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 Verma11

1Duke Cancer Institute, Durham, NC, ABD; 2Mount Vernon Cancer Center,

Northwood, İngiltere; 3San Raffaele Hospital, Milano, İtalya; 4Dana-Farber Cancer

Institute, Boston, MA, ABD; 5Medical Office Hematology, Aschaffenburg, Almanya; 6Massachusetts General Hospital, Boston, MA, ABD; 7University of Miami Sylvester

Comprehensive Cancer Center, Miami, FL, ABD; 8Seoul National University College

of Medicine, Seoul, Kore; 9Institut Curie, Paris, Fransa; 10Genentech, Inc, South San

Francisco, CA, ABD; 11Sunnybrook Odette Cancer Center, Toronto, Kanada

HER2+ Meme Kanseri İçin Hedefe Yönelik Tedaviler: Trastuzumab, Lapatinib ve T-DM1

T-DM1

Antikor: Trastuzumab

HER2

Trastuzumab

4

Lapatinib

Nukleus

Spector NL, Blackwell KL. J Clin Oncol 2009; Nelson MH, et al. Ann Pharmacother 2006;

Lewis Phillips GD, et al. Cancer Res 2008.

P P

P

P P

P

Emtansin

Sitotoksik:

DM1

Stabil

bağlayıcı:

MCC

T-DM1: Etki Mekanizması

Emtansin

salımı

Mikrotübül

polimerizasyonunun

inhibisyonu

5

Hücreye giriş

HER2

Adapted from LoRusso PM, et al. Clin Cancer Res 2011.

T-DM1

Lizozom

Nukleus

P P

P

≥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

1Burris HA, et al. J Clin Oncol 2011; 2Krop I, et al. J Clin Oncol 2012; 3Hurvitz S, et al. ESMO 2011; 4Geyer CE, et al. N Engl J Med 2006.

EMILIA Araştırmasının Tasarımı

• 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

1:1

HER2+ (santral)

LABC ya da MBC

(N=980)

•Daha önce taksan ve

trastuzumab

•Metastaz tedavisi

sırasında ya da

adjuvan tedavi

uygulanan 6 ay içinde

progresyon

PD

T-DM1

3.6 mg/kg q3w IV

Kapesitabin 1-14. günler arasında, q3w, oral yolla

1000 mg/m2 bid

+

Lapatinib oral yolla 1250 mg/gün qd

PD

Kap + Lap (n=496)

T-DM1 (n=495)

Bağımsız incelemeye göre ölçülebilir hastalık, n (%) 389 (78) 397 (80)

Metastatik tutulum, n (%)

Viseral Viseral olmayan

335 (68) 161 (33)

334 (68) 161 (33)

Metastaz alanları, n (%)

<3 ≥3 Bilinmeyen

307 (62) 175 (35)

14 (3)

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)

Hastaların Demografik Özellikleri ve Başlangıçtaki Özellikleri

Daha Önceki Sistemik Tedavi

Kap + Lap (n=496)

T-DM1 (n=495)

Daha önce uygulanan tedavinin tipi, n (%)

Taksanlar Antrasiklinler Endokrin ajanlar

494 (100)

302 (61) 204 (41)

493 (100)

303 (61) 205 (41)

Daha önce MBC nedeniyle tedavi, n (%)

Evet Hayır

438 (88) 58 (12)

435 (88) 60 (12)

Daha önce trastuzumab tedavisi, n (%) Yalnızca EBC

495 (100) 77 (16)

495 (100) 78 (16)

Trastuzumab tedavisinin süresi, n (%) <1 yıl ≥1 yıl

212 (43) 284 (57)

210 (42) 285 (58)

Son trastuzumab uygulamasından itibaren geçen süre, ay (aralık) 1.5 (0–98) 1.5 (0–63)

Ölçülebilir Hastalığı Olan Olgularda Objektif Yanıt Oranı (ORR) ve Yanıt Süresi (DOR)

ORR

0.0

0.2

0.4

0.6

0.8

1.0

Pro

gre

syo

n g

örü

lme

ye

n h

as

ta

ora

nı

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Medyan, ay (%95 CI)

Kap + Lap 6.5 (5.5, 7.2)

T-DM1 12.6 (8.4, 20.8)

Ora

n (

%)

Farklılık: %12.7 (%95 CI, 6.0, 19.4) P=0.0002

0

20

30

40

50

10

T-DM1

173/397 120/389

%43.6

%30.8

Kap + Lap

120 105 77 48 32 14 9 8 3 3 1 1 0 0 0 0

173 159 126 84 65 47 42 33 27 19 12 8 2 0 0 0

Kap + Lap

T-DM1

Risk altındaki hasta sayısı:

0

0

0

0

0

0

Bağımsız İncelemeye Göre PGS

496 404 310 176 129 73 53 35 25 14 9 8 5 1 0 0

495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0

Kap + Lap

T-DM1

Bağımsız incelemeye göre risk altındaki hasta sayısı:

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

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

Pro

gre

syo

n g

örü

lmeyen

hasta

ora

nı

Süre (ay)

Katmanlandırılmamış HR=0.66 (P<0.0001).

Genel Sağkalım: Ara Analiz

496 469 438 364 296 242 195 155 129 97 74 52 31 17 7 3 2 1 0

495 484 461 390 331 277 220 182 149 123 96 67 46 29 16 5 2 0 0

Kap + Lap

T-DM1

Risk altındaki hasta sayısı: Süre (ay)

Sağ

kalım

ora

nı

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

%77.0 %65.4

%47.5

%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

Katmanlandırılmamış HR=0.63 (P=0.0005).

NR=ulaşılmamıştır.

Advers Olayların Özeti

aKap + Lap: CAD, çoğul organ yetersizliği, koma, hidrosefali, ARDS; aT-DM1: metabolik ensefalopati. bDeğerlendirilebilen hastalar: 445 (Kap + Lap); 481 (T-DM1).

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)

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

ALT, alanin aminotransferaz; AST, aspartat aminotransferaz.

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

Anemi

8.0 1.6 0.0 10.4 2.7 0.0

Trombositopeni

2.5 0.0 0.2 28.0 10.4 2.4

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

CLEOPATRA

NEJM 2012

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

Primary Outcome: PFS

Randomize

MA.31/ EGF108919: Design

Sample Size: ~ 600 (536 centrally confirmed HER2+ patients)

EXPERIMENTAL ARM

24 Weeks:

Lapatinib

plus

Taxane

Until PD:

Lapatinib

STANDARD ARM

24 Weeks:

Trastuzumab

plus

Taxane

Until PD:

Trastuzumab

Taxane (Tax)

P 80 mg/m2 IV weekly (3/4) or

D 75 mg/m2 IV q3 weekly

Anti HER2/neu therapy:

Lapatinib (L)

Plus taxane: 1250 mg po daily

Monotherapy 1500 mg po daily

Trastuzumab (T)

Plus taxane: loading 6 mg/kg IV q3

weekly or 2 mg/kg IV weekly

Monotherapy 6 mg/kg IV q3 weekly

Centrally Her-2 +

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

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

Progression Free Survival Centrally-confirmed HER2+ Analysis

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

12 255 158 (62)

0 (0) 261 180 (69)

0 (0)

24 199 126 (63)

0 (0) 208 142 (68)

3 (1)

36 145 95 (66) 0 (0) 154 106 (69)

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

31

EVE 10 mg daily +

EXE 25 mg daily (n = 485)

Placebo +

EXE 25 mg daily (n = 239)

R

Endpoints •Primary: PFS (local assessment)

•Secondary: OS, ORR, QOL, safety, bone markers, PK

2:1

N = 724 •Postmenopausal ER+

•Unresectable locally advanced or metastatic BC

•Recurrence or progression after letrozole or anastrozole

Stratification: Sensitivity to prior hormone therapy and presence of visceral metastases

Abbreviations: BC, breast cancer; ER+, estrogen receptor-positive; EVE, everolimus; EXE, exemestane; ORR, overall response rate; OS, overall survival;

PFS, progression-free 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

32

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 diseasea 70 68

a All other patients had ≥ 1 bone lesion.

Adapted from: Baselga J, et al. N Engl J Med. 2012;366(6):520-529.

BOLERO-2: Prior Therapies Were Balanced Between Treatment Arms

33

Therapy

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.

EVE 10 mg + EXE

PBO + EXE

Number of patients still at risk

0

20

40

60

80

100

Time (week)

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120

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

Censoring times

EVE 10 mg EXE (n/N = 310/485)

PBO + EXE (n/N = 200/239)

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

Pro

babili

ty (

%)

of E

vent

PFS Based on Local Assessment at 18-mo Follow-up

in BOLERO-2 Confirms Earlier Reports

Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo.

