0005
55. Olaparib Active, Well Tolerated in Heavily Pretreated Patients With Advanced Breast Cancer and BRCA1/BRCA2 Mutations Tutt A et al. Asco 2009 Abstract CRA501 Outcome Olaparib 400 mg BID Olaparib 100 mg BID Intent-to-treat cohort, n 27 27 ORR, n (%) 11 (41) 6 (22) CR, n (%) 1 (4) 0 (0) PR, n (%) 10 (37) 6 (22) Per protocol cohort, n 26 24 ORR, n (%) 11 (42) 6 (25) CR, n (%) 1 (4) 0 (0) PR, n (%) 10 (39) 6 (25) Median PFS, mos (95% CI) 5.7 (4.6-7.4) 3.8 (1.9-5.5)
58. HER Ailesi : Ligan dın Bağlanması , Dimeriza sy on, ve Fosforilazyon EGF EGF Alt İleti Yolllarının Aktivasyonu HER2 ( Açık ) HER1 ( Kapalı ) HER1 ( Açık ) Dimeriza sy on Fosforilazyon Roskoski. Biochem Biophys Res Commun. 2004;319:1; Herbst. Int J Radiat Oncol Biol Phys . 2004;59(suppl):21.
59. HER2+ Meme Kanserlerinde Prognoz 0 2 4 6 8 10 12 14 16 Yıl 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Sağkalım P <0.0001 HER2 – HER2+ 0 0.1 Witton et al. J Pathol . 2003;200:290. N=220 ( Çoğu >1 cm); bütün hastalara standard tedavi verildi
60. HER2-Po zitif Metastati k Meme Kanserinde Tedavi Trastuzumab Mono terapisi
61. Trastuzumab Monot erapi Çalışmaları : Etkinlik Özeti MMK için KT Ref n Toplam FISH+ FISH– Yok 1, 2 111 26 * 34 7 Yok 3 105 19 † – – 1 – 2 1, 4 222 15 * 19 0 0 - >2 5 43 11.6* – – * Bütün hastalar IHC olarak HER2+; haftalık tarstuzumab tedavisi † Bütün hastalar HER2+ IHC 3+ veya FISH+ ; trastuzumab tedavisi 3 haftada bir . 1. Vogel et al. Proc Am Soc Clin Oncol. 2001;20:22a. Abstract 86; 2. Vogel et al. J Clin Oncol. 2002;20:719; 3. Baselga et al. J Clin Oncol. 2005;23:2162; 4. Cobleigh et al. J Clin Oncol. 1999;17:2639; 5. Baselga et al. J Clin Oncol . 1996;14:737. Cevap Oranı (%)
62. HER2-Po zitif Metastati k Meme Kanserinde Tedavi Trastuzumab ile Kemoterapi -İkili Kombinasyon-
64. MMK de Birinci Basamak Tedavide Kemoterapi Trastuzumab Pivotal Çalışma AC = do ksorubisin 60 mg/m 2 ( veya epirubisin 75 mg/m 2 ) + siklofosfamid 600 mg/m 2 ; q3 hafta 6. Paclitaxel 175 mg/m 2 q3 hafta 6. Trastuzumab 4 mg/kg yükleme dozu , sonra 2 mg/kg haftada bir progresyona kadar . Slamon et al. N Engl J Med. 2001;344:783 . Adjuvan ant rasiklin var A djuvan ant rasiklin yok Paclitaxel (n=96) Trastuzumab + paclitaxel (n=92) AC (n=138) Trastuzumab + AC (n=143) S R R HER2 IHC 2+/3+ (N=469)
65. MMK de Birinci Basamak Tedavide Kemoterapi Trastuzumab Pivotal Çalışma: Etkinlik ORR P <0.001 Med yan TTP P <0.001 Med yan sağkalım P =0.046 Ay (TTP, s ağkalım ) ORR (%) Trastuzumab + kemoterapi (n=235) Kemoterapi (n=234) Slamon et al. N Engl J Med . 2001;344:783.
