Breast Cancer Highlights From San Antonio

Breast Cancer Highlights From San Antonio

Joyce O'Shaughnessy, MDKimberly Blackwell, MD

Hope Rugo, MD

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Updates on Chemotherapy and Other Novel Agents

Joyce O'Shaughnessy, MD

Adjuvant Chemotherapy

CALOR: Adjuvant Chemotherapy for Isolated Local or Regional Recurrence

• Rationale:– Isolated local or regional recurrence (ILRR) of breast cancer has a poor prognosis– No randomized studies of adjuvant chemotherapy for ILRR have been published

in the last 30 years– Objective: Evaluate the effect of adjuvant chemotherapy on patients with ILRR

• CALOR study design:

– Chemotherapy chosen by investigators– Recommendation: at least 2 drugs, 3-6 months of therapy

Aebi et al., SABCS 2012; abstract S3-2

Eligibility criteria:• First ILRR• Complete gross excision of recurrence

•No evidence of positive supraclavicular LNs

•No evidence of distant metastasis

Adjuvant chemotherapy

RANDOMIZE

(N=162)

No chemotherapy

+ Endocrine therapy for HR-positive disease

+ HER2-directed therapy (optional)

+ Radiation therapy (mandatory for those with positive margins)

Primary endpoint: DFSSecondary endpoint: OS


• Sample size:– Original target was 977 patients and HR = 0.74– Amended in 2008; target was 265 patients and HR = 0.60– Actual enrollment: 162 patients

• Results:


Site of first failure (after ILRR)Chemotherapy*

(n=85)No chemotherapy*

(n=77)

Total failures 24 34Local/regional 6 (25%) 9 (26%)

Distant Soft tissue Bone Viscera

15 (63%)087

22 (65%)25

15

Contralateral breast 1 (4%) 1 (3%)

Secondary non-breast malignancy 1 (4%) 0

Deaths without failure 1 (4%) 2 (6%)

* 42% of patients in the chemotherapy arm and 32% in the no-chemotherapy arm had not received previous chemotherapy. The median time from primary surgery to ILRR was 5 and 6 years, respectively.


• Efficacy results:

– Multivariate analysis showed treatment (chemo/no chemo) to have significant impact on both DFS (HR = 0.50; P = .01) and OS (HR = 0.37; P = .02)


Survival ChemotherapyNo

chemotherapy HR (95% CI) P-value

5-yr DFS ER-positive ER-negative

69%70%67%

57%69%35%

0.59 (0.35-0.99)0.94 (0.47-1.89)0.32 (0.14-0.73)

.046.87

.007

5-yr OS ER-positive ER-negative

88%94%79%

76%80%69%

0.41 (0.19-0.89)0.40 (0.12-1.28)0.43 (0.15-1.24)

.02

.12

.12

UK TACT2: Comparison of Standard vs Accelerated Epirubicin in Early Breast

Cancer• The objective was to test the following 2 hypotheses:

– Acceleration of anthracycline chemotherapy offers improved efficacy (these results presented here)

– Capecitabine has similar efficacy but less toxicity compared with CMF• UK TACT2 Phase III trial with 2x2 factorial study design:

Cameron et al., SABCS 2012; abstract S3-3

RANDOMIZATION

(N=4391)

CMF600/40/600 mg/m2

IV bolus, days 1 & 8 or 100/40/600 mg/m2 PO, days 1-14, for 4 cycles

Capecitabine (X)2500 mg/m2 bid, days 1-14, for 4 cycles

Standard epirubicin (E) 100 mg/m2, q3w, for 4 cycles

followed by:

CMF600/40/600 mg/m2

IV bolus, days 1 & 8 or 100/40/600 mg/m2 PO, days 1-14, for 4 cycles

Capecitabine (X)2500 mg/m2 bid, days 1-14, for 4 cycles

Accelerated epirubicin (aE)100 mg/m2, q2w, for 4 cyclesPegfilgrastim 6 mg on day 2

followed by:

Primary endpoint: TTR (time to tumor recurrence)Secondary endpoints: DFS, OS, toxicity, QOL

UK TACT2: Comparison of Standard vs Accelerated Epirubicin in Early Breast

Cancer• Safety results:


– There were 167 breast cancer deaths in the E arm and 179 in the aE arm


Grade 3/4 AEsStandard E

(n=2221)Accelerated E

(n=2170)

Hand-foot syndrome 0% 0.9%

Leukopenia 3.8% 1.0%

Neutropenia 16.4% 1.7%

Febrile neutropenia 3.6% 1.4%

Outcome Standard E Accelerated E HR (95% CI) P-value3-year TTR 90.9% 91.0% 0.96

(0.81-1.13) .605-year TTR 85.2% 86.4%

3-year OS 95.4% 94.4% 1.13(0.93-1.37) .23

5-year OS 89.3% 88.6%

10-Year Follow Up of Intense Dose-Dense Chemotherapy vs. Conventional

Chemotherapy in High-Risk Patients with ≥4 Positive LNs• Rationale: There are no published reports of long-term survival and toxicity data

with dose-dense regimens

• Objective: Confirm the Norton-Simon hypothesis of dose density and evaluate the safety of epoetin alfa as primary prophylaxis

• Study design:

Moebus et al., SABCS 2012; abstract S3-4

epirubicin 150 mg/m2

q2w x 3paclitaxel 225 mg/m2

q2w x 3

cyclophosphamide 2500 mg/m2

q2w x 3

+ tamoxifen

+ tamoxifenEC 90/600 mg/m2

q3w x 4paclitaxel 175 mg/m2

q3w x 4

G-CSF ± epoetin alfa

RANDOMIZE

(N=1284)

Primary endpoint: RFSSecondary endpoint: OS, QOL, toxicity

10-Year Follow Up of Intense Dose-Dense Chemotherapy vs. Conventional

Chemotherapy in High-Risk Patients with ≥4 Positive LNs


– No therapy-related death or long-term toxicity was observed with iddETC

• Transfusion results:

– Negative impacts of epoetin alfa on RFS and OS were not observed

Moebus et al., SABCS 2012; abstract S3-4

Outcome IDD-ETC EC→T HR (95% CI) P-value10-yr RFS 56% 47% 0.74 (0.63-0.87) .0001410-yr OS 4-9 positive LNs 10+ positive LNs

69%74%62%

59%66%48%

0.72 (0.60-0.87)0.77 (0.59-1.01)0.66 (0.51-0.86)

.0007.06

.0016

Transfusion-related outcomesIDD-ETC(n=324)

IDD-ETC + EPO

(n=319)P-value

Median hemoglobin (g/dL) -- -- < .001 (favoring +EPO arm)Need for ≥1 transfusion 28% 13% < .0001Patients with venous thrombotic event 7% 13% .029

BEATRICE: Phase III Trial of Adjuvant Bevacizumab in Triple-Negative Breast

Cancer


• BEATRICE study design

Eligibility criteria:•Resected triple-negative (centrally confirmed) invasive early breast cancer

4-8 cycles of standard chemotherapy (investigator’s choice)R

ANDOMIZE

(N=2591)

4-8 cycles of standard chemotherapy (investigator’s choice) + bevacizumab 5 mg/kg/wk equivalent for 1 year duration

Chemotherapy options:•Taxane-based (≥4 cycles)•Anthracycline-based (≥4 cycles)•Anthracycline + taxane (3-4 cycles each)

Primary endpoint: DFSSecondary endpoints: OS, breast cancer-free interval, DFS, distant DFS, safety, biomarkers


Cancer


• Efficacy results

– None of the subgroups examined (age, baseline ECOG performance status, region, race, menopausal status, tumor size, # of positive LNs, adjuvant chemotherapy, HR status, and surgery) showed a significant effect on invasive DFS

