A Phase III, Randomized, Double-Blind, Placebo-Controlled Registration Trial to Evaluate the Efficacy and Safety of Placebo + Trastuzumab + Docetaxel vs.Pertuzumab + Trastuzumab + Docetaxelin Patients with Previously Untreated HER2-Positive Metastatic Breast Cancer (CLEOPATRA)

J Baselga, J Cortés, S-B Kim, S-A Im,

R Hegg, Y-H Im, L Roman, J L Pedrini, T Pienkowski, A Knott, E Clark, M C. Benyunes, G Ross, and S M Swain

1. Baselga et al. N Engl J Med 2011

2

HER2, human epidermal growth factor receptor 2;MBC, metastatic breast cancer

1. Slamon et al. N Engl J Med 2001; 2. Nahta & Esteva Oncogene 2007;3. Franklin et al. Cancer Cell 2004; 4. Baselga et al. J Clin Oncol 2010;

5. Gianni et al. Cancer Res 2010 Suppl 2; 6. Baselga & Swain Clin Breast Cancer 2010

Introduction and study objective

• Trastuzumab-based therapy is the current standard of care inHER2-positive MBC1

– However, progression of breast cancer still occurs in a majority of patients2

• Pertuzumab is a humanized monoclonal antibody and HER2 dimerization inhibitor that binds HER2 at a different epitope than trastuzumab3

• Phase II trials in patients with HER2-positive breast cancer have shown improved activity, and a good safety profile with pertuzumab-trastuzumab-based therapy4,5

• CLEOPATRA assessed efficacy and safety of a pertuzumab-trastuzumab-based regimen in first-line treatment of patients with HER2-positive MBC6

3

Study design

MBC, metastatic breast cancer; PD, progressive disease

Patients withHER2-positive MBCcentrally confirmed

(N=808)

Placebo + trastuzumab

1:1

• Randomization was stratified by geographic region and prior treatment status (neo/adjuvant chemotherapy received or not)

• Study dosing q3w:- Pertuzumab/Placebo: 840 mg loading dose, 420 mg maintenance- Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance - Docetaxel: 75 mg/m2, escalating to 100 mg/m2 if tolerated

Docetaxel*≥6 cycles

recommended

n=406

n=402

Pertuzumab + trastuzumab

Docetaxel*≥6 cycles

recommended

*<6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at investigator discretion

PD

PD

4

Key patient eligibility criteria

• Centrally confirmed HER2-positive (IHC 3+ and/or FISH-positive; ratio ≥2.0) locally recurrent, unresectable, or metastatic breast cancer

• Measurable and/or non-measurable disease

• LVEF ≥50% at baseline

• No more than one hormonal regimen for MBC prior to randomization

• (Neo)adjuvant systemic breast cancer chemotherapy including trastuzumab and/or taxanes allowed if followed by a disease-free interval of ≥12 months

• No history of CHF or LVEF decline to <50% during or after prior trastuzumab therapy

CHF, congestive heart failure; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; LVEF, left ventricular ejection fraction;MBC, metastatic breast cancer

5

Study endpoints

• Primary endpoint– Independently assessed progression-free survival (PFS)

• Secondary endpoints

– Overall survival

– Objective response rate

– Safety

– PFS by investigator assessment

– Duration of response

– Evaluation of biomarkers and correlation with clinical outcomes

– Time to symptom progressionBaselga et al. Clin Breast Cancer 2010.

6

Statistics

• Progression-free survival– 800 patients and ~381 PFS events were required to

provide 80% power to detect a 33% improvement in independently assessed PFS(HR = 0.75) at the two-sided significance level of 5%

• Overall survival– 800 patients and 385 OS events were required to provide

80% power to detect a 33% improvement in OS (HR = 0.75) at the two-sided significance level of 5%

– The interim OS analysis (estimated at 50% of events for final analysis) was planned at the time of the primary independently assessed PFS analysis

OS, overall survival; PFS, progression-free survival

7

Baseline characteristics (I)

ECOG PS, Eastern Cooperative Oncology Group performance status

Placebo+ trastuzumab +

docetaxel(n = 406)

Pertuzumab+ trastuzumab +

docetaxel(n = 402)

Median age, years(range)

54.0 (27–89)

54.0 (22–82)

Region, n (%) Asia Europe North America South America

128 (31.5)152 (37.4)68 (16.7)58 (14.3)

125 (31.1)154 (38.3)67 (16.7)56 (13.9)

