A Report from SABCS Up-to-Date Review of the Treatment of Advanced Breast Cancer

A Report from SABCS

Up-to-Date Review of the Treatment of Advanced Breast Cancer

William J. Gradishar, MDDirector, Breast Medical Oncology

Professor of Medicine

Robert H. Lurie Comprehensive Cancer Center

Northwestern University Feinberg School of MedicineChicago, IL

Chemotherapy for MBC

Gemcitabine/Docetaxel vs. Capecitabine/Docetaxel in Anthracycline-Pretreated MBC (Phase III)

Efficacy Results

• 305 patients randomized • GD: Gemcitabine 1000 mg/m2 d1,8 Docetaxel 75 mg/m2 d1 q 3 w• CD: Capecitabine 1250 mg/m2 b.i.d. d1-14 Docetaxel 75 mg/m2 d1 q 3 w

Chan S, et al. SABCS 2007 Abstract 1078.

GD(N = 153)

CD(N = 152)

P-value

ORR 32% 32% .93

First-line 43% 29% .051

Second-line 14% 36% .008

Median PFS 8.05 mos 7.98 mos .121

First-line 8.51 mos 7.69 mos .499

Second-line 6.60 mos 8.51 mos .073

Median OS 19.29 mos 21.45 mos .98

Gemcitabine/Docetaxel vs. Capecitabine/Docetaxel in Anthracycline-Pretreated MBC (Phase III)

Toxicities

Grade 3/4 Adverse Events (≥ 10% patients)

GD CD

Grade 3 Grade 4 Grade 3 Grade 4

Neutropenia 36% 48% 26% 53%

Febrile Neutropenia/ Neutropenic Sepsis

5% 3% 7% 7%

Leukopenia* 57% 20% 44% 22%

Hand-foot syndrome* 0 0 26% 0

Diarrhea* 7% < 1% 17% 1%

Mucositis* 4% 0 12% 3%

Asthenia 7% 0 11% 0

* P < .05 Chan S, et al. SABCS 2007 Abstract 1078.

Vadhat LT, et al, ASCO 2007 Abstract 1006.

Study Design: International, Randomized, Open-Label, Phase III Trial

Trial Design

Ixabepilone(40 mg/m2 IV over 3 hr d1 q 3 wk)

+Capecitabine(2000 mg/m2/day PO 2 divided doses d1-d14 q 3 wk)

(N = 375)

Capecitabine(2500 mg/m2/day PO 2 divided doses d1-d14 q 3 wk)

(N = 377)

Metastatic or locally advanced breast cancer

RESISTANT to anthracyclines

and taxanes(N = 752)

Stratification:• Visceral metastases• Prior chemotherapy for MBC• Anthracycline resistance• Study site

Median 95% CI

Ixabepilone + Capecitabine 5.8 mo (5.5–7.0)

Capecitabine 4.2 mo (3.8–4.5)

HR: 0.75 (0.64–0.88)

P = 0.0003

Pro

port

ion

Pro

gres

sion

-Fre

e

1.0

0.8

0.6

0.4

0.2

00 4 8 12 16 20 24 28 32 36

Months

Capecitabine ± IxabepiloneProgression-free Survival by Independent Radiologic Review


Capecitabine ± IxabepiloneResponse


Unable to determine 129108

27152914Progressive disease

46413836Stable disease

P < .0001P < .0001

14352342ORR (CR + PR)

Capecitabine

(N = 377)

Ixabepilone +

Capecitabine (N = 375)

Capecitabine

(N = 377)

Ixabepilone +

Capecitabine(N = 375)

IRRInvestigator

% Response

Capecitabine ± IxabepiloneToxicity

• All toxicity-related deaths in combination arm attributable to neutropenia:

– Incidence with baseline ≥ grade 2 LFTs was 31% (5/16)

– Incidence post amendment with baseline ≤ grade 1 LFTs was 2% (7/353)

• Grade 3/4 hematologic:

– 4 versus < 1% FN (0.001)

– 8 versus 4% thrombocytopenia (0.011); 10 versus 4% anemia (0.005)

• Grade 3/4 nonhematologic:

– 23% peripheral neuropathy:

• Primarily sensory

• Cumulative

• Reversible:

– Median time to resolution 6 weeks


Efficacy of Ixabepilone/Capecitabine in ER/PR/HER2-Negative MBC Resistant to Anthracyclines and Taxanes

Rugo H, et al. SABCS 2007, Abstract 6069.

Receptor Subgroup

All PatientsER/PR/HER2

NegativeNon-Triple-Negative

HER2+ ER+

I + C

(N = 375)

C

(N = 377)

I + C

(N = 91)

C

(N = 96)

I + C

(N = 284)

C

(N = 281)

I + C

(N = 59)

C

(N = 53)

I + C

(N = 173)

C

(N = 178)

ORR35% 14% 27% 9% 37% 16% 31% 8% 40% 19%

Median PFS 5.8 mo 4.2 mo 4.1 mo 2.1 mo 7.1 mo 5.0 mo 5.3 mo 4.1 mo 7.6 mo 5.7 mo

HR0.75 0.68 0.74 0.69 0.81

Hormonal Therapy for MBC

Fulvestrant vs. Exemestane Following Prior Nonsteroidal AI Therapy: EFECT, a Phase III Trial in Postmenopausal

Women With Advanced Breast Cancer

Chia S, et al. SABCS 2007, Abstract 2091.

Eligibility Criteria:• Postmenopausal women• HR+• Measurable disease• Prior nonsteroidal AI failure

for advanced breast cancer or for adjuvant therapy or within 6 months of its discontinuation

(N = 693)

Primary Endpoint: • Time to disease progression

Primary Endpoint: • Time to disease progression

RANDOMIZE

RANDOMIZE

Fulvestrant: loading dose 500 mg on d 0, followed by 250 mg on d 14, 28 q 28 ± 3 days thereafter(N = 351)

Fulvestrant: loading dose 500 mg on d 0, followed by 250 mg on d 14, 28 q 28 ± 3 days thereafter(N = 351)

Exemestane: 25 mg orally daily + placebo (N = 342)

Exemestane: 25 mg orally daily + placebo (N = 342)

Fulvestrant vs. Exemestane Following Prior Nonsteroidal AI Therapy: EFECT Trial

Efficacy

Previous Analysis

Median Follow-Up 13 months

Fulvestrant Exemestane HR P-Value

Time to Progression 3.7 mos 3.7 mos 0.963 0.6531

Objective Response Rate 7.4% 6.7% 1.120* 0.7364

Clinical Benefit Rate 32.2% 31.5% 1.035* 0.8534

Duration of Response 13.5 mos 9.8 mos – –

Duration of Clinical Benefit 9.3 mos 8.3 mos – –

* Odds ratio

Gradishar WJ, et al. Breast Cancer Res Treat 2006; 100(suppl 1):S8 (abstract 12).

Fulvestrant vs. Exemestane Following Prior Nonsteroidal AI Therapy: EFECT Trial

Efficacy

Current AnalysisMedian Follow-Up 20.9 months

Fulvestrant Exemestane HR P-Value

Overall Survival 24.3 mos 23.1 mos 1.012 0.9072

ER+ and PgR+ 24.4 mos 22.6 mos 0.992 0.9488

Not ER+ and PgR+ 24.3 mos 23.7 mos 1.040 0.8044

Adverse events (all grades) similar between arms:• Injection site pain (F 9.7%; E 8.8%)• Hot flashes (F 8.8%; E 11.5%)• Fatigue (F 6.3%; E 10%)

Chia S, et al. SABCS 2007, Abstract 2091.

HER2-Targeted Therapy for MBC

Trastuzumab Beyond Progression TrialStudy Design

Eligibility Criteria:

• Progressive MBC or LABC

• HER2 overexpression

• Previous trastuzumab

• Trastuzumab-free interval < 6 wks

• LVEF ≥ 50

• Primary endpoint: time to progression• Secondary endpoints: OS, ORR, safety• Primary endpoint: time to progression• Secondary endpoints: OS, ORR, safety

RANDOMIZE

RANDOMIZE

*Study closed at 156 patients due to slow accrual following FDA registration of lapatinib for this indication

Von Minckwitz G, et al. SABCS 2007. Poster 4056.

Capecitabine 2,500 mg/m2 d1-14 q21 days(N = 78)

Capecitabine 2,500 mg/m2 d1-14 q21 days

+

Continuation of Trastuzumab 6 mg/kg

every 3 weeks(N = 78)

Trastuzumab Beyond Progression TrialResults

Capecitabine(N = 78)

Capecitabine/Trastuzumab

(N = 78)

Overall Response Rate 24.6% 48.9%

Stable Disease 49.1% 35.1%

Median PFS 5.6 mos 8.5 mos

Median OS 19.9 mos 20.3 mos

Grade 3/4 Adverse Events (> 5% of patients)

Neutropenia 3.3% 5.3%

Vomiting 6% 1.6%

Diarrhea 20.9% 14.8%

Hand-foot syndrome 23.9% 31.1%

Fatigue 6% 4.9%

• Severe cardiac events: 2.9% capecitabine; 4.9% capecitabine/trastuzumab

Von Minckwitz G, et al. SABCS 2007. Poster 4056.