• Safety results

OutcomeChemo alone

(n=1290)Chemo + bevacizumab

(n=1301) HR (95%CI) P-value

3-yr invasive DFS 82.7% 83.7% 0.87 (0.72-1.07) .18

OS -- -- 0.84 (0.64-1.12) .23

Adverse eventsChemo alone

(n=1271)Chemo + bevacizumab

(n=1288)

Any AE Grade ≥3 AE Grade 5 AE

99%57%0.2%

99%72%0.3%

AE leading to chemo and/or bev discontinuation AE leading to bev discontinuation

2%--

20%18%


Cancer


• Grade ≥3 AEs of special interest by treatment phase

– 5%-8% of patients taking bevacizumab + an anthracycline-based regimen experienced an LVEF decline, and ~1% experienced class III/IV CHF. Over 80% of these AEs resolved at the time of data cut-off

Adverse eventsChemotherapy phase Observation/bev only phase

Chemo Chemo + bev Chemo Chemo + bev

All grade ≥3 AEs of special interest 3% 11% <1% 9%

Arterial thrombotic event <1% <1% <1% <1%

Venous thromboembolic event 1% 2% <1% <1%

Bleeding <1% <1% <1% 0

CHF/left ventricular dysfunction <1% <1% <1% 2%

Hypertension <1% 7% <1% 5%

Fistula/abscess <1% 0 0 <1%

Gastrointestinal perforation 0 <1% 0 0

Proteinuria <1% <1% 0 2%

RPLS 0 <1% 0 <1%

Wound-healing complication <1% <1% 0 <1%

BEATRICE Trial: Biomarker Results

Baseline Plasma Concentration HR* P-ValueMedian VEGF-AHigh 0.81

.7415Low 0.89

3rd Quartile VEGF-AHigh 0.64

.3551Low 0.92

Median VEGFR-2High .61

.0291Low 1.24

• Biomarker analysis performed to investigate potential predictive markers of benefit from adjuvant bevacizumab

• Sub-study included 45% of total patient population• Evaluated correlation of biomarkers with invasive disease-free survival

* HR <1.0 indicates CT plus Bev better than CT alone

Carmeliet et al., SABCS 2012; abstract P3-06-34

NCCN Analysis of Leukemia Diagnoses in Breast Cancer Patients

• Rationale:– Adjuvant therapy provides great benefit but also infrequently causes leukemia

• Objective:– Examine the incidence of leukemia among breast cancer survivors– Identify clinical characteristics of women with breast cancer who develop leukemia

Karp et al., SABCS 2012; abstract S3-5

Prior history of cancern=1715

First diagnosis of breast cancern=20,533

Stage I-III breast cancer diagnosis at NCCN (July 1997 – Dec 2008)

N=22,248

Died while being followed at NCCN

n=455

Patients with leukemia

n=51; 0.25%

Censored at first date of other cancer event

n=3935

Censored at date of last NCCN contact

n=16092

Patients without leukemia, n=20,482

excluded



Patient characteristicNo leukemia

(n=20,482)Leukemia

(n=51) P-valueMedian age 53.9 years 60.2 years .02Race White African American Other

87%8%5%

92%6%2%

.72

Surgery Breast conservation Mastectomy None

57%42%1%

55%45%

0.85

Radiation therapy After breast conservation or none After mastectomy None

54%17%29%

55%24%22%

.32

Chemotherapy “A and/ or C”* 4 cycles 6 cycles None or endocrine therapy only

51%11%38%

61%12%27%

.31

Local and systemic therapy Radiation but no chemotherapy Chemotherapy but no radiation Chemotherapy and radiation None

25%16%46%13%

24%18%55%4%

.22

*Chemotherapy Regimens Included:4 Cycles: AC or EC, FA50C or FE100C, TC6 Cycles: CMF, CAF, TAC, FA50C or FE100C

• Characteristics of leukemia cohort:

• Hazard ratios for risk of developing leukemia:

• Incidence of developing leukemia:– 0.32% at 5 years– 0.52% at 10 years


Event n Median time to leukemiaLeukemia 51 3.3 years

Myeloid leukemia (with cytogenetics) 40 3.5 years

Lymphoid leukemia 7 2.0 years


Risk factor HR P-valueRadiation vs. no radiation 1.29 (0.66-2.54) .46Chemotherapy vs. no chemotherapy 2.51 (1.29-4.9) .007

Chemotherapy + radiation vs. chemotherapy only or radiation only

1.59 (0.88-2.88) .127

Metastatic Breast Cancer

Phase III Trial of Eribulin vs. Capecitabine in Previously Treated Advanced Breast

Cancer

Kaufman et al., SABCS 2012; abstract S6-6

• Study 301 global, open-label design

Eligibility criteria:• Locally advanced or

metastatic breast cancer• 0-3 prior chemotherapies

(≤ 2 for advanced disease)• Prior anthracycline and

taxane• Refractory to most recent

chemotherapy

Eribulin 1.4 mg/m2, days 1 & 8, q3wRANDOMIZE

(N=1102)

Capecitabine 1250 mg/m2 BID PO, days 1-14, q3w

Primary endpoint: OS and PFSSecondary endpoints: QOL, ORR, duration of response, 1-, 2-, 3-yr survival rates, tumor-related symptom assessments, safety parameters, population PK

Final analysis declared positive if either eribulin OS significantly better than capecitabine OS or eribulin PFS significantly better than capecitabine PFS and if OS HR < 1.0


Cancer


• Study 301 efficacy results

– Pre-specified exploratory analyses suggest that 3 subgroups may have increased therapeutic benefit with eribulin: Triple-negative (HR 0.70, 0.55-0.91)

ER-negative (HR 0.78, 0.64-0.96) HER2-negative (HR 0.84, 0.72-0.98)

Outcome Eribulin(n=554)

Capecitabine(n=548) HR (95%CI) P-value

Median PFS (independent review) (investigator review)

4.1 months4.2 months

4.2 months4.1 months

1.08 (0.93-1.25)0.98 (0.86-1.11)

.31

.74

Median OS 15.9 months 14.5 months 0.88 (0.77-1.003) .056

3-yr OS 17.8% 14.5% -- .18

Objective response rate (independent review) (investigator review)

11%16%

12%20%

----

.850.10

Clinical benefit rate (independent review) (investigator review)

26%33%

27%34%

----

----


Cancer


• Study 301 safety results

Adverse eventsEribulin(n=544)

Capecitabine(n=546)

Any AEsTreatment-related AEsSerious AEs

94.1%84.6%17.5%

90.5%77.1%21.1%

Fatal AEsTreatment-related fatal AEs

4.8%0.9%

6.6%0.7%

Treatment-related AEs leading to: Discontinuation of treatment Dose reduction Dose delay

5.7%31.1%22.8%

6.2%31.3%29.3%


Cancer


• Study 301 hematologic AEs

Hematologic AEs

Eribulin(n=544)

Capecitabine(n=546)

All grades Grade 3 Grade 4 All grades Grade 3 Grade 4

Neutropenia 54% 25% 21% 16% 4% <1%

Leukopenia 31% 13% 2% 10% 2% <1%

Anemia 19% 2% 0 18% <1% <1%

Thrombocytopenia 5% <1% 0 6% <1% <1%

Febrile neutropenia 2% 2% <1% <1% <1% <1%


Cancer


• Study 301 non-hematologic AEs

Non-hematologic AEsEribulin (n=544) Capecitabine (n=546)

All grades Grade 3 Grade 4 All grades Grade 3 Grade 4

Hand-foot syndrome <1% 0 0 45% 14% 0

Alopecia 35% - - 4% - -

Diarrhea 14% 1% 0 29% 5% <1%

Nausea 22% <1% 0 24% 2% 0

Vomiting 12% <1% <1% 17% 2% 0

Fatigue 17% 2% 0 15% 2% <1%

Asthenia 15% 4% <1% 15% 4% 0

Decreased appetite 13% <1% 0 15% 2% 0

Peripheral sensory neuropathy 13% 4% 0 7% <1% 0

Pyrexia 13% <1% 0 6% <1% 0

Headache 13% <1% 0 10% <1% <1%

Dyspnea 10% 2% <1% 11% 3% <1%

Back pain 10% 2% 0 8% <1% 0

Phase II Trial of Eribulin Mesylate as First-Line Therapy for HER2- Locally

Recurrent or Metastatic Breast Cancer• Eribulin: 1.4 mg/m2 days 1, 8 every 3 weeks• 48 patients enrolled