ECOG PS, n (%) 0 1 ≥2

248 (61.1)157 (38.7)

1 (0.2)

274 (68.2)125 (31.1)

3 (0.7)

8

Baseline characteristics (II)

ER, estrogen receptor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; PgR, progesterone receptor

Placebo+ trastuzumab +

docetaxel(n = 406)

Pertuzumab+ trastuzumab +

docetaxel(n = 402)

HER2 status IHC, n (%) 0 and 1+ 2+ 3+ No data

2 (0.5)32 (7.9)

371 (91.4)1 (0.2)

4 (1.0)47 (11.7)350 (87.1)

1 (0.2)

HER2 status FISH, n (%) Positive Negative No data

383 (94.3)4 (1.0)19 (4.7)

384 (95.5)1 (0.2)17 (4.2)

Hormone receptor status, n (%) ER- and/or PgR-positive ER- and PgR-negative Unknown

199 (49.0)196 (48.3)11 (2.7)

189 (47.0)212 (52.7)

1 (0.2)

Disease type at screening, n (%) Non-visceral Visceral

90 (22.2)316 (77.8)

88 (21.9)314 (78.1)

9

Prior therapy for breast cancer

Placebo+ trastuzumab

+ docetaxel(n = 406)

Pertuzumab+ trastuzumab

+ docetaxel(n = 402)

Prior (neo)adjuvant chemotherapy, n (%) Yes No

192 (47.3)214 (52.7)

184 (45.8)218 (54.2)

Prior (neo)adjuvant chemotherapy received, n (%)Components of (neo)adjuvant therapy*, n (%) Anthracycline Hormones Taxane Trastuzumab

192 (100)

164 (85.4) 97 (50.5) 94 (49.0) 41 (21.4)

184 (100)

150 (81.5) 106 (57.6) 91 (49.5) 47 (25.5)

* Numbers add up to more than 100% because patients could have received more than one therapy

Efficacy results

11Stratified by prior treatment status and region

Primary endpoint: Independently assessed PFSMedian follow-up: 19.3 months

D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab

0 5 10 15 20 25 30 35 40

0

10

20

30

40

50

60

70

80

90

100

n at risk 402 345 267 139 83 32 10 0 0Ptz + T + D

406 311 209 93 42 17 7 0 0Pla + T + D

Time (months)

Ptz + T + D: median 18.5 monthsPla + T + D: median 12.4 months

HR = 0.6295% CI 0.51‒0.75

p<0.0001

∆ = 6.1 months

Pro

gre

ssio

n-f

ree s

urv

ival

(%)

12

Independently assessed PFS in pre-defined subgroups

ER, estrogen receptor; IHC, immunohistochemistry; FISH, fluorescence in situ hybridization;PgR, progesterone receptor; PFS, progression-free survival

All

NoYes

EuropeNorth AmericaSouth America

Asia

<65 years≥65 years

<75 years≥75 years

WhiteBlackAsianOther

Visceral diseaseNon-visceral

diseasePositive

NegativeUnknown

IHC 3+FISH-positive

Favors placeboFavors pertuzumab

0 1 2 30.5

ER/PgR status

Disease type

Race

Age group

Region

Prior (neo)adjuvant chemotherapy

HER2 status

Unstratified analyses

808 0.63 0.52‒0.76

432 0.63 0.49‒0.82376 0.61 0.46‒0.81

306 0.72 0.53‒0.97135 0.51 0.31‒0.84114 0.46 0.27‒0.78253 0.68 0.48‒0.95

681 0.65 0.53‒0.80127 0.52 0.31‒0.86789 0.64 0.53‒0.7819 0.55 0.12‒2.54

480 0.62 0.49‒0.8030 0.64 0.23‒1.79261 0.68 0.49‒0.9537 0.39 0.13‒1.18

630 0.55 0.45‒0.68178 0.96 0.61‒1.52

388 0.72 0.55‒0.95408 0.55 0.42‒0.72

12 - -

721 0.60 0.49‒0.74767 0.64 0.53‒0.78

n HR 95% CI

13

Overall survival: Pre-defined interim analysisMedian follow-up: 19.3 months, n = 165 OS events

D, docetaxel; OS, overall survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab

0 5 10 15 20 25 30 35 40 45

0

10

20

30

40

50

60

70

80

90

100

n at risk

Ptz + T + D 402 387 367 251 161 87 31 4 0 0

406 383 347 228 143 67 24 2 0 0Pla + T + D

Time (months)

