MAMA DISEMINADA

RAFAEL TRUJILLO VILCHEZ POST-ASCO 2013

Efficacy and safety of first-line pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer (CLEOPATRA) in patients previously exposed to trastuzumab
Eva Ciruelos,1 Adam Brufsky,2 Young-Hyuck Im,3 Sung-Bae Kim,4 Emma Clark,5 Adam Knott,5 Graham Ross,5 David Miles6
Hospital 12 de Octubre, Medical Oncology Department, Madrid, Spain; 2Division of Hematology and Oncology, University of Pittsburgh, Pittsburgh, PA; 3Division of Hematology and Medical Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 4Department of Oncology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea; 5Roche Products Limited, Welwyn, UK; 6Mount Vernon Cancer Centre, Middlesex, UK
1University

Presented at the ASCO Annual Meeting, May 31June 4, 2013, Chicago, IL

Introduction to pertuzumab and trastuzumab

The humanized monoclonal antibodies trastuzumab and pertuzumab bind to different extracellular domains of HER2, a protein overexpressed in ~20% of breast cancers1 Preclinical studies have shown that trastuzumab binds to subdomain IV of HER2,2 inhibiting ligand-independent signaling3 and preventing cleavage of the receptor and formation of the constitutively active p95 fragment4 Pertuzumab binds to the dimerization domain (subdomain II) of HER25 and inhibits ligand-dependent signaling6
Binding of trastuzumab and pertuzumab to HER2 also promotes antibody-dependent cell-mediated cytotoxicity7

Due to their complementary modes of action, the combination of these two HER2targeted agents results in a more comprehensive blockade of HER2 signaling than either agent alone7
1. Wolff AC, et al. J Clin Oncol 2007; 25:118145; 2. Cho HS, et al. Nature 2003; 421:756760; 3. Junttila TT, et al. Cancer Cell 2009; 15:429440; 4. Molina MA, et al. Cancer Res 2001; 61:47444749; 5. Franklin MC, et al. Cancer Cell 2004; 5:317328; 6. Agus DB, et al. Cancer Cell 2002; 2:127137; 3 7. Scheuer W, et al. Cancer Res 2009; 69:93309336.

HER2, human epidermal growth factor receptor 2

Mode of action of pertuzumab and trastuzumab

HER2

Pertuzumab

HER1,3,4

Trastuzumab

Dimerization

Intracellular signaling

HER2 binding sites of trastuzumab and pertuzumab

HER2, human epidermal growth factor receptor 2

Clinical efficacy of pertuzumab in combination with trastuzumab

It has been proposed that patients may progress on trastuzumab therapy due to the development of resistance However, there is clinical evidence that pertuzumab in combination with trastuzumab is active when used to treat patients with HER2-positive MBC who have progressed during trastuzumab therapy1,2 In the global Phase III clinical study CLEOPATRA, patients with HER2-positive MBC who received pertuzumab plus trastuzumab plus docetaxel as first-line treatment had significantly increased PFS3 and OS4 compared with those who received placebo plus trastuzumab plus docetaxel Adverse events reported at the primary analysis3 and after one additional year of follow-up4 were similar with respect to frequency, specificity, and severity. At this point, there is no evidence of late or cumulative toxicity with the study regimens Of note, cardiac adverse events were not increased in the pertuzumab arm compared with the placebo arm5
1. Baselga J, et al. J Clin Oncol 2010; 28:11381144; 2. Cortes J, et al. J Clin Oncol 2012; 30:15941600; 3. Baselga J, et al. N Engl J Med 2012; 366:109119; 4. Swain SM, et al. Lancet Oncol 2013; 14:461471; 5 5. Swain SM, et al. Oncologist 2013; 18:257264.

HER2, human epidermal growth factor receptor 2 MBC, metastatic breast cancer; OS, overall survival; PFS, progression-free survival

Objective
Analysis of the efficacy of the combination of pertuzumab, trastuzumab, and docetaxel compared with placebo, trastuzumab, and docetaxel in the subgroup of patients who had previously received trastuzumab in the (neo)adjuvant setting in CLEOPATRA

Study treatment
Patients were randomized to receive pertuzumab plus trastuzumab plus docetaxel or placebo plus trastuzumab plus docetaxel Study drugs: Pertuzumab: 840 mg initial dose, followed by 420 mg q3w Trastuzumab: 8 mg/kg initial dose, followed by 6 mg/kg q3w Docetaxel: 75 mg/m2 q3w (with escalation to 100 mg/m2 at the investigators discretion) Pertuzumab and trastuzumab were administered until investigatorassessed disease progression, unmanageable toxicity, or withdrawal of consent Docetaxel was administered for a recommended 6 cycles, and then continuation was at the investigators discretion, or until disease progression, unmanageable toxicity, or withdrawal of consent

Key eligibility criteria

Centrally confirmed HER2-positive MBC or locally recurrent, unresectable breast cancer No prior biologic or chemotherapy in the metastatic setting, with the exception of one previous hormonal regimen for MBC, which had to be stopped prior to randomization No prior approved or investigative tyrosine kinase/HER inhibitors for breast cancer in any treatment setting, with the exception of (neo)adjuvant trastuzumab Patients who received (neo)adjuvant therapy for breast cancer were eligible if they had a disease-free interval of 12 months Baseline LVEF 50% and no LVEF decline to <50% during or after prior trastuzumab therapy ECOG performance status of 0 or 1 Measurable and/or non-measurable disease
ECOG, Eastern Cooperative Oncology Group; HER, human epidermal growth factor receptor; LVEF, left ventricular ejection fraction; MBC, metastatic breast cancer

Statistical analyses
The primary endpoint was independently assessed PFS, and secondary endpoints included OS and safety The study was designed to have 80% power to detect a 33% improvement in median PFS in the pertuzumab arm (HR = 0.75) at a two-sided significance level of 5% Post-hoc analyses of PFS and OS were conducted in the subgroup of patients who received prior (neo)adjuvant therapy with trastuzumab

HR, hazard ratio; OS, overall survival; PFS, progression-free survival

Baseline demographics and disease characteristics

Overall study population Placebo arm (n = 406) 54.0 2789 128 (31.5) 152 (37.4) 68 (16.7) 58 (14.3) 248 (61.1) 157 (38.7) 0 (0) 1 (0.2) 316 (77.8) 196 (48.3) 199 (49.0) 11 (2.7) Pertuzumab arm (n = 402) 54.0 2282 125 (31.1) 154 (38.3) 67 (16.7) 56 (13.9) 274 (68.2) 125 (31.1) 3 (0.7) 0 (0) 314 (78.1) 212 (52.7) 189 (47.0) 1 (0.2) Patients with (neo)adjuvant trastuzumab exposure Placebo arm (n = 41) 54.0 3277 7 (17.1) 16 (39.0) 16 (39.0) 2 (4.9) 28 (68.3) 12 (29.3) 0 (0) 1 (2.4) 33 (80.5) 25 (61.0) 15 (36.6) 1 (2.4) Pertuzumab arm (n = 47) 51.0 3471 5 (10.6) 25 (53.2) 15 (31.9) 2 (4.3) 33 (70.2) 12 (25.5) 2 (4.3) 0 (0) 33 (70.2) 30 (63.8) 17 (36.2) 0 (0)

n (%) Median age (years) Range Region Asia Europe North America South America ECOG PS 0 1 2* 3* Visceral disease

ER/PgR status Negative Positive Unknown

* Protocol violation

ECOG PS, Eastern Cooperative Oncology Group performance status; ER, estrogen receptor; PgR, progesterone receptor

10

Baseline demographics and disease characteristics

Overall study population Placebo arm (n = 406) 192 (47.3) 214 (52.7) 97 (23.9) 164 (40.4) 94 (23.2) 41 (10.1) 286 (70.4) 175 (43.1) Pertuzumab arm (n = 402) 184 (45.8) 218 (54.2) 106 (26.4) 150 (37.3) 91 (22.6) 47 (11.7) 285 (70.9 ) 171 (42.5) Patients with (neo)adjuvant trastuzumab exposure Placebo arm (n = 41) 41 (100) 0 (0) 15 (36.6) 37 (90.2) 36 (87.8) 41 (100) 41 (100) 36 (87.8) Pertuzumab arm (n = 47) 47 (100) 0 (0) 17 (36.2) 37 (78.7) 36 (76.6) 47 (100) 47 (100) 39 (83.0) n (%) Prior (neo)adjuvant chemotherapy Yes No (Neo)adjuvant treatments Hormone Anthracycline Taxane Trastuzumab Other prior therapy Surgery Radiotherapy Hormone treatment for metastatic disease (prior to enrollment) Treatment-free interval (months) n* Median Range Sites of recurrence at baseline Visceral Bone Breast Lymph nodes Skin Soft tissue Measurable tumor burden (mm) n Median Range

29 (7.1)

20 (5.0)

1 (2.4)

1 (2.1)

187 29.0 0259

173 31.0 0276

41 16.0 074

43 19.0 086

316 (77.8) 176 (43.3) 148 (36.5) 250 (61.6) 24 (5.9) 20 (4.9)

313 (77.9) 187 (46.5) 156 (38.8) 261 (64.9) 28 (7.0) 15 (3.7)

33 (80.5) 16 (39.0) 0 (0) 15 (36.6) 1 (2.4) 1 (2.4)

33 (70.2) 25 (53.2) 2 (4.3) 26 (55.3) 2 (4.3) 6 (12.8)

369 79.0 10455

366 79.0 10422

33 58.0 12200

40 45.0 12195

* In patients with (neo)adjuvant treatment; some patients had missing data Only in patients with target lesions

11

Baseline demographics and disease characteristics

In the overall study population, 47.3% and 45.8% of patients in the placebo and pertuzumab arms, respectively, had received (neo)adjuvant chemotherapy
10.1% and 11.7% of patients in the placebo and pertuzumab arms, respectively, had received (neo)adjuvant trastuzumab

The demographics of the subgroup of patients with (neo)adjuvant trastuzumab exposure were generally balanced between arms and similar to the overall study population Of patients with prior trastuzumab exposure, 82% came from Europe or North America, reflecting the timing of adjuvant trastuzumab approval in these regions compared with the rest of the world There was a shorter median treatment-free interval in the subgroup of patients with prior trastuzumab exposure compared with the overall study population In the prior trastuzumab subgroup, more patients in the pertuzumab arm had bone and soft tissue metastases and positive lymph nodes at baseline compared with the placebo arm

12

Progression-free survival
100 90 80 70 Ptz + T + D: No prior T Pla + T + D: No prior T

Ptz + T + D: Prior T Pla + T + D: Prior T

Progression-free 50 survival (%)

40

60

30
20 10 0 0
n at risk Ptz + T + D: No prior T Pla + T + D: No prior T Ptz + T + D: Prior T Pla + T + D: Prior T 137 151 47 41 120 119 39 34 99 80 29 22 52 39 12 5 31 20 8 4 14 6 4 3 4 2 1 2 0 0 0 0 0 0 0 0 13

10

15

20

25

30

35

40

Time (months)

D, docetaxel; Pla, placebo; Ptz, pertuzumab; T, trastuzumab

Progression-free survival
Progression-free survival by independent assessment Overall population (N = 808) Median (months) HR (95% CI) p-value Patients with (neo)adjuvant therapy without trastuzumab (n = 288) Median (months) HR (95% CI) Patients with (neo)adjuvant therapy with trastuzumab (n = 88) Median (months) HR (95% CI) Placebo + trastuzumab + docetaxel 12.4 0.62 (0.51, 0.75) p < 0.0001 Pertuzumab + trastuzumab + docetaxel 18.5

12.6 0.60 (0.43, 0.83)

21.6

10.4 0.62 (0.35, 1.07)

16.9

CI, confidence interval; HR, hazard ratio

14

Overall survival
Overall survival Overall study population (N = 808) HR (95% CI) p-value Patients without (neo)adjuvant therapy (n = 432) HR (95% CI) Patients with (neo)adjuvant therapy (n = 376) HR (95% CI) Patients with (neo)adjuvant therapy with trastuzumab (n = 88) HR (95% CI) 0.66 (0.52, 0.84) p = 0.0008

0.66 (0.47, 0.93)

0.66 (0.46, 0.94)

0.68 (0.30, 1.55)

The PFS and OS HR 95% CIs are wide for patients who received (neo)adjuvant therapy with trastuzumab due to the small number of patients in this subgroup

CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival

15

Potential risk factors for the development of LVSD

A univariate Cox regression analysis was performed to assess the influence of the predefined potential risk factors: prior anthracycline exposure, prior radiotherapy, prior trastuzumab therapy, age, smoking history, diabetes mellitus, and hypertension, on the time to development of asymptomatic or symptomatic LVSD Prior anthracycline exposure (HR = 2.21; 95% CI 1.27, 3.86; p = 0.0053) and prior radiotherapy (HR = 2.43; 95% CI 1.37, 4.31; p = 0.0025) were identified as potentially important risk factors for developing LVSD Prior trastuzumab therapy was not associated with the development of LVSD

CI, confidence interval; HR, hazard ratio; LVSD, left ventricular systolic dysfunction

16

Discussion
The proportion of patients in CLEOPATRA who had prior trastuzumab exposure was lower than would be expected based on current clinical practice However, this proportion was consistent with that expected during the trial recruitment period Recruitment into CLEOPATRA began in February 2008, less than 2 years after the first approval of trastuzumab in the adjuvant setting (May 2006) The standard duration of adjuvant trastuzumab treatment is 1 year, and a disease-free interval of 12 months was mandatory for CLEOPATRA, limiting the number of eligible patients who had previously received trastuzumab
First patient in

CLEOPATRA 2006 2007 2008 2009

1 year trastuzumab treatment Adjuvant trastuzumab EU approval 1 year disease-free interval

17

Conclusions
This post-hoc analysis demonstrates that patients with HER2-positive MBC in the first-line setting who had received prior trastuzumab in the (neo)adjuvant setting derive similar benefit in terms of PFS and OS from the combination of pertuzumab, trastuzumab, and docetaxel when compared with the whole study population or patients who are trastuzumab-naive. There is further evidence of the benefit from pertuzumab plus trastuzumab in patients with HER2-positive MBC whose disease had progressed on trastuzumab-based therapy,1,2 and more data including patients previously exposed to trastuzumab are anticipated from the randomized study PHEREXA (NCT01026142),3 and from the single-arm global safety study PERUSE (NCT01572038).4

HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; OS, overall survival; PFS, progression-free survival

1. Baselga J, et al. J Clin Oncol 2010; 28:11381144; 2. Cortes J, et al. J Clin Oncol 2012; 30:15941600; 3. Urruticoechea A, et al. Eur J Cancer 2012; 48(suppl. 1):194; 18 4. Bachelot T, et al. Cancer Res 2012; 72(suppl. 3):OT1-1-02.

Enfermedad HER2-positiva
Abstract 505. Oral abstract session. Phase III, randomized, double-blind,

placebo-controlled multicenter trial of daily everolimus plus weekly

trastuzumab and vinorelbine in trastuzumab-resistant, advanced breast cancer (BOLERO-3). Abstract 517. Poster discussion session. Phase III trial of non-pegylated liposomal doxorubicin (M) in combination with trastuzumab (T) and paclitaxel (P) in HER2+ metastatic breast cancer (MBC).

Phase 3, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and vinorelbine in trastuzumab-resistant, advanced breast cancer (BOLERO-3)
R. M. ORegan, M. Ozguroglu, F. Andr, M. Toi, G. Jerusalem,
S. Wilks, C. Isaacs, B. Xu, N. Masuda, F. Arena, D. Yardley, Y. S. Yap, Y. Zhang, S. Douma, M. El-Hashimy, T. Taran, T. Sahmoud, D. Lebwohl, L. Gianni On behalf of the BOLERO-3 Investigators

BOLERO-3: Study Design

N = 572* Locally advanced or metastatic HER2+ breast cancer Prior taxane required TRAS resistance
Adjuvant: progression on or within 12 months of TRAS Metastatic: progression within 4 weeks of TRAS

Everolimus (5 mg PO daily) + Vinorelbine (25 mg/m2 weekly) + TRAS (2 mg/kg week) (n = 284)

1:1 randomization
Placebo (PO daily) + Vinorelbine (25 mg/m2 weekly) + TRAS (2 mg/kg weekly*) (n = 285)

Therapy until PD or intolerable toxicity

Measurable disease only

Stratification by prior lapatinib use (yes/no)

Endpoints: Primary: PFS Secondary: OS, ORR, time to deterioration of ECOG PS, safety, DoR, CBR, and QoL
* Actual enrollment was 569. Following a 4-mg/kg loading dose on day 1, cycle 1 (1 cycle = every 21 days). Abbreviations: CBR, clinical benefit rate; DoR, Duration of response; ECOG, Eastern Cooperative Oncology Group; HER2, human epidermal growth factor receptor 2; ORR, overall response rate; OS overall survival; PD, progressive disease; PFS, progressive-free survival; PO, oral; PS, performance status; QoL, quality of life.

BOLERO-3: Primary Endpoint

Progression-Free Survival by Local Assessment
100 Hazard ratio = 0.78; 95% CI [0.65, 0.95] Log-rank P value = .0067

80 Probability, %

Median PFS Everolimus: 7.00 months; 95% CI [6.74, 8.18] Placebo: 5.78 months; 95% CI [5.49, 6.90]

60 Censoring times Everolimus (n/N = 196/284) Placebo (n/N = 219/285) 20

40

0 0 6 12 18
200 177

24
161 138

30
126 109

36
98 85

42 48 54 60 Time, weeks
78 64 54 49 40 38 35 26

66
26 23

72
18 19

78
14 16

84
14 12

90
9 10

96 102
5 7 4 4

Number of Patients Still at Risk Everolimus 284 259 233 Placebo 285 253 202
Abbreviations: CI, confidence interval.

BOLERO-3: PFS Subgroup Analyses by Local Assessment

Subgroup
All Age Region < 65 years 65 Europe North America Asia Latin America Other Yes No Yes No 0 1 or 2 ER/PgR ER+/PgR+ Yes No

N
569 472 97 223 123 166 36 21 161 408 251 318 382 186 250 317 439 130

Hazard Ratio [95% CI]

0.78 [0.65-0.95] 0.77 [0.62-0.95] 0.93 [0.56-1.57] 0.72 [0.53-0.99] 0.86 [0.55-1.32] 0.83 [0.59-1.18] 0.61 [0.27-1.38] 1.28 [0.48-3.45] 0.79 [0.56-1.11] 0.78 [0.62-0.99] 0.65 [0.48-0.87] 0.92 [0.71-1.18] 0.79 [0.63-1.00] 0.75 [0.53-1.05] 0.65 [0.48-0.87] 0.93 [0.72-1.20] 0.89 [0.72-1.10] 0.48 [0.30-0.76]

Prior lapatinib
Prior adj/neo trastuzumab Baseline ECOG PS Hormonal status Visceral involvement

Abbreviations: CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status.

Favors EVE

Favors PBO

BOLERO-3: Overall Response

Everolimus + Trastuzumab + Vinorelbine Placebo + Trastuzumab + Vinorelbine

Best Overall Response, % Complete response (CR) Partial response (PR) Stable disease (SD) Progressive disease (PD) Unknown

(N = 284) 3.2 37.7 48.2 4.9 6.0

P value

(N = 285) 2.5 34.7 41.4 13.0 8.4

Overall response rate (CR or PR) 95% CI

Clinical benefit rate (Objective response or SD 24 wks) 95% CI

40.8 35.1, 46.8

59.2 53.2, 64.9

0.2108

37.2 31.6, 43.1

53.3 47.4, 59.2

0.0945

Abbreviation: CI, confidence interval.

BOLERO-3: Most Common Adverse Events

Everolimus Arm (N = 280) Adverse Event, % All Grades Stomatitis 63 Fatigue 43 Pyrexia 39 Diarrhea 38 Nausea 35 Decreased appetite 33 Constipation 30 Rash 25 Hyperglycemia 9 Noninfectious 6 pneumonitis Hyperlipidemia 2 Neutropenia 81 Anemia 49 Febrile neutropenia 17 Thrombocytopenia 14 Grade 3 13 12 3 4 3 1 <1 0 4 <1 0 35 17 11 3 Grade 4 0 <1 0 0 0 0 0 0 2 <1 0 38 2 5 1 Placebo Arm (N = 282) All Grades 28 42 23 31 37 17 31 18 5 3 1 70 29 4 2 Grade 3 1 4 1 1 1 1 <1 1 2 1 0 32 6 3 <1 Grade 4 0 0 0 0 0 0 0 0 1 <1 0 30 <1 1 0

Phase III trial of non-pegylated liposomal doxorubicin (M) in combination with trastuzumab (T) and paclitaxel (P) in HER2+ metastatic breast cancer (MBC)
First-Line HER2+ MBC N = 363
Prior (neo)adjuvant anthra, taxanes, or trastuzumab permitted, if completed >1 year before If prior HT, it had to be discontinued before study entry One measurable lesion per RECIST Normal LVEF, no history of cardiac disease

Trastuzumab 4 mg/kg loading dose,

followed by 2 mg/kg qw

PRIMARY EFFICACY ENDPOINT PFS by independent review PRIMARY CARDIAC ENDPOINT NYHA Class III or IV CHF and cardiac death by independent, blinded CSMC

Paclitaxel 80 mg/m2 qw

1:1 randomization
Trastuzumab 4 mg/kg loading dose,
followed by 2 mg/kg qw

Paclitaxel 80 mg/m2 qw Myocet

50 mg/m2 q3w x 6

STRATIFICATION
Prior anthracycline: yes/no ER/PgR: yes/no Age: 50, >50 Geographic region: NA, EU, ROW

SECONDARY ENDPOINTS OS ORR Asymptomatic LVEF Composite cardiac endpoint (death, CHF, grade 3-4 myocardial ischemia/infarction, grade 3-4 arrhythmia) Other AEs

De la Pena et al.