All Patients(n=48)

ER+(n=35)

ER-/PR-/HER2-(n=10)

CR 0 0 0

PR 27% 29% 30%

ORR 27% 29% 30%

SD 48% 54% 30%

CBR * 46% 54% 30%

Median PFS 5.9 months 6.7 months 4.7 months

TTR 1.4 months 1.4 months 2.9 months

DOR 7.4 months 7.4 months Not Evaluable

Vahdat et al., SABCS 2012; abstract P1-12-02

* CBR = CR + PR + durable SD

Retrospective Analysis of nab-Paclitaxel as First-Line Therapy for MBC with Poor

Prognostic Factors• Retrospective analysis of the efficacy and safety of patients with poor

prognostic factors (DFI ≤ 2 years or visceral-dominant metastases) who received first-line treatment in 2 previous randomized trials.

ORRVisceral-Dominant Metastases Short DFI

Study CA012

nab-Paclitaxel (260 mg/m2 q3w) 42% (P=.022) 43%

Paclitaxel (175 mg/m2 q3w) 23% 33%

Study CA024

nab-Paclitaxel (300 mg/m2 q3w) 44% 35%

nab-Paclitaxel (100 mg/m2 qw 3/4) 63% 52%

nab-Paclitaxel (150 mg/m2 qw 3/4) 76% 64%

Docetaxel (100 mg/m2 q3w) 37% 21%

P<.001P=.002

P<.001

P=.020

O’Shaughnessy et al., SABCS 2012; abstract P1-12-07

Retrospective Analysis of nab-Paclitaxel as First-Line Therapy for MBC with Poor

Prognostic FactorsMedian PFS (months)

Visceral-Dominant Metastases

Short DFI

Study CA012

nab-Paclitaxel (260 mg/m2 q3w) 5.6 5.0

Paclitaxel (175 mg/m2 q3w) 3.8 3.5

HR (P-Value) 0.717 (P=.094) 0.729 (P=.220)

Study CA024

nab-Paclitaxel (300 mg/m2 q3w) 10.9 7.4

nab-Paclitaxel (100 mg/m2 qw 3/4) 7.5 7.3

nab-Paclitaxel (150 mg/m2 qw 3/4) 13.1 14.1

Docetaxel (100 mg/m2 q3w) 7.8 5.5

HR (P-Value) C vs D: 0.600 (P=.019)B vs C: 1.731 (P=.010)

Overall P=.049

All NS

O’Shaughnessy et al., SABCS 2012; abstract P1-12-07

Impact of BRCA1/2 Mutation Status on Response to Platinum-Based Chemotherapy in

Triple-Negative Breast Cancer in the TBCRC009 Trial

• The TBCRC009 phase II trial evaluated single-agent cisplatin or carboplatin as first- or second-line therapy for metastatic TNBC

• 6 patients (7%) are long-term survivors who achieved durable responses and remain off all therapy (22+ - 53+ months); all of these patients are BRCA1/2 WT (5) or unknown (1), and received platinum therapy as first-line treatment for MBC

All Patientsn=86

BRCA1/2 Positive

n=11

BRCA1/2 WTn=65

Unknown n=10

ORR 30.2% 54.6%* 26.2% 30%

Median PFS 88 days 96 days 86 days --

* P=.079 versus BRCA1/2 WT

Isakoff et al., SABCS 2012; abstract PD-09-03

Neoadjuvant Chemotherapy

Neoadjuvant Chemotherapy in Breast Cancer Patients ≤ 35 Years Old

• Rationale:– Previous studies have shown that patients who are diagnosed with

breast cancer at a young age have distinctly different disease characteristics, including pCR rate,1 biomarker profile,2 and prognosis3,4

– Objective: Compare the impact of age on pCR (pathologic complete response) rate, DFS, LRFS (local recurrence-free survival), and OS in patients receiving neoadjuvant chemotherapy for breast cancer

• Study design:– A meta-analysis was performed on 8 neoadjuvant trials describing

almost 9000 patients– Patients were divided into 3 age groups:

• ≤ 35 (n=704) • 36-50 (n=4167)• ≥ 51 (n=4078) 1Huober et al. Breast Cancer Res Treat. 2010;124:133-40

2Colleoni et al. Ann Oncol. 2002;13:273-93Kroman et al. BMJ. 2000;320:474-8

4Anders et al. J Clin Oncol. 2008;26:3324-30Loibl et al., SABCS 2012; abstract S3-1

Neoadjuvant Chemotherapy in Breast Cancer Patients ≤ 35 Years Old

• pCR rate results:– pCR rates were significantly higher in patients ≤35

years old (23.6%) compared with those 36-50 (17.5%) and with those ≥ 51 (13.5%; P < .0001)

– Age was an independent predictor of pCR for those patients with HR-positive, HER2-negative or triple-negative (TNBC) tumors

– For patients ≤35 years old with HR-positive, HER2-negative tumors, a pCR predicted better DFS

Loibl et al., SABCS 2012; abstract S3-1

pCR rate Age ≤ 35 vs. age ≥ 51

Overall P = .002HR+/HER2- P = .013

HR+/HER2+ P = .73

HR-/HER2+ P = .61

TNBC P = .004

Survival Age ≤ 35 vs. age 36-50

Age 36-50 vs. age ≥ 51

Age ≤ 35 vs. age ≥ 51

DFS P = .031 P = .057 P = .022LRFS P = .017 P = .024 P = .00018

OS P = .22 P = .14 P = .64

• Survival results:– Very young patients had

significantly worse DFS and LRFS, but not OS, when compared with either of the older age groups

Clinical Implications

• ‘Adjuvant’ chemotherapy may benefit ER-negative patients with treated locoregional recurrence

• Leukemia risk may be 0.5% at 10 years after adjuvant anthracycline or cyclophosphamide chemotherapy

• Eribulin effective after A/T early in MBC treatment. Efficacy in TNBC promising

• First-line eribulin is safe and active• Nab-paclitaxel retains efficacy in poor-prognosis MBC

patients• Platinum has activity in mTNBC and some first-line patients

can have very durable response

Advances in the Treatment of ER+ Breast Cancer

Kimberly Blackwell, MD

Adjuvant Therapy

Relative Effectiveness of Letrozole vs Tamoxifen for Lobular Cancer in BIG 1-98

Cohort• Rationale:

– Most classic lobular carcinoma is HR-positive and HER2-negative– However, limited data are available regarding the use of letrozole in

classic lobular cancers– Objective: Evaluate the effectiveness of adjuvant letrozole

compared with adjuvant tamoxifen in patients with lobular cancer (broken down by Luminal A and Luminal B subtypes) enrolled in the BIG 1-98 trial

• Patient cohort:– Patients from BIG 1-98 with postmenopausal HR-positive disease

receiving 5 years of letrozole or 5 years of tamoxifen (n=4922)– Patients eligible for this analysis with HR-positive, HER2-negative

disease:• Ductal histology (n=2,599): 55.3% Luminal A, 44.7% Luminal B• Classic lobular histology (n=324): 73.1% Luminal A, 26.9% Luminal B

Filho et al., SABCS 2012; abstract S1-1


Cohort• Ductal DFS results:

• Lobular DFS results:

• Luminal A/B DFS results:– Luminal A disease showed an interaction P-value of .049 for DFS– Luminal B disease was not significant for DFS (P = .23)

Treatment 5-yr DFS 8-yr DFS HR (95% CI)Letrozole 88% 82% 0.80

(0.68-0.94)Tamoxifen 84% 75%


Treatment 5-yr DFS 8-yr DFS HR (95% CI)Letrozole 89% 82% 0.48

(0.31-0.74)Tamoxifen 75% 66%

Interaction P-value:

.03


Cohort• Multivariate analysis for DFS:

• Interactions:– Treatment by histology (ductal vs. lobular): P = .006– Treatment by subtype (Luminal A vs. Luminal B): P = .01

• Multivariate analysis for OS:

• Interaction: treatment by histology: P = .035

Histology HR (95% CI) FavorsDuctal Luminal A 0.95 (0.76-1.20) --Ductal Luminal B 0.64 (0.53-0.79) LetrozoleLobular Luminal A 0.49 (0.32-0.78) LetrozoleLobular Luminal B 0.33 (0.21-0.55) Letrozole


Histology HR (95% CI) FavorsDuctal 0.69 (0.57-0.85) Letrozole

Lobular 0.39 (0.22-0.68) Letrozole

ATLAS: Effect of 10 vs 5 Years of Adjuvant Tamoxifen in the First 2 Decades After

Diagnosis • Rationale:– An EBCTCG meta-analysis has shown that 5 years of adjuvant tamoxifen

produces a lower risk of breast cancer death compared with no tamoxifen (23.6% vs. 32.7% at 15 years, P < .00001)1

– Treatment with 5 years of tamoxifen is currently the standard hormonal therapy for premenopausal women with early-stage, ER-positive breast cancer

– Objective: Estimate the effect of 10 years of tamoxifen on ER-positive breast cancer recurrence and mortality compared with 5 years of tamoxifen

• ATLAS study design:

1EBCTCG, Lancet 2011;378:771-84Davies et al., SABCS 2012; abstract S1-2

Eligibility criteria:• ER-positive breast cancer• Completed 5 years of tamoxifen therapy

Discontinue tamoxifenRANDOMIZE

(N = 6846)

Continue tamoxifen daily for 5 years


Diagnosis

Davies et al., SABCS 2012; abstract S1-2

Tamoxifen treatmentduration

Recurrence at 15 years

(%)

Risk of recurrence during

years 5-9HR (95% CI)

Risk of recurrence during

years 10+HR (95% CI)

P-value(all

years)

5 years 711 (25.1%) 0.90 (0.79-1.02)

0.75 (0.62-0.90) .00210 years 617 (21.4%)

Median F/u = 8 years for compliance, recurrence, death


Diagnosis • Breast cancer mortality:

– 10 years of tamoxifen is estimated to reduce breast cancer mortality by one-third in the first decade and by one-half in the second decade


Period (years)

10 vs 5 years tamoxifen (ATLAS)

HR (95% CI)

5 vs 0 years tamoxifen (EBCTCG)

HR (95% CI)

10 vs 0 years tamoxifen (estimated

as the product of HRs)HR (95% CI)

0-4 1.0 0.71*** (0.62-0.80) 0.71*** (0.62-0.81)

5-9 0.97 (0.79-1.18) 0.66*** (0.58-0.75) 0.64** (0.50-0.82)

10+ 0.71* (0.58-0.88) 0.73** (0.62-0.86) 0.52*** (0.40-0.68)

*P = .0016**P = .0001***P < .00001


Diagnosis • Mortality comparison:

– The above chart shows that the risk of death caused by tamoxifen side effects is greatly outweighed by the benefit in the reduced risk of death from breast cancer provided by 10 years of tamoxifen therapy


Mortality cause

10 vs 5 years tamoxifen (ATLAS)

5 vs 0 years tamoxifen (EBCTCG)

10 vs 0 years tamoxifen (estimated

by addition)

Due to side effects (endometrial cancer and pulmonary embolisms)

0.2% loss 0.2% loss 0.4% loss

Due to breast cancer 3% gain 9% gain 12% gain


CONFIRM: Effect of Fulvestrant 500 mg vs

250 mg on Survival in Postmenopausal Women• Objective:

– Compare fulvestrant 500 mg/month with 250 mg/month (approved dosing) for the treatment of postmenopausal women with ER-positive advanced breast cancer whose disease progressed after previous hormonal therapy

• CONFIRM Phase III study design:

Di Leo et al., SABCS 2012; abstract S1-4

Eligibility criteria:• Postmenopausal• Advanced ER-positive breast cancer

• Disease progression during or after prior hormonal therapy

Fulvestrant 500 mgIntramuscular injections on days 0, 14, 28, and every 28 days thereafter

RANDOMIZE

(N = 735)

Fulvestrant 250 mgIntramuscular injections on days 0, 28, and every 28 days thereafter (with placebo injections on day 14)

Primary endpoint: PFS

• Baseline characteristics appeared well-balanced between treatment arms• Efficacy results:

– Subsequent therapies were well-balanced between arms, with approximately 60% of patients receiving subsequent chemotherapy and approximately one-third receiving other hormonal therapy


OutcomeTiming of analysis

Fulvestrant500 mg

Fulvestrant250 mg HR (95% CI)

Median PFS First† 6.5 months 5.5 months 0.80* (0.68-0.94)

Median OS First† 25.1 months 22.8 months 0.84** (0.69-1.03)

Median OS Final‡ 26.4 months 22.3 months 0.81*** (0.69-0.96)

*P = .006**P = .001***P = .016


250 mg on Survival in Postmenopausal Women

†First analysis was performed at 50% maturity‡ Final analysis was performed at 75% maturity

• Safety results (reported during main trial + follow-up phase) :

• A total of 11 SAEs led to death:


Serious AEsFulvestrant 500 mg

n=361Fulvestrant 250 mg

n=374 Any serious AE 35 (9.7%) 27 (7.2%)

Any causally related serious AE 8 (2.2%) 4 (1.1%)


250 mg on Survival in Postmenopausal Women

Fulvestrant 500 mg Fulvestrant 250 mg Cardiopulmonary failure (1) Acute myocardial infarction (1)

Cause unknown (1) Acute renal failure

Dyspnea (2) Aspiration

Intestinal adenocarcinoma (1) Suicide

Hypertension

Meningitis

Phase III BOLERO-2 Trial: Exemestane +/- Everolimus in Advanced BC

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

Hortobagyi G et al. SABCS 2011 (Abstract #S3-7), Baselga, NEJM 2011

BOLERO-2 Trial: Final Progression-Free Survival Analysis (18-month

follow-up)PFS (months) EVE + EXE PBO + EXE HR (95% CI) P-ValueLocal review 7.8 3.2 0.45

(95% CI, 0.38-0.54)<.0001

Central review 11.0 4.1 0.38(95% CI, 0.31-0.48)

<.0001

w/ visceral mets 6.83 2.76 0.47(95% CI, 0.37-0.60)

--

w/o visceral mets 9.86 4.21 0.41(95% CI, 0.31-0.55)

--

Bone-only mets 12.88 5.29 0.33(95% CI, 0.21-0.53)

--

Progression after neoadj therapy

11.50 4.07 0.39(95% CI, 0.25-0.62)

--

• PFS impact consistent across all prospectively defined subgroups• Overall survival data still not mature (HR=0.77; 95% CI, 0.57-1.04)• Most common grade 3 or 4 AEs were stomatitis (8%), hyperglycemia (5%), and fatigue (4%)

Swain et al., SABCS 2012; abstract P6-04-02

LEA: Effect of Adding Bevacizumab to First-Line Endocrine Therapy in Advanced

Breast Cancer• Rationale:

– Clinical data suggest that downregulation of VEGF may overcome endocrine therapy resistance and improve efficacy to hormonal therapy1

– Endocrine therapy + bevacizumab has been shown to be safe and active in phase II testing2,3

– Objective: Determine whether bevacizumab can delay resistance to endocrine therapy in patients with HR-positive advanced breast cancer

• LEA Phase III, open-label, multicenter study design:

1Ryden et al. J Clin Oncol. 2005;23:4695-7042Forero-Torres et al. Clin Breast Cancer. 2010;10(4):275-80

3Traina et al. J Clin Oncol, 2010;28(4):628-33Martin et al., SABCS 2012; abstract S1-7

Eligibility criteria:• Postmenopausal•Advanced HR-positive, HER2-negative breast cancer

• No previous therapy for advanced disease

Endocrine therapy Letrozole 2.5 mg/d or fulvestrant 250 mg q28d

RANDOMIZE

(N = 380)

Endocrine therapy + bevacizumabLetrozole 2.5 mg/d or fulvestrant 250 mg q28d + bevacizumab 15 mg/kg q


LEA: Effect of Adding Bevacizumab to First-Line Endocrine Therapy in Advanced

Breast Cancer• Results:

– Baseline characteristics were well-balanced:• Approximately 80% had metastatic disease• Approximately 50% had received previous adjuvant hormonal therapy• Approximately 90% of patients received letrozole; the remainder

received fulvestrant

– Adverse events increased on the bevacizumab-containing arm included leukopenia and thrombocytopenia (P < .01); also fatigue, hypertension, hemorrhage, elevated liver enzymes, and proteinuria (P < .001). Martin et al., SABCS 2012; abstract S1-7

Outcome Endocrine therapyEndocrine therapy

+ Bevacizumab HR (95% CI) P-valueMedian PFS 13.8 months 18.4 months 0.83 (0.65-1.06) .14

Median OS 42 months 41 months 1.18 (0.77-1.81) .47

• Rationale: – PD 0332991 is an oral highly selective cyclin-dependent kinase (CDK) 4/6

inhibitor that prohibits cell cycle progression– It has been shown that PD 0332991 has synergistic activity in combination

with hormonal therapy (tamoxifen)1

– A Phase I/II study of letrozole and PD 0332991 was initiated – The phase 1 portion has been completed and the dose of PD 0332991

selected – Phase II study design

1Musgrove et al. Nat Rev Can. 2011;11:558-72Finn et al., SABCS 2012; abstract S1-6

TRIO-18: Addition of CDK Inhibitor PD 0332991 to Letrozole for Advanced Breast

Cancer

Eligibility criteria:•ER-positive, HER2-negative disease

•Locally recurrent or metastatic

•Previously untreated for advanced disease

•CCND1 amplification and/or loss of p16

PD 0332991 125 mg QD* + letrozole 2.5 mg QD

RANDOMIZE

(N=99)

Letrozole 2.5 mg QD


*3 weeks on, 1 week off

• Second interim analysis (50% of events) efficacy results:

• Second interim analysis treatment administration results:

Finn et al., SABCS 2012; abstract S1-6

OutcomePD 991 + letrozole

(n=84)Letrozole

(n=81) HR (95% CI) P-valueMedian PFS, months 26.1 7.5 0.37 (0.21-

0.63)< .001

Objective response rate

34% 26% -- --

Clinical benefit rate 70% 44% -- --

OutcomePD 991 + letrozole

(n=83)Letrozole

(n=77)Median duration of treatment 8.9 months 5.1 months

Dose interruptions, % of cycles 71% 22%

Cycle delays 75% NA

Dose reductions 35% NA


Cancer

• Second interim analysis most common treatment-related AE results (≥10%):

Finn et al., SABCS 2012; abstract S1-6

AE

PD 991 + letrozole(n=83)

Letrozole(n=77)

Grade 1/2 Grade 3 Grade 4 Grade 1/2 Grade 3 Grade 4

Neutropenia 19 46 5 1 1 0

Leukopenia 24 14 0 0 0 0

Anemia 19 4 1 0 0 0

Fatigue 17 2 0 13 0 0

Alopecia 18 0 0 3 0 0

Hot flush 17 0 0 10 0 0

Arthralgia 16 0 0 10 0 0

Nausea 12 2 0 1 0 0

Thrombocytopenia 11 1 0 0 0 0


Cancer

Neoadjuvant Therapy

Z1031B Phase II Neoadjuvant AI Trial: Triage to Chemotherapy If Ki67 Level >10%

at 2-4 Weeks • Postmenopausal patients with stage 2 or 3 ER+ breast cancer

initiated preoperative AI therapy and underwent biopsy at 2-4 weeks. – If Ki67 >10%: switch to NCCN-guideline chemotherapy or

immediate surgery – If Ki67 <10%: continue on AI for 16-18 weeks

• 49 patients had a Ki67 score >10%– 35 received standard neoadjuvant chemotherapy– pCR rate was only 6% and did not meet criteria for adequate

activity• 166 patients had a Ki67 score <10%

– 37% had a preoperative endocrine prognostic index (PEPI) score of 0, indicating a very low relapse risk

– 94% of these patients accepted a recommendation of no adjuvant chemotherapy

Ellis et al., SABCS 2012; abstract PD-07-01

FEMZONE Trial: Phase II Study of Neoadjuvant Letrozole With or Without

Zoledronic Acid for Postmenopausal ER+ Breast Cancer

• Postmenopausal patients with ER+/PgR+ breast cancer received 6 months of preoperative therapy with letrozole alone (n=79) or with zoledronic acid 4 mg q4w (n=89); accrual did not reach planned numbers.

• Adverse events were consistent with known safety profiles of individual agents; no deaths or reports of osteonecrosis of the jaw; no differences in QoL between arms.

LET LET + ZA P ValueORR (6 month;Central Review) 54.5% 69% .106

Breast-conserving surgery 76% 72% --

Fasching et al., SABCS 2012; abstract PD-07-02

UNICANCER CARMINA 02 Trial Evaluating Neoadjuvant Anastrozole or

Fulvestrant for Postmenopausal ER+/HER2- Breast Cancer

• Randomized Phase II Trial– Anastrozole 1 mg/day for 4-6 months (n=59)– Fulvestrant 500 mg days 1, 15, and 29, then q4w (n=57)

• No grade 3/4 adverse events or SAEs reported• Most common AEs were grade 1 hot flushes and

musculoskeletal symptoms

Anastrozole FulvestrantClinical Response Rate 62% 53%

Breast Conservation 64% 53%

Lerebours et al., SABCS 2012; abstract PD-07-04

Bone-Targeted Therapies

Bone Biomarker Analysis From AZURE Study of Zoledronic Acid Added to

Standard Therapy

1Coleman et al. N Engl J Med. 2011;365:1396-1405Rathbone et al., SABCS 2012; abstract S6-4

• AZURE study design and primary results

– No difference in invasive DFS between groups (HR 0.98, P = .73), but, among postmenopausal women, invasive DFS favored zoledronic acid group (HR 0.75, P = .02) and OS favored zoledronic acid group (HR 0.74, P = .04)1

Eligibility criteria:•Stage II/III breast cancer

Standard therapyRANDOMIZE

(N=3360)

Standard therapy + zoledronic acid 4 mgFirst 6 months: q3-4 weeksNext 2 years: q3 monthsNext 2.5 years: q6 months

Both groups were instructed to take calcium and vitamin D supplements for 6 months; supplements were at the discretion of the physician thereafter


Standard Therapy

Rathbone et al., SABCS 2012; abstract S6-4

• AZURE biomarker study design– Goals

• Identify specific prognostic factors for development of bone metastasis• Identify predictive markers for benefit from zoledronic acid treatment• Classify menopausal status using reproductive hormone levels

– Biomarker population consisted of 872 patients who consented to serum storage at baseline

• Biomarker population was similar to the overall population in baseline characteristics and in primary outcomes

– Bone biomarkers analyzed:• PINP (measure of bone formation)• CTX (measure of bone turnover)• Vitamin D

• N=766 (87.8%) had insufficient levels <30 ng/mL


Standard Therapy

Rathbone et al., SABCS 2012; abstract S6-4

• Biomarker results for overall biomarker population

– Insufficient baseline vitamin D levels predict recurrence

• Biomarker results among postmenopausal women (who appear to benefit from zoledronic acid, according to AZURE)

• Increased bone markers do not predict treatment benefit• High vitamin D levels predict benefit for zoledronic acid: HR 0.09 (0.01-0.82)

Biomarker (levels at baseline)

Time to bone recurrence Time to distant recurrenceHR (95% CI) P-

valueHR (95% CI) P-value

PINP 1.15 (0.68-1.94) .60 0.86 (0.60-1.23) .41

CTX 1.43 (0.87-2.35) .16 1.21 (0.87-1.70) .26

Vitamin D 0.11 (0.02-0.76) .03 0.56 (0.31-1.01) .05

ZICE Trial: Phase III Comparison of Zoledronate vs Ibandronate for the

Treatment of Bone Metastases• Patients with histologically confirmed breast cancer with bone

metastases were randomized to 96 weeks of therapy with either:– Zoledronate: 4 mg IV every 3-4 weeks (n=699)– Ibandronate 50 mg PO daily (n=705)

• Ibandronate failed to demonstrate non-inferiority with regard to annual skeletal event rate (0.412 for Z vs. 0.495 for I; P=.13)

• Both agents similar in delaying time to first SRE (HR 1.04; P=.63)

• Similar median survival between arms• Renal AEs more frequent with zoledronate• Osteonecrosis similar between arms

– 0.71% with I vs. 1.29% with Z; P = 0.28

Barrett-Lee et al., SABCS 2012; abstract PD-07-09

Clinical Implications

• The more endocrine-sensitive a ESBC is, the larger proportional benefit for adjuvant endocrine therapy (esp. estrogen-deprivation approaches).

• Longer duration of endocrine therapy appears to have a net + survival benefit.

• HD Fulvestrant improves survival in MBC.• Novel targeted therapies are making impact on

DFS/OS in ER+ MBC.• No clear marker of benefit with adjuvant zoledronic

acid, although relationship between low vitamin D levels and risk for recurrence.

Emerging Therapies for HER2+ Breast Cancer

Hope S. Rugo, MD

Adjuvant Therapy

Questions• What is the most appropriate duration for adjuvant trastuzumab?

• Is the benefit of adjuvant trastuzumab maintained with long-

term follow-up?• Does compliance with adjuvant

trastuzumab matter?

HERA Final Analysis: 2 Years vs. 1 Year of Trastuzumab After Adjuvant

Chemotherapy• HERA study design and previous results

– First interim analysis at median 2 years follow-up showed significant DFS benefit for 1 year trastuzumab over observation (HR = 0.54, P < .0001)1

Eligibility criteria:•HER2-positive invasive early breast cancer

•Received surgery + (neo)adjuvant chemotherapy ± radiation therapy

•Then, centrally confirmed IHC 3+ or FISH+ and LVEF ≥55%

1 year trastuzumab (n=1703)8 mg/kg loading dose, 6 mg/kg maintenance, q3w

RANDOMIZE

(N=5102)

2 years trastuzumab (n=1701)8 mg/kg loading dose, 6 mg/kg maintenance, q3w

Observation (n=1698)After ASCO 2005, patients given option to switch to trastuzumab

Stratification: nodal status, adjuvant chemotherapy regimen, HR status and endocrine therapy, age, region

1Piccart-Gebhart et al., N Engl J Med 2005;353:1659-72Goldhirsch et al., SABCS 2012; abstract S5-2

Primary endpoint: DFS (1 yr vs. obs, 2 yr vs. obs)Secondary endpoint: DFS (1 yr vs. 2 yr), OS


Chemotherapy• 8-year median follow-up, efficacy results for 2 years vs. 1 year trastuzumab

• 8-year median follow-up, safety results for 2 years vs. 1 year trastuzumab

Goldhirsch et al., SABCS 2012; abstract S5-2

Outcome2 years

trastuzumab1 year

trastuzumab HR (95% CI) P-value

8-yr DFS HR-positive HR-negative

75.8%76.1%75.4%

76.0%77.2%74.7%

0.99 (0.85-1.14)1.05 (0.85-1.25)0.93 (0.76-1.14)

.86

.67

.51

8-yr OS 86.4% 87.6% 1.05 (0.86-1.28) .63

Outcome

2 years trastuzumab

(n=1673)

1 year trastuzumab

(n=1682)

≥ 1 grade 3/4 AE 20.4% 16.3%

Secondary cardiac event

7.2% 4.1%

Primary cardiac event 1.0% 0.8%

Fatal AE 1.2% 1.1%


Chemotherapy• 8-year efficacy results for 1 year trastuzumab vs. observation

– Results are complicated by the fact that 52.1% of the patients in the observation group crossed over to receive trastuzumab after ASCO 2005

Goldhirsch et al., SABCS 2012; abstract S5-2

Outcome

Overall population

HR, (P-value)

HR-positive population

HR, (P-value)

HR-negative population

HR, (P-value)

DFS benefit 1 yr MFU 2 yr MFU 4 yr MFU 8 yr MFU

0.54, (<.0001)0.64, (<.0001)0.76, (<.0001)0.76, (<.0001)

0.60, (.003)0.68, (.005)0.84, (.09)0.81, (.03)

0.50, (<.0001)0.62, (<.0001)0.70, (<.0001)0.72, (<.0001)

OS benefit 1 yr MFU 2 yr MFU 4 yr MFU 8 yr MFU

0.76, (.26)0.66, (.01)0.85, (.11)

0.76, (.0005)

1.67, (.21)0.69, (.21)1.03, (.86)0.84, (.14)

0.47, (.02)0.64, (.03)0.75, (.03)

0.70, (.0007)

PHARE: Subset Analysis Comparing 6 Months vs. 12 Months of Trastuzumab as

Adjuvant Therapy• PHARE non-inferiority randomized study design

Eligibility criteria:•HER2-positive early breast cancer•Tumor size ≥ 10 mm•Received surgery + at least 4 cycles (neo)adjuvant chemotherapy ± radiation therapy

6 months trastuzumab RANDOMIZE

(N=3384)

No further trastuzumab

Randomization was stratified by chemotherapy /trastuzumab timing, hormonal therapy, recruiting center

Pivot et al., SABCS 2012; abstract S5-3

Primary endpoint: non-inferiority of DFS with 6 months trastuzumab

6 months trastuzumab +

any chemotherapy

regimen


Adjuvant Therapy• DFS results, 42.5 months median follow-up

– To be considered non-inferior, HR and CI should be between 1.0 and 1.15 DFS HR was 1.28 (1.05-1.56), which does not meet non-inferiority requirements1

1Pivot et al., ESMO 2012, LAB5_PR Pivot et al., SABCS 2012; abstract S5-3

DFS event

12 months trastuzumab

(n=1690)

6 months trastuzumab

(n=1690)

Total events (n=394) 10.4% 13.0% Local recurrence 1.1% 1.4%

Regional recurrence 0.6% 0.5%

Distant recurrence 6.4% 8.3%

Contralateral breast cancer 0.4% 0.7%

Second primary malignancy 1.5% 1.5%

Death 0.4% 0.5%


Adjuvant Therapy• DFS subset analysis results, 42.5 months median follow-up


DFS subset HR (95%CI)Meet non-inferiority

requirements?

ER-negative 1.34 (1.02-1.76) No

ER-positive 1.23 (0.92-1.65) No

Sequential chemotherapy 1.41 (1.06-1.86) No

Concomitant chemotherapy 1.15 (0.87-1.53) No

<50 years old 1.38 (1.01-1.89) No

≥50 years old 1.22 (0.94-1.57) No

Node-negative 1.33 (0.95-1.87) No

Node-positive 1.25 (0.97-1.60) No

< 2-cm tumor 1.02 (0.72-1.44) No

≥2-cm tumor 1.41 (1.09-1.81) No


Adjuvant Therapy• DFS subset analysis interaction results, 42.5 months median follow-up

– To be considered a significant interaction, HR and CI should be > 1.15


DFS interaction HR (95% CI)Meet significant interaction

requirements?

ER-negative and sequential chemotherapy

1.57 (1.08-2.28) No, but almost

ER-positive and sequential chemotherapy

1.25 (0.81-1.91) No

ER-negative and concomitant chemotherapy

1.10 (0.73-1.65) No

ER-positive and concomitant chemotherapy

1.23 (0.83-1.82) No

NSABP B-31 and NCCTG N9831: Final Joint Analysis of Survival for

Adjuvant Chemotherapy ± Trastuzumab • NSABP B-31 study design

• NCCTG N9831 study design

Romond et al., SABCS 2012; abstract S5-5

Arm 1

Arm 2

Control: AC→T

Investigational: AC→T+H

= paclitaxel (T) 175 mg/m2 q3w x 4= paclitaxel (T) 80 mg/m2/wk x 12= trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51

Arm A

Arm B

Arm C

= doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q3w x 4

Control: AC→T

Investigational: AC→T+H


Adjuvant Chemotherapy ± Trastuzumab


• Efficacy outcomes: 8.4 years of median follow-up

– The results likely underestimate the treatment effect because• 5% of the women in the AC→T+H arm did not receive trastuzumab

because of cardiac concerns• 20% of the women in the AC→T arm received trastuzumab after

ASCO 2005

OutcomeAC→T+H(n=2028)

AC→T(n=2018) HR (95% CI) P-value

10-yr DFS 73.7% 62.2% 0.60 (0.53-0.68) < .000110-yr OS 84.0% 75.2% 0.63 (0.54-0.73) < .0001




• First DFS events

• Distant recurrence by HR status

First DFS eventAC→T+H(n=2028)

AC→T(n=2018)

Distant recurrence 11.2% 19.4%

Local/regional recurrence 4.1% 6.1%

Contralateral breast cancer 2.3% 2.0%

Other second primary cancer 3.3% 3.7%

Death without recurrence 1.9% 1.5%

Distant recurrenceAC→T+H AC→T

n % n %

HR-positive 1110 12.7% 1105 22.3%

HR-negative 917 11.9% 911 21.5%




OS by subgroup HR

Significantly favors

trastuzumab arm?

Age, years < 40 40-49 50-59 60+

0.670.650.680.52

YesYesYesYes

# of positive nodes 0 1-3 4-9 10+

0.940.590.720.56

NoYesYesYes

OS by subgroup HR

Significantly favors

trastuzumab arm?

HR status Negative Positive

0.650.61

YesYes

Tumor size, cm 0-2 2.1-5.0 5.1+

0.510.680.58

YesYesYes

Histologic grade Good Intermediate Poor

0.110.520.67

YesYesYes

• OS by subgroup

• Cumulative incidence of distant recurrence as first event at 10 years– ER and or PR positive

• 22.3 vs 12.7% (9.6% difference)• No clear plateau in relapse

– ER and PR negative• 21.5 vs 11.9% (9.6% difference)

• Improvement in OS increased over time



Years from randomization 4 6 8 10

Difference in OS 2.9 5.5 7.6 8.8

Reasons for and Impact of Noncompliance With NCCN Guidelines for Trastuzumab

Use• Rationale

– NCCN guidelines recommend 1 year of adjuvant trastuzumab for patients with stage I-III HER2-positive breast cancer, but many patients fail to complete therapy

• Study design– Retrospective analysis of patients from a single institution

(N=331) who were eligible for adjuvant trastuzumab– Clinician-documented reasons for noncompliance with NCCN

adjuvant trastuzumab guidelines were examined– Impact of noncompliance on disease-related outcomes was

tested

Mullins et al., SABCS 2012; abstract P5-18-17

Reasons for and Impact of Noncompliance With NCCN Guidelines

for Trastuzumab Use• Results

– Median age was 53, and most patients had stage I (37%) or II (41%) disease

– Physician-cited reasons for noncompliance included:• Small tumor size (30%)• Baseline cardiac dysfunction (24%)• Patient refusal (16%)• Advanced age (6%)• Development of metastases (6%)• Medication toxicity (5%)

– Multivariate analysis identified age ≥70 (P < .001) and stage I disease (P = .001) as risk factors for noncompliance

– Failure to complete adjuvant trastuzumab therapy was associated with:

• Shorter DFS (P = .03)• Shorter OS (P = .0002)

Mullins et al., SABCS 2012; abstract P5-18-17


Metastatic: Questions• Is survival improved with the addition of pertuzumab to

standard chemotherapy/trastuzumab in the CLEOPATRA Trial?

• Is this combination effective and safe in older patients?• Do biomarkers help us to identify those who might benefit

from the addition of pertuzumab?• Can we substitute weekly paclitaxel for docetaxel?• How safe is T-DM1?• Can we safely substitute vinorelbine for capecitabine in

combination with lapatinib?

CLEOPATRA Biomarker Analysis: Phase III Placebo-Controlled Study of Pertuzumab

• CLEOPATRA study design and primary results

– Significant improvements were observed in both PFS and OS with the addition of pertuzumab to trastuzumab and docetaxel for the treatment of HER2-positive metastatic breast cancer

Eligibility criteria:•HER2-positive centrally confirmed metastatic breast cancer

•First-line

Placebo + trastuzumabRANDOMIZE

(N=808)

Pertuzumab + trastuzumab

Docetaxel (≥6 cycles recommended)

Docetaxel (≥6 cycles recommended)

Study dosing q3w until progression:− 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

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

Baselga et al., SABCS 2012; abstract S5-1

CLEOPATRA: Confirmatory Overall Survival Analysis of Phase III Pertuzumab

Study• Rationale– Interim (immature) OS results from the CLEOPATRA trial showed a trend in favor of

adding pertuzumab to trastuzumab and docetaxel therapy (HR 0.64, 0.47-0.88)1

– This analysis provides confirmatory OS data using mature data • Study design

– A second interim analysis of OS was performed with an additional 1 year of follow-up• Results at median follow-up of 30 months

– This survival benefit was observed in nearly all subgroups analyzed

– This second interim OS analysis was considered significant and confirmatory

• Now crosses the O’Brien-Fleming stopping boundary

1Baselga et al. N Engl J Med. 2012;366:109-19Swain et al., SABCS 2012; abstract P5-18-26

Second interimOS analysis Pertuzumab arm Placebo arm HR (95% CI) P-value

3-year estimated 66% 50% HR =0.66 (0.52-0.84) .0008

Median OS Not reached 37.6 months

Effect of Pertuzumab Added to Trastuzumab and Docetaxel in Older

Patients From CLEOPATRA• Patients were divided into 2 age groups: <65 and ≥65

– Evaluates the benefit-risk ratio of adding pertuzumab in older patients– Of the 808 patients enrolled, 127 (15.7%) were ≥65 years old

• Safety– Diarrhea, fatigue, asthenia, decreased appetite, vomiting, and dysgeusia were

more frequent in older patients, neutropenia and febrile neutropenia were less frequent; neuropathy was increased with pertuzumab in older patients

– Dose reductions were more frequent in older patients• 26%-31% vs. 22%-25%

– Older patients received fewer median cycles of docetaxel • 6.0-6.5 vs. 8.0

• Efficacy was similar

1Baselga et al. N Engl J Med. 2012;366:109-19 Miles et al., SABCS 2012; abstract P5-18-01

SubsetImprovement in median PFS with pertuzumab HR (95% CI) P-value

< 65 years old 4.7 months HR =0.65 (0.53-0.80) P < .0001

≥ 65 years old 11.2 months HR = 0.52 (0.31-0.86) P = .0098


• Biomarker analysis study design– Biomarkers were chosen from different parts of the HER2 signaling

pathway:• HER2 ligands: AREG, EGF, TGFα, IGF1R, EGFR, HER2, HER3• HER2 receptor, including soluble HER2 receptor• Intracellular signaling components: PI3K, Akt, PTEN• Nuclear component: c-Myc

– Biomarkers were assayed using a number of methods:• IHC, qRT-PCR, FISH, mutational analysis, and ELISA

– Two types of correlations were investigated:• Predictive effects

– Associations of biomarkers with pertuzumab benefit• Prognostic effects

– Relationship of biomarker to outcome independent of treatment arm



• Biomarker predictive effects– Pertuzumab demonstrated PFS benefit across nearly all biomarker subgroups

examined• Of 38 subgroups examined, 33 showed a significant PFS benefit for

pertuzumab• The following biomarker subgroups favored pertuzumab but were not

significant predictors: betacellulin mRNA high, HER3 membrane H-score high, IGF1R membrane H-score high, pAKT cytoplasm H-score high, pAKT nuclear H-score high

• Biomarker prognostic effects


BiomarkerLevel correlating

with better prognosis HR (95% CI) P-value

Serum sHER2 Low 1.23 (1.01-1.49) .04HER2 mRNA High 0.77 (0.63-0.93) .008HER2 membrane H-score High 0.83 (0.69-1.00) .05

HER3 mRNA High 0.81 (0.66-0.98) .03PIK3CA wildtype High 0.63 (0.49-0.80) .0001


• Biomarker results: focus on PIK3CA– PIK3CA mutations were associated with poorer prognosis in the placebo arm:

5.2-month reduction in median PFS – PIK3CA mutation were associated with poorer prognosis in the pertuzumab

arm: 9.3-month reduction in median PFS

– Mutations in PIK3CA were not associated with resistance to pertuzumab• Patients derived similar additional benefit from pertuzumab

independent of PIK3CA mutational status– HER2 remains the best marker to predict benefit from HER2-directed therapy


PIK3CA statusPlacebo armMedian PFS

Pertuzumab armMedian PFS HR (95%CI)

Mutated 8.6 months 12.5 month 0.64 (0.43-0.93)

Wild-type 13.8 months 21.8 months 0.67 (0.50-0.89)

Prognostic ability

Prognostic ability

Predictive abilityPredictive ability

A Phase II Study of Pertuzumab + Trastuzumab + Weekly

Paclitaxel• Rationale

– Evaluate the addition of pertuzumab to a regimen similar to that used in CLEOPATRA trial in a similar patient population

• Replace q3w docetaxel with weekly paclitaxel, which may be more tolerable than docetaxel1

• Study design– Patients with HER2-positive metastatic breast cancer

• 0-1 prior treatment for metastatic disease • Treated with pertuzumab (840 mg loading dose, 420 mg maintenance),

trastuzumab (8 mg/kg loading dose, 6 mg/kg maintenance) q3w and paclitaxel 80 mg/m2 weekly

– A target 6-month PFS rate of ≥65% was considered promising• Results

– Of the 50 patients enrolled at the time of analysis, 33 were evaluable– The 6-month PFS rate was 76% and the response rate was 52%– No cardiac events were recorded at the time of analysis, although one woman

was taken off study for an asymptomatic LVEF decline

1Sparano et al. N Engl J Med. 2008;358:1663-71Datko et al., SABCS 2012; abstract P5-18-20

A Phase II Study of Eribulin + Trastuzumab in Advanced HER2-Positive

Breast Cancer• Rationale

– The microtubule inhibitor eribulin was approved as monotherapy for patients with relapsed/refractory advanced breast cancer based on a 2.5-month improvement in OS over physician’s choice treatment1

– Objective: Explore the activity and safety of eribulin + trastuzumab in the first-line treatment of patients with HER2-positive advanced breast cancer

• Study design– Patients with chemotherapy-naïve HER2-positive locally recurrent or metastatic

breast cancer • Treated q3w with eribulin 1.4 mg/m2 on days 1 & 8 and trastuzumab 8 mg/kg

loading dose (6 mg/kg subsequent doses) until progression• Results

– 40 evaluable patients– The median number of cycles received was 7.0 for both eribulin and trastuzumab– Median PFS was 9.2 months and response rate was 55%– Most common treatment-related AEs were alopecia, fatigue, neutropenia, nausea,

and peripheral neuropathy. The most common grade 3/4 AE was neutropenia (35%)

1Cortes et al. Lancet. 2011;377:914-23Vahdat et al., SABCS 2012; abstract P5-20-04

Pooled Safety Analysis: Trastuzumab Emtansine in HER2-Positive Metastatic

Breast Cancer• Rationale

– Trastuzumab emtansine (T-DM1) produced a 5.8-month improvement in OS over lapatinib + capecitabine in patients with HER2-positive advanced breast cancer1

– Objective: • Perform an integrated safety analysis of 882 patients who

have been treated with single-agent T-DM1 in clinical trials• Study design

– Patients from 6 clinical trials and 1 extension study who received single-agent T-DM1 3.6 mg/kg q3w were included in this integrated safety analysis

1Verma et al. N Engl J Med. 2012;367:1783-91 Dieras et al., SABCS 2012; abstract P5-18-06

Pooled Safety Analysis: Trastuzumab Emtansine in HER2-Positive Metastatic

Breast Cancer• Results

– The most common AEs were:• Fatigue, nausea, headache, and thrombocytopenia

– With the exception of fatigue, the most common grade ≥3 AEs were:

• Thrombocytopenia, increased AST, hypokalemia, and anemia– Serious AEs were reported in 18.6%

• 6.2% discontinued treatment due to an AE– There were 3 cases of NRH (nodular regenerative hyperplasia) and

3 patients discontinued treatment due to cardiac disorders– Four of the 9 AEs leading to death were deemed related to

treatment: • Hepatic failure, hepatic function abnormal, bacterial sepsis, and

metabolic encephalopathy

VITAL: Phase II Randomized Trial of Lapatinib + Capecitabine or Vinorelbine in

MBC• Rationale

– Lapatinib is approved for use in combination with capecitabine• Also has activity in combination with vinorelbine1-3

– Objective: • Evaluate the efficacy and safety of lapatinib when combined with

either capecitabine or vinorelbine in women with HER2-positive breast cancer

• Study design– Phase II, open-label, multicenter study– Patients with HER2-positive MBC (N=112) – Randomized to lapatinib + capecitabine or lapatinib + vinorelbine– The primary endpoint was PFS

1Brain et al., Br J Cancer. 2012;106:673-72Lu et al., SABCS 2010; abstract P3-14-183Bisagni et al., ESMO 2010; abstract 3529

Janni et al., SABCS 2012; abstract P5-18-21

VITAL: Phase II Randomized Trial of Lapatinib + Capecitabine or Vinorelbine in

MBC• Results

– Baseline characteristics were well-balanced between arms– Median PFS in both arms was 6.2 months (HR 0.84, 0.53-1.35)– The most common AEs for the capecitabine-containing arm were:

• Palmar-plantar erythrodysesthesia, diarrhea, and rash– The most common AEs for the vinorelbine-containing arm were:

• Neutropenia, diarrhea, rash, nausea, and fatigue– More serious AEs were observed in the vinorelbine-containing arm

• 33% vs. 11%

Clinical Implications• The optimal duration of adjuvant trastuzumab remains 1 year• Long-term follow-up confirms the marked benefit of adjuvant

trastuzumab• Pertuzumab, trastuzumab and docetaxel are a new standard for

the first-line treatment of HER2+ metastatic breast cancer– Safe and effective in the older population– Reasonable to substitute weekly paclitaxel – HER2 remains the best predictive marker for benefit– Higher exposure to adjuvant trastuzumab in the US

population• T-DM1 is a safe and effective therapy for metastatic HER2+

breast cancer– Approved by FDA 2/22/2013

• The best chemotherapy agent to partner with lapatinib remains capecitabine

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