Ptz + T + D: 69 eventsPla + T + D: 96 events

HR = 0.64*95% CI 0.47‒0.88

p = 0.0053*

* The interim overall survival analysis did not cross the pre-specified O’Brien-Fleming stopping boundary (HR ≤0.603; p≤0.0012)

Overa

ll s

urv

ival (%

)

14

Independently reviewed objective responseIn patients with measurable disease at baseline

Placebo+ trastuzumab +

docetaxel(n = 336)

Pertuzumab+ trastuzumab +

docetaxel(n = 343)

Objective response rate, n (%)

Complete response rate, n (%)

Partial response rate, n (%)

233 (69.3)

14 (4.2)

219 (65.2)

275 (80.2)

19 (5.5)

256 (74.6)

p = 0.0011*

Stable disease, n (%) 70 (20.8) 50 (14.6)

Progressive disease, n (%) 28 (8.3) 13 (3.8)

Unable to assess or no assessment, n (%)

5 (1.5) 5 (1.5)

* The statistical test result is deemed exploratory

Exploratory efficacy results

By prior trastuzumab therapy

16

PFS, progression-free survival

Independently assessed PFS by prior trastuzumab therapy in patients with (neo)adjuvant therapy

Placebo+ trastuzumab +

docetaxelMedian PFS, months

Pertuzumab+ trastuzumab +

docetaxelMedian PFS, months

Hazard ratio(CI)

Prior (neo)adjuvant trastuzumab treatment(n = 88)

10.4 16.90.62

(0.35‒1.07)

No prior (neo)adjuvant trastuzumab treatment(n = 288)

12.6 21.60.60

(0.43‒0.83)

Safety results

18

Withdrawals from study treatment in the safety population

* Protocol violation, failure to return, or other

Placebo+ trastuzumab +

docetaxel(n = 397)

Pertuzumab+ trastuzumab +

docetaxel(n = 407)

Safety reasons, n (%)

Adverse event Death

31 (7.8)

2011

30 (7.4)

237

Non-safety reasons, n (%)

Progressive disease Refused treatment Other*

248 (62.5)

227183

203 (49.9)

180167

Total, n (%) 279 (70.3) 233 (57.2)

19

Exposure to study treatment

Placebo+ trastuzumab

+ docetaxel(n = 397)

Pertuzumab+ trastuzumab

+ docetaxel(n = 407)

Study treatment Time on any treatment (median), months

11.8 18.1

Docetaxel Dose intensity (median), mg/m2/week Number of cycles administered, median (range)

24.88 (1‒41)

24.68 (1‒35)

20

Cardiac tolerability

LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction

Pertuzumab

+ trastuzumab + docetaxel(n = 407)

Placebo+ trastuzumab + docetaxel

(n = 397)

LVSD (any grade) 4.4% 8.3%

LVSD (grade >3) 1.2% 2.8%

Fall in LVEF to <50% and by ≥10 percentage points from baseline

3.8% 6.6%

21

Adverse events (all grades)≥25% incidence or ≥5% difference between arms

Adverse event, n (%)

Placebo+ trastuzumab +

docetaxel(n = 397)

Pertuzumab+ trastuzumab +

docetaxel(n = 407)

Diarrhea 184 (46.3) 272 (66.8)

Alopecia 240 (60.5) 248 (60.9)

Neutropenia 197 (49.6) 215 (52.8)

Nausea 165 (41.6) 172 (42.3)

Fatigue 146 (36.8) 153 (37.6)

Rash 96 (24.2) 137 (33.7)

Decreased appetite 105 (26.4) 119 (29.2)

Mucosal inflammation 79 (19.9) 113 (27.8)

Asthenia 120 (30.2) 106 (26.0)

Peripheral edema 119 (30.0) 94 (23.1)

Constipation 99 (24.9) 61 (15.0)

Febrile neutropenia 30 (7.6) 56 (13.8)

Dry skin 17 (4.3) 43 (10.6)

22

Grade ≥3 adverse events (incidence ≥5%)

Adverse event, n (%)

Placebo+ trastuzumab +

docetaxel(n = 397)

Pertuzumab+ trastuzumab +

docetaxel(n = 407)

Neutropenia 182 (45.8) 199 (48.9)

Febrile neutropenia 30 (7.6) 56 (13.8)

Leukopenia 58 (14.6) 50 (12.3)

Diarrhea 20 (5.0) 32 (7.9)

23

Conclusions

• The combination of pertuzumab with trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects.