ASCO 2012: Breast Cancer Updates

Hope S. Rugo, MD Professor of Medicine Director, Breast Oncology and Clinical Trials Education UCSF Helen Diller Family Comprehensive Cancer Center

Outline
Whats new in the treatment of HER2 positive metastatic breast cancer?
Emilia - TDM1 compared to lapatinib/capecitabine
Blackwell et al, #LBA1

MA.31 - Is lapatinib as good or better than trastuzumab?

Gelmon et al, #LBA671

NSABP B-41 lapatinib as neoadjuvant therapy

Robidoux et al, #LBA506

Do bisphosphonates improve breast cancer outcome?

MA.27 Impact of osteoporosis and osteoporosis therapy
Sheperd et al, #501

AZURE impact in postmenopausal women

Marshal, Coleman et al, #502

Outline (2)
DCIS
RTOG 9804 - does everyone with DCIS need radiation?
McCormick et al, #1004

Evaluating chemotherapy combinations, doses

NSABP B-38 adding gemcitabine, sequential versus combination chemotherapy in early stage disease?
Swain et al, #LBA1000

CALGB 40502 comparing microtubule toxins in the metastatic setting

Rugo et al, #CRA1002

What is the role of maintenance chemotherapy for patients with metastatic disease?
Im et al, #1003

Can we target the androgen receptor in TNBC?

Gucalp et al, #1006

HER2 Positive MBC

The problem
Despite high response rates, almost all patients eventually develop progressive disease

How can we overcome resistance that we dont understand? Data before pertuzumab and T-DM1:
Start with trastuzumab + chemotherapy/hormone rx Continue HER2 directed therapy through progression
Capecitabine/lapatinib > capecitabine (Geyer et al) Capecitabine/trastuzumab > capecitabine (von Minckwitz et al) Lapatinib/trastuzumab > lapatinib (Blackwell et al)

T-DM1: Dual Mechanisms of Action

Combined Targeted Therapy

Trastuzumab Biologic Activity

Blocks downstream HER2 signaling to inhibit proliferation of tumor cells Flags HER2-positive tumor cells for destruction via antibody-dependent cellmediated cytotoxicity Inhibits HER2 shedding
aDM1

Targeted Intracellular Delivery of DM1a

T-DM1 binds to the HER2 receptor and is internalized DM1 is released inside the cell, resulting in mitotic arrest and apoptosis Systemic toxicity is limited due to low HER2 expression in normal tissues

is 25500 fold more potent than taxane in cytotoxic assays.

T-DM1 selectively delivers DM1 to HER2-positive tumor cells

Targeted intracellular delivery of a potent antimicrotubule agent, DM1 T-DM1 binds to the HER2 protein Spares normal tissue from toxicity of free DM1 on cancer cells HER2 to HER2 Trastuzumab-like activity by binding

Receptor-T-DM1 complex is internalized into HER2-positive cancer cell

Potent antimicrotubule agent is released once inside the HER2-positive tumor cell

Phase II Randomized International Open Label Studyb

Trastuzumab

HER2-positive, recurrent locally advanced breast cancer or MBC (N=137) First line setting

8 mg/kg loading dose; 6 mg/kg q3w IV

PDa

1:1

+ Docetaxel 75 or 100 mg/m2 q3w

Crossover to T-DM1 (optional)

(n=70) T-DM1
3.6 mg/kg q3w IV

PDa

(n=67)

Stratification factors: World region, prior adjuvant trastuzumab therapy, disease-free interval Primary end points: PFS by investigator assessment, and safety Data analyses were based on clinical data cut of Nov 15, 2010 prior to T-DM1 crossover

Key secondary end points: OS, ORR, DOR, CBR, and QOL
Demographics imbalanced: 29 vs 34 % stage IV at diagnosis, 27 vs 18% exposed to prior trastuzumab, 40 vs 33% exposed to prior taxanes
Hurvitz et al, ESMO 2011

aPatients bThis

were treated until PD or unacceptable toxicity. was a hypothesis generating study; the final PFS analysis was to take place after 72 events had occurred.

PFS by Investigator
1.0

N=137

Median PFS, mos

Hazard ratio 95% CI 0.364 0.968

Log-rank P value

Proportion progression-free

0.8

Trastuzumab + docetaxel (n=70) 9.2 T-DM1 (n=67) 14.2

0.594

0.0353

0.6

0.4

0.2

Crossover allowed to TDM1 Significantly less toxicity with TDM1, better patient reported outcomes

0.0 0 2 4 6 53 46 Number of patients at risk T+D 70 66 63 T-DM1 67 60 51 8 10 Time (months) 43 42 27 35 12 12 22 14 4 15 16 2 6 18 2 3 20 0 0

Hazard ratio and log-rank P value were from stratified analysis.

Hurvitz SA, et al. Abstract 5.001. ESMO 2011.

Clinical Rationale for EMILIA

T-DM1
Two single-arm phase 2 trials in patients who received 1 HER2-directed therapies for MBC ORR: 25.9% (N=112)1 and 34.5% (N=110)2

Capecitabine + lapatinib
Randomized phase 3 trial in patients who received prior trastuzumab Median TTP longer with capecitabine + lapatinib (n=163) vs. capecitabine (n=161), no difference in OS 8.4 vs. 4.4 months (HR=0.49; P<0.001)4
1Burris

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

EMILIA Study Design

HER2+ (central) LABC or MBC (N=980) Prior taxane and trastuzumab Progression on metastatic tx or within 6 mos of adjuvant tx

T-DM1 3.6 mg/kg q3w IV

1:1

PD

Capecitabine
1000 mg/m2 orally bid, days 114, q3w

+ Lapatinib
1250 mg/day orally qd

PD

Stratification factors: World region, number of prior chemo regimens for MBC or unresectable LABC, presence of visceral disease

Primary end points: PFS by independent review, OS, and safety

Key secondary end points: PFS by investigator, ORR, duration of response, time to symptom progression
Blackwell et al, ASCO 2011

EMILIA - Demographics
496 vs 495 randomized Median age 53, 27% from U.S. Prior therapy
All treated with prior taxane 16% received prior trastuzumab for early stage disease 57% received at least one year of prior trastuzumab, 88% prior treatment for MBC 79% measurable disease, 53-57% HR+

Progression-Free Survival by Independent Review

Median (mos) No. events Cap + Lap 6.4 304 T-DM1 9.6 265 Stratified HR=0.650 (95% CI, 0.55, 0.77) P<0.0001
Subroup analysis: TDM1 superior regardless of line of therapy (1-3) and HR status

No. at risk by independent review: Cap + Lap 496 404 310 176 T-DM1 495 419 341 236

129 183

73 130

53 101

35 72

25 54

14 44

9 30

8 18

5 9

1 3

0 1

0 0

Unstratified HR=0.66 (P<0.0001).

Overall Survival: Interim Analysis

Unstratified HR=0.63 (P=0.0005). NR=not reached.

Objective Response Rate (ORR) and Duration of Response (DOR) in Patients with Measurable Disease
ORR DOR

Overview of Adverse Events

Cap + Lap (n=488) All-grade AE, n (%) Grade 3 AE, n (%) AEs leading to treatment discontinuation (for any study drug), n (%) AEs leading to death on treatment, n (%)
a

T-DM1 (n=490) 470 (95.9) 200 (40.8) 29 (5.9) 1 (0.2) 8 (1.7)

477 (97.7) 278 (57.0) 52 (10.7) 5 (1.0) 7 (1.6)

LVEF <50% and 15-point decrease from b baseline, %

aCap

+ Lap: CAD, multiorgan failure, coma, hydrocephalus, ARDS; aT-DM1: metabolic encephalopathy. bEvaluable pts: 445 (Cap + Lap); 481 (T-DM1).

Cap and Lap: More grade 3 diarrhea (21 vs 1.6%), hand foot syndrome (16 vs 0%) TDM1: More transaminiitis (4 vs 1%), grade 3/4 thrombocytopenia (13 vs 0%)

Summary and Ongoing Trials

T-DM1 superior to cap/lap
PFS, interim OS, response, safety Will clearly be a new standard in this setting Approval expected towards the end of 2012

Marianne (n=1092, untreated HER2+ MBC)

Three arms Trastuzumab + taxane TDM1 + pertuzumab TDM1 plus placebo

Th3RESA (n=795)
Prior trastuzumab/lapatinib/anthra/taxane/cape 2:1 randomization to TDM1 v TPC

Early Stage Trials

Post-neoadjuvant cooperative group Neoadjuvant company sponsored Adjuvant small tumors: ATTEMPT Trial
Tolaney PI (DFCI)
Randomize 3:1
3 Trastuzumab emtansine q 3 weeks x 17 N=375 Paclitaxel + Trastuzumab weekly x 12 Trastuzumab every 3 weeks x 13 N=125

Stage I BC HER2+ N=500

Two Questions
Can lapatinib overcome trastuzumab resistance?
Doesnt require externalized receptor Can this agent overcome resistance mediated by alterations of the PI3K pathway?

Can dual targeting of the HER2 Receptor overcome resistance more effectively?
Maintains benefits of trastuzumab while targeting the pathway through an alternate mechansim

Trastuzumab 2 1

Lapatinib

Downstream signaling pathways Cell proliferation Cell survival

MA.31/ EGF108919: Metastatic Disease

Randomize
EXPERIMENTAL ARM
24 Weeks: Lapatinib plus Taxane Until PD: Lapatinib

STANDARD ARM
24 Weeks: Until PD: Trastuzumab plus Trastuzumab Taxane

Primary Outcome: PFS

Sample Size: ~ 600 (536 centrally confirmed HER2+ patients)
Gelmon et al, LBA671, ASCO 2012

Progression Free Survival Centrally-confirmed HER2+ Analysis

Median PFS TTAX/T= 13.7 months Median PFS LTAX/L = 9.0 months HR = 1.48 (95% CI = 1.15 1.92), P = 0.003

TTAX/T LTAX/L

TTAX/T LTAX/L

Serious Adverse Events

LTAX/L (Total SAE reports = 136)
EVENT Diarrhea Febrile Neutropenia Total Number* 32 17 Number post amendment ** 25 7

TTAX/T (Total SAE reports = 78)

EVENT Diarrhea Febrile Neutropenia Total Number* 5 7 Number post amendment ** 3 6

** Protocol Amendment after first 189 patients were randomized mandated * Included as one of the adverse terms a single SAE report primary GCSF prophylaxis for event patients onwithin docetaxel and lapatinib

Discontinuation rates significantly higher for lapatinib arm

Gelmon et al, LBA671, ASCO 2012

Neo-Altto
(N=455)

GeparQuinto
(N=615)

Baselga J et al. Lancet 2012 Untch M et al. Lancet Oncology 2012

Pertuzumab + trastuzumab: improved pCR (NeoSphere, Tryphaena)

NSABP B-41
Schema (n=529)
Tissue for Biomarkers Tissue for Biomarkers

Operable Breast Cancer

HER-2 neu Positive T > 2 cm

AC WP + T
R

AC WP + L1250
AC WP + T + L 750
WP=Weekly Paclitaxel

S U R Trastuzumab for a total of G 1 year E R Y

Endpoints: pCR, cardiac events, DFS, OS WP: d 1, 8, 15 q 28 d x 4 Robidoux et al, #LBA506

Results
pCR breast
53% (T) vs 53% (L)vs 62% (TL) (P 0.095 for TL vs T) pCR breast and nodes 49% (T) vs 47% (L) vs 60% (TL) (p=0.056 TL vs T) pCR based on HER2 (IHC 3+, n=421, 81%) 55% (T) vs 53% (L) vs 71% (TL) (p=0.006 TL vs T) Completion of protocol defined neoadjuvant Rx 78% (T) vs 68% (L) vs 63% (TL) (p=0.01)

Toxicity similar except diarrhea and overall

Grade 3: 2% (T) vs 20% (L) vs 27% (TL) (p<0.001)

ALTTO
Paclitaxel weekly or TCH
Lapatinib Closed due to futility

Surgery

+/Anthracycline containing CT

Trastuzumab

Lapatinib

Trastuzumab

Lapatinib Trastuzumab

1 year

Clinical Context
What does this data mean to our clinical practice?
TDM-1 is a new and effective treatment for HER2+ metastatic disease progressing on trastuzumab Toxicities are unique but generally well tolerated Likely to be FDA approved by the end of the year

Pertuzumab approved in the first-line setting in combination with trastuzumab/docetaxel (PFS 18.5 mo.) Lapatinib is associated with more toxicity and less efficacy than trastuzumab in the first-line metastatic setting Lapatinib/capecitabine is still an option for later line therapy or in special settings (low EF (?), brain metastases)
Pertuzumab/ Trastuzumab/ Taxane Pertuzumab/ Trastuzumab TDM-1

Lapatinib/ Capecitabine

Multiple drugs in clinical trials: inhibitors of mTOR, HSP90, TKs, vaccines

Osteoporosis
Osteoporosis is characterized
by decreased bone mineral density.