Piccart M, et al. ASCO 2012; abstract 559 (poster). 34

EVE 10 mg + EXE

PBO + EXE

Number of patients still at risk

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

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108

485

239

427

179

359

114

292

76

239

56

211

39

166

31

140

27

108

16

77

13

62

9

48

6

32

4

21

1

18

0

11

0

10

0

5

0

0

0

Censoring times

EVE 10 mg + EXE (n/N = 188/485)

PBO + EXE (n/N = 132/239)

0

20

40

60

80

100

Pro

babili

ty (

%)

of E

vent

Time (week)

Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo

Piccart M, et al. ASCO 2012; abstract 559 (poster).

PFS Based on Central Review at 18-mo Follow-up in BOLERO-2

Confirms Earlier Reports and Local Assessment

35

BOLERO-2 (18 mo f/up): Response Rates & Clinical Benefit Were Significantly Higher in the Everolimus Arm

36

P < 0.0001

Pe

rce

nt

Piccart M, et al. ASCO 2012; abstract 559 (poster).

P < 0.0001

BOLERO-2 (18 mo f/up): Overall Survival Was Numerically Better

With Everolimus

37

PFS

Interim1

(7 mo follow-up)

PFS

Update2 (12 mo follow-up)

PFS

Final3 (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 G, et al. SABCS 2011; abstract S3-7 (oral).

3. Piccart M, et al. ASCO 2012; abstract 559 (poster).

Everolimus + Exemestane (N=482), %

Placebo + Exemestane (N=238), %

Grade 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

31 19 10 1 0 13 8 4 1 0

Non-infectious pneumonitis*

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).

BOLERO-2 (18 mo f/up): Common Adverse Events Were Consistent With the Established Safety Profile of Everolimus

38

PFS Benefits Were Consistent in All Subgroups

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

HR

Median PFS, months

EVE + EXE PBO + EXE

Favors PBO + EXE Favors EVE + EXE Abbreviations: EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO,

placebo; PFS, progression-free survival.; PgR, progesterone receptor.

Piccart M, et al. ASCO 2012; abstract 559 (poster). 39

PFS Benefits Were Consistent in All Subgroups

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

HR

Median PFS, months

EVE + EXE PBO + EXE

Favors PBO + EXE Favors EVE + EXE

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).

40

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

1

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

2

EVE Disease Progression in Bone: BOLERO-2 Overall Population

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

Figure 3. Everolimus decreases disease PD in bone in the overall population (N = 724).

EVE Disease Progression in Bone: Patients With Bone Metastases at Baseline

44 a Cumulative incidence of disease progression was determined using the competing risk method ; exploratory P = .0165 by Gray’s test. Abbreviations: EVE, everolimus; EXE, exemestane; PBO, placebo. Gnant M, et al. ASCO 2012, Abstract 512

Figure 4. Everolimus decreases disease progression in bone in subgroup of patients

with bone metastases at baseline

(n = 556)

3

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

- -

Control

Exp 1

Exp 2

N = 900 (planned) Strata: Adj taxanes ER/PR status

-

nab-paclitaxel 150 mg/m2 weekly + bevacizumab 10 mg/kg q 2 wks2

ixabepilone 16 mg/m2 weekly +

bevacizumab 10 mg/kg q 2 wks3

Restage q 2 cycles until

disease progression

CALGB 40502 - NCCTG N063H - CTSU 40502 An Open Label Phase III Trial of Firstline Therapy for Locally Recurrent or Metastatic Breast Cancer

• 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

paclitaxel 90 mg/m2 weekly + bevacizumab 10 mg/kg q 2 wks1

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

N=262*

pac

N=274*

ixa

N=241* Site of metastases

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)