RegistHER: CNS Metastases in Patients with HER2-Postitive MBC

• Multicenter prospective, observational study

• 1023 patients enrolled, 768 included in present analysis

• 30.7% developed CNS metastases, 6.8% at time of initial diagnosis

• Median time to first CNS event: 12.1 mos

• Median survival following first CNS metastases: 13.9 mos

• Characteristics of patients who developed CNS metastases:

– Younger (< 50: 45.3% vs. 39.3% others; P = .0347)

– HR-negative (53.4% vs. 39.6% others; P = .0044)

– Greater tumor burden (2+ metastatic sites 61% vs. 51.6% others; P = .0356)

Yardley D, et al. SABCS 2007 Abstract 6049.

Lapatinib + Capecitabine for the Treatment of Brain Metastases in Patients With HER2+ Breast Cancer

Trial Design and Parent Study Results

Lapatinibmonotherapy750 mg BID

Lapatinib 1,250 mg/day continuously

+Capecitabine

2,000 mg/m2/d po d1-14 q 3 wk

CNS PD*

Parent Study Extension Study

Lin NU, et al. SABCS 2007. Poster 6076.

• Parent Study Results:

– (N = 242)

– ≥ 50% CNS volumetric tumor reduction 6%

– ≥ 20% CNS volumetric tumor reduction 17%

– Median PFS: 9.3 weeks

Lapatinib + Capecitabine for the Treatment of Brain Metastases in Patients With HER2+ Breast Cancer

Extension Study Results

Extension Study Results(N = 51)

Complete Response 0

Partial Response 20%

Stable Disease 39%

Median PFS (all patients) 15.8 weeks

Median PFS (Pts with ≥ 20% reduction in tumor volume)*

20.0 weeks

Median PFS (Pts without ≥ 20% reduction in tumor volume)

8.21 weeks

* HR 0.34 (Patients with ≥ 20% tumor volume reduction versus all others); P =.0013

• Most frequent grade 3/4 adverse events: palmoplantar erthrodysesthesia, diarrhea, nausea, vomiting, and fatigue

Lin NU, et al. SABCS 2007. Poster 6076.

EGFR-Targeted Therapy for MBC

SABCS Abstract 307

TBCRC 001: EGFR Inhibition with Cetuximab in

Metastatic Triple Negative Breast Cancer

Carey LA, Mayer E, Marcom PK, Rugo H, Liu M, Ma C, Rimawi M, Storniolo A, Forero A, Esteva F, Wolff A, Ingle J, Ferraro M, Sawyer L,

Davidson N, Perou CM, Winer EP

Rationale for Combination Cetuximab/Carboplatin in Basal-like Breast Cancer

• Basal-like breast cancer is characterized by high expression of EGFR (one of the basal gene cluster)

• EGFR targeting is effective in basal-like preclinical models.

• Basal-like are "triple negative" (ER-, PR-, and HER2-negative) limiting options to chemotherapy.

• Association with BRCA1 mutation carriers raises question of platinum sensitivity.

Carey LA, et al. SABCS 2007. Abstract 307.

TBCRC 001: Cetuximab in Stage IVTriple Negative Breast Cancer

Study Design

Cetuximab PD Cetuximab + carboplatin

Cetuximab + carboplatin

Randomized Phase II

Tissue, circulating tumor cells

Germline DNA

Arm 1

Arm 2



Objectives• Primary Objectives:

– ORR single agent cetuximab in triple negative metastatic breast cancer (MBC).

– ORR to combination cetuximab/carboplatin in triple negative MBC

• Secondary Objectives:

– Time to disease progression on single agent cetuximab

– Time to disease progression on combination cetuximab/carboplatin.

– Correlation of downstream effects of EGFR inhibitor on MAPK, AKT, Ki67 and EGFR-dependent signaling, proliferation, and apoptosis with toxicity and response (serial bx pts)

– Changes in biomarkers and gene expression in circulating tumor cell

– Overall survival



Patient Population and Treatment

• Patient population

– 100 patients for 93 evaluable

– Stage IV, measurable disease

– ER, PR, and HER2-negative (HER2 0-1+ IHC or FISH-negative)

– 0-3 prior chemotherapy regimens

– Otherwise healthy

– Available archival tissue

• Treatment

– Arm 1:

• Cetuximab 400 mg/m2 load then 250 mg/m2 iv q wk

• Upon progression – add carboplatin AUC 2 iv q wk (3 of 4 wks)

– Arm 2:

• Cetuximab + carboplatin (same doses/schedule)

– Desired 20% of patients undergo serial biopsyCarey LA, et al. SABCS 2007. Abstract 307.


Study Status

Spring 2006Study opens

Arm 1 closes

3/07Interim analysis

10/07Completed

accrual

Arm 1: 31 patients, 24 evaluableArm 2: 69 patients, 44 evaluable

Being reported SABCS 12/07

Data analysis in progress



Patient/Tumor CharacteristicsFactor Arm 1

Median age 51

Race: White 40 (61%)

Black 18 (27%)

Hispanic 5 (8%)

Other 3 (6%)

Post-menopause 49 (75%)

ECOG PS 0-1 59 (93%)

Visceral disease 32 (48%)

Prior chemotherapy 64 (97%)

Anthracycline 3 (80%)

Taxane 41 (62%)

1st line treatment 30 (45%)

2nd- 3rd line treatment 36 (55%)


TBCRC 001: Toxicity

Toxicity % pts any grade (Gr 3-4)

Arm 1a:Cetuximab alone

(N = 31)

Arm 1b: Cetuximab + carboplatin

(N = 22)

Rash 59% (6%) 63% (23%)

Fatigue 33% (6%) 63% (18%)

Pain 17% (3%) 9% (5%)

Mucositis 17% (0) 9% (0)

Nausea/vomiting 17% (3%) 41% (0)

Other GI 13% (0) 18% (0)

Anorexia 10% (0) 9% (0)

Hypomagnesemia 7% (0) 23% (5%)

Neutropenia 0 14% (9%)

Anemia 0 9% (0)

Thrombocytopenia 0 5% (0)

Pneumonitis/bronchospasm 0 14% (9%)


Efficacy Arm 1 (ITT)

ResponseArm 1a: Ct alone

(N = 31)

Arm 1b: C → Ct + Cp

(N = 22)

CR 0 0

PR 2 (6%) 4 (18%)

SD 5 (16%) 5 (23%)

EPD 2 (6%) 3 (14%)

PD 22 (71%) 10 (45%)

RR 6% 18%

CB 10% 27%



Conclusions• Single agent cetuximab is well tolerated, but only 2 RR of 31

evaluable patients were seen, prompting closure of Arm 1 according to a priori stopping rules.

• Disease stabilization was seen in 16%, 1 durable

– Two patients are still in PR at 69 and 42 weeks, respectively

• Analysis of combination therapy on arm 1 reveals a 18% RR and 27% CB rate

– This is encouraging in a largely pretreated population

• Arm 2 analysis is in progress

• Early progression limited treatment in some, supporting the biologically aggressive nature of triple negative breast cancer and potentially complicating efforts to treat


SABCS Abstract 308

Randomized Phase II Study of Weekly Irinotecan/Carboplatin With or Without

Cetuximab in Patients With Metastatic Breast Cancer

O’Shaughnessy J; Weckstein DJ; Vukelja SJ; McIntyre K;

Krekow L; Holmes FA; Asmar L; Blum JL

Weekly Irinotecan/Carboplatin With or Without Cetuximab in Patients With MBC

Rationale• Irinotecan and carboplatin (ICb) is a synergistic antineoplastic

combination in several cancers• Weekly irinotecan is an active agent in MBC1 • Epidermal growth factor receptor (EGFR) inhibition enhances antitumor

activity of both irinotecan and cisplatin in breast cancer preclinical models2,3

• EGFR is overexpressed in over 50% of triple negative breast cancers4 and may be involved in endocrine-therapy resistance as well5

• It is hypothesized that the addition of cetuximab (E) to ICb will increase the overall response rate of the ICb combination and will prolong the median time to progression for patients with metastatic breast cancer

References:1Perez EA, Hillman DW, Mailliard JA, et al. J Clin Oncol. 2004;22:2849-2855.2Ciardiello F, Bianco R, Damiano V, et al. Clin Cancer Res. 2000;6:3739-3747.3Ciardiello F, Tortora G. Expert Opin Investig Drugs. 2002;11:755-768.4Nielsen TO, Hsu FD, Jensen K, et al. Clin Cancer Res. 2004; 10:5367-5374.5Johnston SR, Head J, Pancholi S, et al. Clin Cancer Res. 2003; 9:524S-532S.


Key Eligibility

• Metastatic breast cancer measurable by RECIST

• 0-1 chemotherapy regimens for metastatic disease

• No prior irinotecan or platinum agent

• If HER2-positive (HER2+), patients must have progressed on trastuzumab

O’Shaughnessy J, et al. SABCS 2007. Abstract 308.


Treatment Schema

STRATIFYTriple negative

(ER-, PR-, HER2-negative)

*Irinotecan (I) 100 mg/m2

Carboplatin (Cb) AUC = 2.5

Day 1, 8 q 21 days

*Irinotecan (I) 100 mg/m2, D1, 8 q 21dCarboplatin (Cb) AUC = 2.5, D1, 8 q 21d

Cetuximab (E) 400 mg/m2, D1, then 250 mg/m2 weekly thereafter

Cetuximab (E) alone

at progression

*Starting ICb doses decreased to 90 mg/m2 and AUC = 2.0 midway through enrollment due to diarrhea with ICb + E

RANDOMIZE


ICb ± E: Patient Characteristics Arm 1 (ICb) Arm 2 (ICb+E) Number of Patients Enrolled* 75 79 Median Age (Years) 53 55 Number and Percentage (%) of Patients ECOG Performance Status

0 52 (69) 44 (56) 1 19 (25) 34 (43) 2 4 (5) 1 (1)

Receptor Status ER-/PR-/HER2- (Triple Negative) 36 (48) 42 (53) HR+/HER2- 38 (51) 35 (44) HER2+ 1 (1) 2 (3)

Metastatic Sites Bone 30 (40) 28 (35) Brain 2 (3) 5 (6) Liver 25 (33) 30 (38) Lung 25 (33) 34 (43) Lymph Node 19 (25) 33 (42)

Prior Treatment Anthracycline 61 (81) 58 (73) Trastuzumab** 2 (3) 3 (4) Taxane 62 (83) 56 (71)

Prior Adjuvant Chemotherapy 57 (70) 57 (70) Prior Metastatic Chemotherapy 33 (40) 22 (27) *154 patients received at least 1 dose of ICb±E **All HER2+ patients received trastuzumab, however additional patients also received trastuzumab. Therefore, numbers for trastuzumab are slightly larger than HER2+ patients.

Note: Percentage totals in this table & subsequent tables may not add up to 100%, due to rounding.

Pts Evaluable for Efficacy (N = 138) Arm 1 (ICb) Arm 2 (ICb+E)

Number of Patients 69 69

Overall Response Rate 21 (31) 26 (38) CR 4 (6) 4 (6) PR 17 (25) 22 (32) SD 31 (45) 28 (40) PD 17 (25) 15 (22)

Triple Negative Pts Number of Patients 33 39 Overall Response Rate 10 (30) 19 (49) CR 3 (9) 3 (8) PR 7 (21) 16 (41) SD 17 (52) 15 (39) PD 6 (18) 5 (13)

HR+/HER2 Negative Pts Number of Patients 35 28 Overall Response Rate 10 (29) 7 (25) CR 1 (3) 1 (4) PR 9 (26) 6 (21) SD 14 (40) 12 (43) PD 11 (31) 9 (32)


Overall Efficacy by Subset



Conclusions

• Cetuximab did not improve the ORR, PFS and OS when added to irinotecan/carboplatin in MBC patients

• On subset analysis, starting dose irinotecan/carboplatin plus cetuximab had a higher ORR than starting dose irinotecan/carboplatin alone

• On subset analysis, the addition of cetuximab increased the ORR associated with irinotecan/carboplatin in triple negative metastatic breast cancer

• Irinotecan/carboplatin is an active regimen for both HR+ and triple negative breast cancer

• Single-agent cetuximab was minimally active following progression on irinotecan/carboplatin

• Diarrhea is the primary toxicity associated with irinotecan/carboplatin and this was exacerbated by the addition of cetuximab


Treatment of Advanced Breast Cancer

Closing Comments

William J. Gradishar, MD

Documents

A Report from SABCS Up-to-Date Review of the Treatment of Advanced Breast Cancer