66. MMK de Birinci Basamak Docetaxel Trastuzumab : Randomize Faz II Çalışma Extra et al. J Clin Oncol. 2005;23(16S):17s. Abstract 555; Marty et al. J Clin Oncol . 2005;23: 4265 . Opsiyonel R HER2 IHC 3+/FISH+ (N=188) Docetaxel 100 mg/m 2 q3 hafta 6 Trastuzumab 4 mg/kg, sonra 2 mg/kg q hafta Progresyona kadar + Docetaxel 100 mg/m 2 q3 hafta 6 PD Trastuzumab
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68. MMK de Trastuzumab ve Gemcitabin kombinasyonu : Faz II Çalışmalar * % 44 hastada HER2+ IHC 3+. O’Shaughnessy et al. Clin Breast Cancer. 2004;5:142. Peacock et al. J Clin Oncol. 2005;23(16S):54s. Abstract 704 . Çalışma HER2+ % , ORR (% 95 CI) Med y an TTP veya PFS ( ay ) Önce den b ir veya daha fazla O’Shaughnessy et al, 2004 (N=61) IHC 2+/3+ 38 * (26-50) 5.8 Önce den 0 -2+ rejim Peacock et al, 2005 (N=40) IHC 3+/ FISH+ 33 (NR) 3.9
69. MMK de Trastuzumab ve Vinorelbin kombinasyonu : Faz II Çalışmalar Jahanzeb et al. Oncologist . 2002;7:410; Bernardo et al. Ann Oncol . 2002;13(suppl 5):51. Abstract 181P; Burstein et al. J Clin Oncol . 2003;21:2889; Chan et al. J Clin Oncol. 2005;23(16S):25s. Abstract 587; Burstein et al. J Clin Oncol. 2001;19:2722. Çalışma n % ORR, (% 95 CI) Birinci Basamak Jahanzeb et al, 2002 37 78 (62-90) Bernardo et al, 2002 32 84 (NR) Burstein et al, 2003 54 68 (54-80) Chan et al, 2005 65 61.5 (NR) Çok-Basamaklı (1 . – 3 . ) Burstein et al, 2001 40 75 (57-89)
70. HER2-Po zitif Metastati k Meme Kanserinde Tedavi Trastuzumab ile Kemoterapi -Üçlü Kombinasyon-
71. MMK Birinci Basamak tedavisinde Trastuzumab ve Paclitaxel ± K arboplatin (TP±C)* *TCH rejimi (Taxol ® -Carboplatin-Herceptin ® ) Robert et al. Proc Am Soc Clin Oncol. 2004;23:20. Abstract 573. Robert et al. J Clin Oncol 2006; 24:2786 T q hft 18 + P q3 hft 6 + C q3 hft 6 T q hft 18 + P q3 hft 6 Prim er : ORR Sekonder : TTP, sağkalım , güvenlik Progresyona kadar hftlık T Progresyona kadar hftlık T Doz : T 4 mg/kg hft 1, sonra 2 mg/kg hftlık ; P 175 mg/m 2 ; Karboplatin AUC 6 R HER2 IHC 2+/3+ (N=188)
72. MMK Birinci Basamak tedavisinde Trastuzumab ve Paclitaxel ± K arboplatin (TP±C) : Etkinlik ORR = Objektif Cevap Oranı Robert et al. Proc Am Soc Clin Oncol . 2004;23:20. Abstract 573 . P =0.04 P =0.016 P =0.496 Tüm Hastalar
73. BCIRG 007: HER2+ M MK de birinci basamak Trastuzumab + Docetaxel ± K arboplatin Forbes JF, et al. ASCO 2006. Abstract 516 . TH kolu Docetaxel 100 mg/m 2 3 hftada bir + Trastuzumab 4 mg/kg yükleme dozu sonra 2 mg/kg hftada bir (n = 131) Tedavi edilmemiş HER2+ (FISH ile ) metastati k meme kanseri (N = 263) TCH kolu Docetaxel 75 mg/m 2 3 hftada bir + Trastuzumab 4 mg/kg yükleme dozu sonra 2 mg/kg hf t ada bir + K arboplatin AUC 6 q 3 hftada bir (n = 132) 8 kür Daha önce aldığı adjuvan ve / veya neoadjuvant kemoterapiye ve merkeze göre stratifikasyon Progresyona kadar Trastuzumab ( 6 mg/kg 3 hftada bir)
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76. TPC: TTP ve S ağkalım Perez et al. Breast Cancer Res Treat. 2003;82(suppl 1):S47. Abstract 216 . 3 hftlık (n=43): med y an TTP, 9.9 ay ; med y an sağkalım , 2.3 y ıl htlık (n=48): med yan TTP, 14.7 ay ; med y an sağkalım , 3.2 y ıl
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78. HER2-Po zitif Metastati k Meme Kanserinde Tedavi Hormon Reseptör Pozitif Hastalarda Trastuzumab ile Aromataz İnhibitör Kombinasyonu
79. HER2 Sinyal İleti Yolları p90 RSK Hücre sağkalımı Sitoplazma N ükleus P Plasma membran HER2 IGFR Trastuzumab Bevacizumab VEGFR SOS RAS RAF Basal transcription machinery p160 ERE ER- gen trans kripsiyonu ER CBP P P P P ER P Akt P MAPK P ER PI3-K P P P P P P MEK Büyüme faktörü Estro j en VEGF
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81. TAnDEM çalışması : Progresyonsuz Sağkalım 103 48 31 17 14 13 11 9 4 1 1 0 0 A+H 104 36 22 9 5 4 2 1 0 0 0 0 0 A 1.0 0.8 0.6 0.4 0.2 0 5 10 15 20 25 30 35 40 45 50 55 60 Ay 0.0 Riskli hasta No. 2.4 ay Mackey et al. Breast Cancer Res Treat 2006; 100(suppl 1):S5 (abstract 3). 95% CI 3.7, 7.0 2.0, 4.6 p değeri 0.0016 Med y an PFS 4.8 ay 2.4 ay Olay 87 99
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83. Progresyonsuz Sağkalım : HER2+ Pop ü la syon Letrozol (N = 108) Letrozole + Lapatinib (N = 111) Progres e veya exitus 89 (82%) 88 (79%) Median PFS, ay 3.0 8.2 Hazard oranı (95% CI) 0.71 (0.53, 0.96) p- değeri 0.019
84. HER2-Po zitif Metastati k Meme Kanserinde Tedavi Trastuzumab İle Progresyon Gösteren Hastalarda Tedavi
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87. Capecitabine 2500 mg/m 2 1 – 14 . günler hftada bir Trastuzumab 6mg/kg 3 hftda bir Capecitabine 2500 mg/m 2 1 – 14 . günler 3 hftada bir RANDOMIZA SYON Von Minckwitz, G et al, SABCS 2007 (Abstract 4056)) Trastuzumab ile Progresyon Gösteren MMK de Tedavi
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91. Lapatinib/Capecitabin vs. Capecitabin Progresyona Kadar Geçen Süre 0.2 0.4 0.6 0.8 0.0 1.0 0 Kümülatif Progresyonsuz 10 20 30 40 50 60 Hafta 70 Cameron et al. ESMO 2006 Capecitabin Lapatinib + Capecitabin 0.00004 P - değeri 72 49 Progr esyon - ölüm 19.1 36.7 Med y an TTP, hafta 161 163 Hasta no. 0.49 (0.34, 0.71) Hazard oranı (95% CI)
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96. HER2-Po zitif Metastati k Meme Kanserinde Tedavi Trastuzumab Çalışmalarında Kardiotoksisite
97. MMK nin Birinci BASAMAK Tedavisinde Pivotal Faz III Kemoterapi Trastuzumab Kardiotoksisite Slamon et al. N Engl J Med . 2001;344:783.
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99. HER2-Po zitif Metastati k Meme Kanserinde Tedavi Trastuzumab Tedavisi Alan Hastalarda Beyin metastaz ı
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103. Guarneri, V. et al. Oncologist 2008;13:838-844 Biyopsi Bölgelerine Ve Önce Aldığı Tedavilere Göre ER ve HER2 Ekspresyonunda Değişme HER2 kaybı 2 HER2 kazancı 10 HER2 de %16 değişme
104. MD Anderson Retrospektif Analizi MMK de Trastuzumab Kullanan Hastaların Genel Sağkalımı Dawood et al. ASCO 2008 HR: HER2 Pos/Trast vs. HER2 Neg = 0.56; p<0.0001 HR: HER2 Pos/No Trast vs HER Neg = 1.23; p<0.123
106. HER2+ Meme Kanserinde Hedefe Yönelik Potansiyel Biyolojik Tedavi Kombinasyonları Kanser Hücresi Endotelyal Hücre Mono klonal Anti kor Trastuzumab Bevacizumab T irozin Kina z İ nhibitor ü Lapatinib Pazopanib
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110. MMK Birinci Basamak Tedavide Bevacizumab (E2100) : PFS 0.0 0.2 0.4 0.6 0.8 1.0 Aylar Progres yonsuz sağkalım Oranı survival proportion 0 6 12 18 24 30 HR = 0. 48 Log rank test p<0.0001 Bevacizumab + P aclitaxel: 1 3 . 3 ay Paclitaxel: 6. 7 ay 6. 7 1 3 . 3 Miller KD, 2006
115. Zaman Kanserin anlaşılması TRANSLA SYONEL ARAŞTIRMA K anser hastalar ı n ı n tedavisi Moleküler Tedaviler İnformasyon
116. Metastatik Meme Kanserinin Tedavisinde Kür Sağlayabilecekmiyiz ? Şu An İçin Hayır, Ama Yeni Tedavi Kombinasyonları Ümit Verici! K Ü R
Editor's Notes
Since advanced breast cancer is a systemic disease, the mainstay of treatment consists of a systemic approach. The decision to use either hormonal therapy or chemotherapy is based on several factors. Because hormonal therapies often have fewer side effects than chemotherapies, hormonal therapies are frequently used as initial systemic treatment in patients likely to respond. Tumors that possess hormone receptors (estrogen receptors [ER] and progesterone receptors [PgR]) are more likely to respond to hormonal therapies than those that do not. Patients who have previously experienced an objective response to hormonal therapy are likely to respond again to the same hormonal agent (if disease progresses after 1 year or more off therapy), or to a new class of hormonal agents. Patients with a long recurrence-free interval (ie, 1-2 years or longer) are also appropriate candidates for hormonal therapy. Patients who initially respond to hormonal therapy before disease progression will most likely benefit from use of a subsequent hormonal agent. 2, 6, 7, 8 Patients who show no clinical response to hormonal therapy should receive chemotherapy. Patients are also candidates for chemotherapy when extensive metastases or visceral disease with organ dysfunction is diagnosed, when tumors have no hormone receptors, or when patients become refractory to hormonal therapy. Chemotherapy is usually maintained as long as there is no disease progression and side effects are manageable; upon disease progression, chemotherapy may be switched to a second-line class of agents. 4
Hormone-receptor-positive breast cancer is treated with hormone therapy with or without additional chemotherapy depending on other patient and disease characteristics. Treatment may include tamoxifen, fulvestrant, an aromatase inhibitor (such as anastrozole, letrozole, exemestane ) or ovarian suppression. Patients with HER2-positive disease should receive Herceptin regardless of their other characteristics. Several trials have shown that Herceptin may be administered in combination with chemotherapy such as Taxotere [1], paclitaxel [2], Xeloda [3] or Xeloda/Taxotere. Patients with hormone-receptor-negative and HER2-negative disease should be offered chemotherapy. The most commonly used cytotoxic agents are the anthracyclines, the taxanes, Xeloda, vinorelbine, liposomal doxorubicin and gemcitabine. These agents are all used alone and in double or triple combinations depending on the patient and disease characteristics. For this particular patient, anthracyclines and taxanes would not be the best options as both had already been used in the adjuvant setting. Several novel agents are in development or in clinical trials for MBC. These include targeted agents such as Avastin and lapatinib and novel cytotoxic agents such as Abraxane (albumin-bound paclitaxel) and the epothilones. Other factors to be considered when choosing therapy for breast cancer include prior adjuvant therapy, the disease-free interval and the burden and distribution of the disease. 1. Extra JM et al. J Clin Oncol 2005;23:17s (Abstract 555). 2. Slamon DJ et al. N Engl J Med 2001;344:783–92. 3. Xu L et al. Breast Cancer Res Treat 2005;94(Suppl. 1):S94 (Abstract 2031). 4. Wardley A et al. Breast Cancer Res Treat 2005;94(Suppl. 1):S281 (Abstract 6094).
Slide 6.11 A Canadian epidemiological study of survival after diagnosis of metastatic disease demonstrates an improvement in median overall survival over the past 10 years with the addition of newer therapeutic agents. From 1991 to 2001, the median overall survival increased from 435 days to 661 days — more than a seven-month improvement.
Slide 20 from Budman’s “Role of Taxanes” file.
Slide 20 from Budman’s “Role of Taxanes” file.
The unique mechanism of activation of Xeloda may provide an advantage over non-specific i.v. 5-FU/LV by providing more effective targeting of tumor cells. Xeloda was rationally designed to mimic continuous infusion 5-FU and to generate 5-FU preferentially in tumor tissue. Xeloda and its intermediate metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR) are cytotoxic only after conversion to 5-FU and its cytotoxic anabolites via a three-step enzymatic cascade [1]. Following rapid and almost complete absorption of the intact molecule, Xeloda is hydrolysed by carboxylesterase in the liver to 5'-DFCR. The next step occurs in the liver and/or tumor tissue, where cytidine deaminase converts 5'-DFCR to 5'-DFUR. The third and final stage of conversion to 5-FU involves thymidine phosphorylase (TP), which is highly active in tumor tissue compared with healthy tissue. This results in the tumor-selective activation of Xeloda [2]. 1. Miwa M et al. Eur J Cancer 1998;34:1274–81. 2. Schüller J et al. Cancer Chemother Pharmacol 2000;45:291–7.
Efficacy results from these five clinical trials show that Xeloda has consistently high efficacy in taxane-pretreated MBC [1]. Objective response rates ranged from 15% to 28%, with consistent disease control rates (complete or partial response or stable disease) in approximately two-thirds of patients. Median overall survival was consistently around 1 year (10.4–15.2 months) and median TTP ranged from 3.0 to 4.9 months in all studies [1]. These results confirm that oral Xeloda is a highly active treatment for MBC. Xeloda has gained regulatory approval for the treatment of patients with taxane-pretreated MBC in more than 80 countries worldwide. Xeloda is the only approved therapy in this setting, and is considered the reference treatment by many oncologists and by regulatory bodies. Other smaller trials support the impressive activity of Xeloda in anthracycline- and taxane-pretreated MBC. 1. Leonard R et al. Semin Oncol 2004;31(Suppl. 10):21–8.
Note to presenter: This slide is animated. At first click, HER1/EGFR is in a “closed” conformation. This is the conformation that exists in the absence of ligand binding. HER2 has no ligand-binding activity and is always in an “open” conformation. At second click, ligand binds to HER1/EGFR, causing a steric change to an “open” conformation. At third click, the steric conformation that exists with bound ligand allows receptor dimerization. The resulting steric change activates the intrinsic kinase activity of these HER family receptor tyrosine kinases. The activated kinase phosphorylates itself and its partner on conserved tyrosine residues and initiates a signal transduction cascade, which eventually activates key downstream regulators such as mitogen-activated protein kinase (MAPK) and PI3K. Roskoski. Biochem Biophys Res Commun . 2004;319:1. Herbst. Int J Radiat Oncol Biol Phys . 2004;59(suppl):21.
Breast carcinoma tissue from 220 primary breast cancer biopsies were tested for HER2 status using IHC. Prospective follow-up data were available for all patients. All patients were treated with surgical removal of the tumor and chemotherapy and/or radiotherapy as appropriate. ER+ patients were treated with tamoxifen. Five percent of tumors were HER2–, 33.8% were IHC 1+, 38.4% were IHC 2+, and 22.8% were IHC 3+. This slide shows Kaplan-Meier survival curves for HER2– (IHC 0 or 1+, n=85) vs HER2+ patients (IHC 3+, n=50). Strongly positive IHC scores (3+) were associated with significantly decreased survival ( P <0.0001). Witton et al. J Pathol. 2003;200:290. Press et al. J Clin Oncol . 1997;15:2894. Slamon et al. Science . 1987;235:177. Pauletti et al. J Clin Oncol . 2000;18:3651. Ross et al. Oncologist . 2003;8:307.
To date, results have been reported for several trastuzumab monotherapy studies in patients with HER2+ MBC, and the efficacy results (response rate) are presented relative to the number of prior CT regimens for metastatic disease. 1-5 As reported, distinction of response rate by patient subgroups that were FISH+ and FISH are included Responsiveness is in general inversely related to the number of prior CT regimens for MBC, but there is no consistent trend for median DOR or median TTP. It is difficult to compare these study results for several reasons: Differences in patient exposure to prior CT 1,4,5 Differences in patient selection, including criteria for HER2 positivity (from IHC only, to IHC 3+ or FISH+, the current standard) Differences in patient characteristics Differences in schedule of trastuzumab treatment (qw vs q3w) 1. Update of Vogel et al. Proc Am Soc Clin Oncol. 2001;20:22a. Abstract 86. 2. Vogel et al. J Clin Oncol. 2002;20:719. 3. Baselga et al. J Clin Oncol. 2005;23:2162. 4. Cobleigh et al. J Clin Oncol. 1999;17:2639. 5. Baselga et al. J Clin Oncol . 1996;14:737.
Slamon et al conducted the first randomized phase III trial of trastuzumab combined with cytotoxic CT as first-line therapy in HER2+ IHC 2+/3+ MBC (trial H0648g). 1,2 Trastuzumab plus AC AC alone (or in some cases, epirubicin + cyclophosphamide) Trastuzumab plus paclitaxel Paclitaxel alone Based on prior adjuvant therapy, patients were stratified to either the AC arms (no prior anthracyclines) or paclitaxel arms (prior anthracyclines permitted). 2 Overall, patients in the 2 paclitaxel treatment arms had somewhat more adjuvant therapy and generally worse prognoses. However, those arms were added to the trial after nearly 1 year of patient accrual to the 2 AC treatment arms, to address the growing use of AC in the adjuvant setting and to improve trial accrual. 2 This trial was powered to evaluate trastuzumab + CT vs CT alone, not for differences between treatment subgroups (eg, trastuzumab + paclitaxel vs paclitaxel alone). 3 At the conclusion of this trial (after disease progression), all patients had the option of entering a nonrandomized, open-label extension study (H0659g) in which trastuzumab was administered at the same weekly dose (2 mg/kg), either alone or in combination with other therapies of the investigators’ choice. 2 1. Update of Slamon et al. Proc Am Soc Clin Oncol . 1998;17:98a. Abstract 377. 2. Slamon et al. N Engl J Med. 2001;344:783. 3. Fleming. Semin Oncol . 1999;26(suppl 12):102.
Efficacy data for the combination trial H0648g reveal that 1,2 Significant improvements in ORR, median TTP, and median survival resulted from the addition of trastuzumab to CT (combined analysis of AC and paclitaxel). Median duration of response, trastuzumab + CT: 9.1 months; CT: 6.1 months ( P <0.001) 1. Slamon et al. N Engl J Med . 2001;344:783. 2. Herceptin ® (trastuzumab) PI.
This was a randomized multicenter phase II trial of first-line therapy in MBC (M77001). Patients were randomized to receive docetaxel 100 mg/m 2 q3w 6 cycles, with or without trastuzumab, to PD. Trastuzumab was given qw until PD. Patients could receive docetaxel beyond 6 cycles at the discretion of the investigator. Patients progressing on docetaxel alone were given the option to cross over to receive trastuzumab as a single-agent treatment at the discretion of their clinicians (n=42). Only prospective analysis of crossover to trastuzumab Results of crossover vs upfront trastuzumab indicate that upfront treatment provides greater benefits than crossover treatment. A total of 188 patients were entered in the trial (94 in each arm). However, 2 patients in the combination arm did not receive study treatment. One patient had abnormal liver function test results, which disqualified her from receiving treatment, and 1 patient refused treatment. Update of Extra et al. Breast Cancer Res Treat. 2003;82(suppl 1):S47. Abstract 217. Update of Extra et al. J Clin Oncol. 2005;23(16S):17s. Abstract 555. Marty et al. J Clin Oncol . 2005;23:e-pub ahead of print.
In trial M77001, compared with docetaxel alone, the first-line trastuzumab (T) plus docetaxel (D) combination (T+D) produced statistically significant improvements in the following efficacy end points, at 24 months minimal follow-up, compared with docetaxel alone 1 : ORR (primary end point): 61% vs 34% ( P =0.0002) Improvement regardless of prior anthracycline use or hormonal receptor status Median TTP: 11.7 vs 6.1 months ( P =0.0001) Median OS: 31.2 vs 22.7 months ( P =0.0325) DOR doubled, from 5.7 to 11.7 months ( P =0.009). Survival ≥ 3 years after randomization, 30 vs 15 patients ( P not determined) 1 Survival ≥ 3 years is uncommon in patients with HER2+ MBC. In the extension phase of this trial, median OS was longer for the 41 patients who crossed over to receive T at PD (21.9 months) compared with the 53 patients who received D only (15.3 months). 2,3 Of the 15 patients on D alone who survived ≥ 3 years, 11 had crossed over to receive T at PD, and only 4 had remained on D alone. 1 Overall, of 45 “long-term” survivors (≥ 3 years), 41 received T upfront or at crossover. 1 Safety: combining T with D added little toxicity and no new long-term safety concerns 1 Slightly higher grade 3/4 hematological toxicity, slightly more left ventricular fraction decreases, and 2 cases of congestive heart failure An accompanying editorial concluded that these results are a convincing demonstration of an overall survival benefit for patients with MBC who have a dismal prognosis. 4 1. Update of Extra et al. J Clin Oncol. 2005;23(16S):17s. Abstract 555. 2. Update of Extra et al. Breast Cancer Res Treat. 2003;82(suppl 1):S47. Abstract 217. 3. Marty et al. J Clin Oncol . 2005;23: TK . 4. Vogel and Tan-Chiu. J Clin Oncol . 2005;23: TK .
A second-line trial in 61 evaluable patients with heavily pretreated MBC (95% received 1 to 3 prior chemotherapy regimens for MBC) treated with gemcitabine (1200 mg/m 2 qw 2, with the third week off, on a 21-day cycle) plus weekly trastuzumab (4 mg/kg week 1, then 2 mg/kg qw), both continued to PD. HER2+ status was based on IHC 2+ and 3+ scores. 1 ORR was 38% (95% CI, 26 to 50) for all patients, but was 44% (95% CI, 29 to 59) for those (n=39) who were HER2+ by the IHC 3+ criterion; median TTP was 5.8 months. A trial in minimally pretreated (0-2+ regimens) patients (40 eligible for evaluation) evaluated gemcitabine 1000 mg/m 2 , days 1, 8 and 15 q28 days, together with standard qw trastuzumab for 8 weeks, followed by the same schedule of gemcitabine; treatment continued to disease progression. 2 19 patients had 0 prior regimens for MBC, 17 patients had 1 prior regimen, and 3 patients had ≥ 2 prior regimens. ORR was 33% (3 CR, 8 PR), and clinical benefit rate was 66% (11 SD); median PFS was 3.9 months, and median survival was 18.8 months An ongoing first-line trial has evaluated 25 patients with MBC treated with gemcitabine 1200 mg/m 2 on days 1 and 8, plus trastuzumab 8 mg/kg week 1 (loading dose) followed by 6 mg/kg qw. Cycles are repeated every 21 days. HER2+ status was based on IHC 3+ or FISH+ test results. 3 After a median of 5 cycles, the ORR was 64% (95% CI, 43 to 82) (12% CR and 52% PR); median TTP was 4.4 months . 1 . O’Shaughnessy et al. Clin Breast Cancer. 2004;5:142. 2 . Peacock et al. J Clin Oncol . 2005;23(16S):54s. Abstract 704. 3. Update of Brufsky et al. Breast Cancer Res Treat. 2004;88(suppl 1):S128. Abstract 3047.
Vinorelbine exhibits a highly synergistic interaction with trastuzumab in preclinical models and is being investigated extensively in MBC as a consequence of early studies that demonstrated favorable efficacy and safety in the multiple-line treatment setting (0-2+ prior regimens for MBC). 1 Median TTP was 34 weeks for first-line therapy, and 16 weeks for second-/third-line. Several phase II studies of weekly vinorelbine plus trastuzumab as first-line treatment of HER2+ MBC have been conducted, and they showed good activity and a favorable safety profile. 2-5 Vinorelbine was administered at 25 or 30 mg/m 2 qw + trastuzumab 4 mg/kg week 1 followed by 2 mg/kg qw, with treatment to PD. ORRs range from 61.5% to 84%, with up to 14% CR. 95% CIs indicate broad range to ORR figures; some CIs were not reported. Median TTP (or PFS) ranged from 34 to 72 weeks (first-line setting) In one study, median survival was recently reported; 24.5 months (95% CI, 18-38) 4 Clinical benefit rates, which include objective responses plus long-term stable disease, were 81% to 97%. Adverse events were primarily grade 3/4 neutropenia, which is manageable. 3 Serious cardiac toxicity was rarely observed. 1. Burstein et al. J Clin Oncol . 2001;19:2722. 2. Burstein et al. J Clin Oncol. 2003;21:2889. 3. Jahanzeb et al. Oncologist. 2002;7:410. 4. Update of Chan et al. J Clin Oncol . 2005;23(16S):25s. Abstract 587. 5. Bernardo et al. Ann Oncol. 2002;13(suppl 5):51. Abstract 181P.
Update of Robert et al. Proc Am Soc Clin Oncol . 2004;23:20. Abstract 573. Phase III randomized trial of first-line trastuzumab and paclitaxel carboplatin (TP C) for MBC that was HER2+ IHC 2+ or 3+ (N=188) Rationale Preclinical synergy of trastuzumab and platinum agents In the pivotal CT trastuzumab trial (H0648g), superior efficacy with the addition of trastuzumab Trial design 1 CT was administered on a q3w schedule, trastuzumab qw. Paclitaxel 175 mg/m 2 ; carboplatin AUC 6 CT was given for at least 6 cycles, with treatment beyond that as clinically indicated and at the investigators’ discretion. Trastuzumab was administered at the standard weekly dose (4 mg/kg week 1, then 2 mg/kg qw thereafter) until PD. Patients: all taxane-naive End points – primary: ORR; secondary: DOR, TTP, survival, and safety
Efficacy: TPC was significantly better than TP in ORR, overall and for those patients with IHC 3+ HER2 status. 1 The ORRs for all patients were 52% for TPC and 36% for TP ( P =0.04). The ORRs for patients with HER2+ IHC 3+ tumors were similar: 57% for TPC and 37% for TP ( P =0.03). The ORR for patients who have FISH+ tumors is also being evaluated, but current data are immature due to small numbers of patients. Median TTP was significantly longer for TPC than for TP, but there was no significant difference in median OS. Median TTP for all patients: 10.7 months for TPC and 7.0 months for TP ( P =0.016); for IHC 3+: 14.0 months for TPC and 7.1 months for TP ( P =0.007) Survival at 48 months was greater for TPC than for TP, for all patients (40% vs 31%) and for IHC 3+ patients (41% vs 28%). It is uncertain whether these results indicate evidence of a carboplatin-trastuzumab interaction, whether there is a paclitaxel-carboplatin interaction, or whether carboplatin is simply additive in efficacy. Previous studies have shown paclitaxel-carboplatin to achieve a response rate of about 60%, 2 so there is no clear indication of further interaction with trastuzumab. 1. Update of Robert et al. Proc Am Soc Clin Oncol . 2004;23:20. Abstract 573. 2. Perez et al. Cancer . 2000;88:124.
AUC, area under the curve; FISH, fluorescence in situ hybridization; MBC, metastatic breast cancer
The TPC combination was evaluated in this phase II trial, conducted by the NCCTG, by comparing qw vs q3w scheduling. Primary end point safety rather than efficacy Small study (N=96, randomized to 2 arms) This trial evaluated 96 patients with HER2+ MBC, randomized to a qw arm (A) vs a q3w arm (B). Treatment with the full combination was for 24 weeks, then trastuzumab was continued to PD. Arm A (q3w): Paclitaxel 200 mg/m 2 ; carboplatin (AUC) 6; trastuzumab 8 mg/kg week 1 then 6 mg/kg qw; cycles repeated q3w (n=43) Arm B (qw): Paclitaxel 80 mg/m 2 on weeks 1 to 3; carboplatin AUC 2 on weeks 1 to 3; trastuzumab 4 mg/kg week 1 then 2 mg/kg qw; cycles repeated q4w (n=48) Update of Perez et al. Breast Cancer Res Treat. 2003;82(suppl 1):S47. Abstract 216.