Months From Study Entry

Pro

po

rtio

n P

rog

ressio

n-F

ree

0 10 20 30

0.0

0.2

0.4

0.6

0.8

1

PacNabIxa

Comparison HR P-value 95% CI

nab vs. pac 1.19 0.12 0.96-1.49

ixa vs. pac 1.53 < 0.0001 1.24-1.90

CALGB 40502 Progression-Free Survival By Treatment Arm

paclitaxel

nab-paclitaxel

ixabepilone

Agent N Median PFS

paclitaxel 283 10.6

nab-Paclitaxel 271 9.2

ixabepilone 245 7.6

Unplanned Subset Analysis of PFS : No Differences

ER+ Disease

Months From Study Entry

Pro

po

rtio

n A

live

0 10 20 30

0.0

0.2

0.4

0.6

0.8

1

PacNabIxa

Comparison HR P-value 95% CI

nab vs. pac 1.38 0.0194 1.05 – 1.81

ixa vs. pac 1.60 0.0006 1.22 – 2.08

paclitaxel

nab-paclitaxel

ixabepilone

Triple Negative Disease

Months From Study Entry

Pro

po

rtio

n A

live

0 5 10 15 20 25 30

0.0

0.2

0.4

0.6

0.8

1

PacNabIxa

ER+ Disease Triple Negative Disease

Comparison HR P-value 95% CI

nab vs. pac 0.93 0.7354 0.62 – 1.40

ixa vs. pac 1.46 0.0647 0.98 – 2.18

Pro

po

rtio

n P

rog

ressio

n F

ree

Pro

po

rtio

n P

rog

ressio

n F

ree

Dose Reductions by Cycle 3

Cycle 2 Cycle 3

Dose reduction

Fre

quen

cy (

%)

010

2030

4050

nab Pac Ixa nab Pac Ixa

Cycle 3

45%

15% 15%

ixa nab pac 0190001900r1l

10190001900r1l

20190001900r1l

30190001900r1l

9190001900r2l

19190001900r2l

29190001900r2l

1 2 3 4 5

Pe

rce

nt

Cycle number

paclitaxel

nab-paclitaxel

ixabepilone

All Cause Cumulative Discontinuation by Cycle

Months From Study Entry

Pro

po

rtio

n A

live

0 5 10 15 20 25 30

0.0

0.2

0.4

0.6

0.8

1

PacNabIxa

CALGB 40502 Time to Treatment Failure

paclitaxel

nab-paclitaxel

ixabepilone

Comparison HR P-value 95% CI

nab vs. pac 1.40 0.0005 1.16-1.70

ixa vs. pac 1.37 0.0014 1.13-1.67

Agent N Median TTF

paclitaxel 283 7.1

nab-Paclitaxel 271 5.4

ixabepilone 245 5.1

Pro

port

ion o

n T

reatm

ent

Months From Study Entry

Pro

po

rtio

n A

live

0 10 20 30

0.0

0.2

0.4

0.6

0.8

1

PacNabIxa

CALGB 40502 Overall Survival

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

paclitaxel

nab-paclitaxel

ixabepilone

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 Grade 3+

2 3 4

nab

(N = 258) 27% 24% 1%

25%

p=0.012

pac

(N = 262) 27% 16% <1% 16%

ixa

(N = 237) 22% 22% 3%

25%

p=0.022

Sensory Neuropathy

nab

(N = 258)

pac

(N = 262)

ixa

(N = 237)

Leukopenia 17%

p = 0.0004 7%

3%

p = 0.042

Neutropenia 47%

p = 0.0001 18%

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

Other AEs – Grade 3+

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 nab-

paclitaxel; 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 :

12 vs 8 ay

36 vs 28 ay

Abbreviations: q, every; R, randomization; SRE, skeletal-related event.

http://www.clinicaltrials.gov. Identifier NCT00375427.

ZOOM Study Design

Arm 1: Zoledronic acid (4 mg q 12 wk)

Arm 2: Zoledronic acid (4 mg q 4 wk)

Treatment duration 1 year

R 1:1

N = 420 (Planned)

Key eligibility criteria •BC stage IV

•Confirmed bone metastasis

•Prior zoledronic acid treatment (4 mg q 4 wk) × 9-12 infusions

Accrual: February 2006 - February 2010

Endpoints:

Primary: Skeletal morbidity rate (SMR) (non-inferiority)

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

ZOOM: A Prospective, Randomized Trial

of ZA for Long-term Treatment

in Patients With Bone-Metastatic BC After 1

yr of Standard ZA Treatment

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

a95% 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.

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.

Change in NTX Levels On-Study C

hange in N

TX

vs B

aselin

e,

%

(media

n w

ith inte

rquart

ile r

ange)

Abbreviations: NTX, N-telopeptide of type I collagen; q, every; ZOL, zoledronic acid.

*P < .05 by Wilcoxon test comparing arms

* * *

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

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.

Open-label design

Different clinic visit frequencies between arms

No prespecified imaging frequency

Single-country study

Study limitataions

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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