O v e r a ll S u r v iv a l ( % O v e r a ll S u r v iv a l ( %

Fig. 2A PFS IRC

100

A significant benefit in PFS OS was No significant benefit in and PFS, but a observed trend to in an exploratory of the ER/PR-negative longeranalysis OS was detected population
Fig. 2B OS Final
100

Fig. 4A PFS ER- & PR-

Fig. 4B OS ER- & PR100 80

P F S (% ) P F S (% )

10080

8060

6040 4020
0 0 3 6 9 12 15 18 21

Medians: 16.1 vs 14.5 mon Log-rank p-value = 0.174 HR = 0.837 (95% CI: 0.648-1.082) Medians: 20.7 vs 14.0 mon Log-rank p-value = 0.042 HR = 0.680 (95% CI: 0.468-0.987)

80 60

60 40

PT
24 27 30 33 36

20

Months At risk 0 MPT 181 161 137 110 88 70 58 45 28 20 0 3 6 9 12 15 18 21 24 27 PT 182 156 134 111 88 69 53 40 31 22 Months At risk
MPT PT 89 88 82 76 71 65 59 55 50 44 42 33 33 21 27 17 16 14 9 9

PT

39

MPT MPT
42

45

Medians: 33.6 vs 29.0 mon Log-rank p-value = 0.083 HR = 0.793 (95% CI: 0.610-1.031) 40 20 Medians: 38.2 vs 27.9 mon Log-rank p-value = 0.018 0 20 HR = 0.627 (95% CI: 0.424-0.926)
0 6 12 18 24

MPT

MPT PT PT
36 42 48 54 60 66

30

15 30 14

9 33 7

5 36 3

3 39

42

45

Months At risk 0 MPT 181 161 147 130 105 86 67 46 29 0 6 12 18 24 30 36 42 48 PT 182 162 144 122 103 73 49 29 18 Months At risk
MPT PT 89 88 80 75 74 66 65 56 55 46 45 31 37 21 26 14 16 10

11 54 8

60

3 1

66

8 5

3 4

2 2

6 4

In terms of RR, the benefit was comparable in the two treatment arms (67% vs. 62%), while response duration was numerically longer in the MTP arm (18.1 months vs. 15.3 months).
MTP = non-pegylated liposomal doxorubicin + trastuzumab + paclitaxel, TP = trastuzumab + paclitaxel, HR = hazard ratio, RR = response rate.

The MTP combination demonstrated a favorable cardiac safety profile

Incidence of NYHA Class III/IV CHF per the blinded review of the CSMC:
3% in the MTP arm 1% in the control arm

No cardiac deaths in the MTP group per blinded central assessment No reports of grade 3-4 myocardial ischemia/infarction, or grade 3-4 arrhythmia in either treatment arm

CSMC = cardiac safety monitoring committee

QT adyuvante

Time trends in the use of chemotherapy and outcomes in women with T1a,b N0 M0 BC in the NCCN

Mediana de seguimiento: 5,5 aos.

Time trends in the use of chemotherapy and outcomes in women with T1a,b N0 M0 BC in the NCCN

QT Neoadyuvante

CALGB 40601: Phase III Trial of Lapatinib Added to Neoadjuvant Therapy of HER2+ Breast Cancer

ACOSOG Z1041 (Alliance): Definitive Analysis of a Randomized Neoadjuvant Trial Comparing FEC Followed by Paclitaxel Plus Trastuzumab with Paclitaxel Plus Trastuzumab Followed by FEC Plus Trastuzumab in HER2+ Operable Breast Cancer

ACOSOG Z1041 (Alliance): Definitive Analysis of a Randomized Neoadjuvant Trial Comparing FEC Followed by Paclitaxel Plus Trastuzumab with Paclitaxel Plus Trastuzumab Followed by FEC Plus Trastuzumab in HER2+ Operable Breast Cancer

Follow-up results of NOAH, a randomized phase III trial evaluating neoadjuvant chemotherapy with trastuzumab followed by adjuvant H versus CT alone, in patients with HER2-positive locally advanced breast cancer