Both treatment arms had a high proportion of patients with visceral metastasis: q3w 67%; qw 83% Both the q3w and qw TPC regimens are highly active. ORR: q3w 65%; qw 81%; nearly twice as many CR with qw (23%) than with q3w (12%) Median duration of response: q3w 10.5 mo; qw 14.8 mo Median TTP: q3w 9.9 mo; qw 14.7 mo Median survival time: q3w 2.3 y; qw 3.2 y 1-year PFS: q3w 41%; qw 62% 2-year PFS: q3w 59% (95% CI, 45 to 76); qw 76% (64 to 90) Update of Perez et al. Breast Cancer Res Treat. 2003;82(suppl 1):S47. Abstract 216.
According to the NCCN guidelines, patients with MBC whose tumors overexpress HER2 may benefit from trastuzumab monotherapy or in combination with chemotherapy. NCCN guidelines’–preferred CT regimens for use in combination with trastuzumab include: Single-agent CT: paclitaxel (either 175 mg/m 2 q3w or 80 to 90 mg/m 2 qw), docetaxel (either 80 to 100 mg/m 2 q3w or 35 mg/m 2 qw), or vinorelbine (25 mg/m 2 qw) Combination CT: paclitaxel + carboplatin (q3w); docetaxel + carboplatin (only evaluated q3w) Trastuzumab qw (4 mg/kg week 1, then 2 mg/kg/wk) or q3w (8 mg/kg week 1, then 6 mg/kg/wk) National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology – v.1.2005; Breast Cancer. At: http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf . Accessed March 2005 .
CCO would like to thank John R. Mackey, MD, FRCP, for his permission to use this figure. The next study again raises the issue of cross-talk between signal transduction pathways. In this case, the focus is on the possibility that HER2 signaling influences the expression of vascular endolethial growth factor, and this leads to a hypothesis that combined antibody therapy could be an effective strategy in the treatment of metastatic breast cancer.
This phase II trial of lapatinib was in patients (N=44) with HER2+ MBC that was refractory to prior therapy with trastuzumab. HER2+ status was determined by IHC. Treatment was with lapatinib daily, until PD; the first 13 patients received 1250 mg/d, but for all subsequent patients the dose was increased to 1500 mg/d. Preliminary efficacy results (n=36): The overall response rate was 8% (3/36 PR) The clinical benefit rate (PR and SD) was 22% (5/36 SD). Preliminary safety results (n=15): There was a single case of grade 3 rash; otherwise, all adverse events were grade 1 or 2 (events in >1 patient: anorexia, nausea, rash, vomiting, diarrhea, and weight loss). Impressive activity in patients who were refractory to trastuzumab therapy. Blackwell et al. Proc Am Soc Clin Oncol. 2004;23:196. Abstract 3006.
In the pivotal trial (H0648g) of chemotherapy trastuzumab, there was more cardiac dysfunction associated with AC alone than with paclitaxel alone, and there were increases with the addition of trastuzumab to both regimens, especially to AC. The greater increase in CD with the AC + trastuzumab combination is evident for the 2 most severe categories, NYHA classes III and IV. These results indicate that the increase in cardiac dysfunction with paclitaxel + trastuzumab is largely a consequence of mild cases (NYHA classes I and II). Most patients with CD responded to appropriate medical intervention, including discontinuation of trastuzumab. Some patients were successfully managed while continuing trastuzumab therapy. Cardiotoxicity risk did not increase with prolonged duration of trastuzumab therapy. Slamon et al. N Engl J Med . 2001;344:783.
In preparation for cliical testing, the murine Ab used in the animal studies was humanized to minimize immunogenicity. As you can see from this cartoon, the entire Ab has been humanized with the exception of a small fraction in the variable region. The antibody binds all isoforms of VEGF A with high affinity and has terminal half life of 2-3 wks
Last updated: January 12, 2007 E2100 is an ongoing open-label, phase III trial in which Avastin is being evaluated in combination with weekly paclitaxel as first-line therapy for MBC. 1 Patients recruited to this trial are less heavily pretreated than patients in AVF2119g. A total of 722 patients have been randomised to one of two arms: paclitaxel 90mg/m 2 alone every week for 3 weeks followed by 1 week without treatment or paclitaxel plus Avastin 10mg/kg every 2 weeks. No cross over is permitted in this trial. Objectives are to compare progression-free survival, overall response rate and overall survival between the arms. MBC = metastatic breast cancer; PD = progression of disease 1. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 2005;94:S6 (Abstract 3).
Last updated: January 12, 2007 The Kaplan-Meier curve shown here demonstrates the effect of Avastin plus paclitaxel on progression-free survival. 1 A significant increase in median progression-free survival was observed in patients receiving Avastin plus paclitaxel compared with paclitaxel alone (11.4 months vs 6.11 months, respectively). The HR for progression was 0.51 (p<0.0001), which corresponds to a two-fold increase in the chance of being progression free. HR = hazard ratio; MBC = metastatic breast cancer 1. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 2005;94:S6 (Abstract 3).
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