The increased bone resorption

associated with osteoporosis may provide fertile soil for cancer growth.

Will osteoporosis or therapy

for osteoporosis affect outcome in patients with early stage breast cancer?

Observational Studies of Bisphosphonate Use and Breast Cancer Incidence

Author Study Design Casecontrol Casecontrol Patient Cases
(% bisphosphonate)

Control Subjects
(% bisphosphonate)

Breast Cancer Association

Rennert Newcomb

1822 (10.5%) 2336 (4.4%)

2207 (14.8%) 2975 (6.2%)

OR 0.72 (0.57-0.90) OR 0.67 (0.51-0.89) HR 0.68 (0.52-0.88)

Chlebowski Cohort

154, 768 women, 2816 (1.8%) bisphosphonate users, 5,092 breast cancer cases

Rennert G, Pinchev M, Rennert HS JCO, 2010 June 12 Epub ahead of print Newcomb PA, Trentham-Dietz A, Hampton JM Bristish J of Cancer 2010;102:799-802 Chlebowski RT, Chen Z, Cauley JA, et al JCO 2010 June 12 Epub ahead of print

 Osteoporosis: 17% (1294) Osteoporosis therapy: 36% (2711)

116 (0.2%) took raloxifene prior to study 39 started after randomization

Of those with osteoporosis

85% (1101) took osteoporosis therapy

Of those taking osteoporosis therapy

25.6% (1610) did not report osteoporosis Shepherd LE et al, ASCO 2012, #501

EFS by Osteoporosis Therapy

HR (Yes/No) = 0.70 p<.00001

Shepherd LE et al, ASCO 2012, #501

Conclusions
Patients with self-reported osteoporosis and osteoporosis therapy had a lower incidence of breast cancer relapse Patients receiving osteoporosis therapy, regardless of report of osteoporosis, had a lower incidence of relapse Limitations
Self reporting Variations in osteoporosis therapy and duration Event rate (9.2%) and distant relapse rate low (4.1%)

The seed and soil hypothesis

'While many researchers have been studying the seed, the properties of the soil may reveal valuable insights into the metastatic peculiarities in cancer cases.'
The Distribution of Secondary Growths in Cancer of the Breast. The Lancet. 1889

Stephen Paget 18551926

AZURE: Study Design

Accrual September 2003 - February 2006

Standard therapy

3,360 Breast Cancer Patients

Stage II/III

Standard therapy + Zoledronic acid 4 mg

No difference in disease free or invasive disease free survival (IDFS)
6 doses Q3-4 weeks
Months

8 doses Q 3 months 30

5 doses Q 6 months 60

Zoledronic acid treatment duration 5 years

Coleman et al. N Engl J Med 2011; 365:1396-1405

AZURE: Invasive DFS and OS by Menopausal Status

IDFS: Pre, Peri, and Unknown Menopause
1.0
Proportion Alive and invasive Disease Free

IDFS: > 5 Yrs Postmenopausal

1.0
Proportion Alive and invasive Disease Free 0.8 0.6 0.4 0.2 0

0.8
0.6

Adjusted HR: 1.15

Adjusted HR: 0.75

(95% CI: 0.59-0.96; P = .02) 116 vs 147 events Pts at Risk, n
ZOL: 519 490 No ZOL: 522 482 0 447 431 418 396 393 368 177 156 25 21 0 0

(95% CI: 0.97-1.36; P = .11) 288 vs 256 events 0.4 Pts at Risk, n 0.2 1162 1088 996 0
No ZOL: 1156 1092 995 ZOL: 919 920 829 853 393 388 57 47 0 0

6 12 18 24 30 36 42 48 54 60 66 72 78 84

6 12 18 24 30 36 42 48 54 60 66 72 78 84

Time From Randomization (Mos)

Time From Randomization (Mos)

N=2318
OS: Pre, Peri, and Unknown Menopause
1.0
Proportion Alive Proportion Alive 0.8 0.6

N=1041
OS: > 5 Yrs Postmenopausal
1.0
0.8 0.6 0.4 0.2 0

Adjusted HR: 0.97

Adjusted HR: 0.74

(95% CI: 0.55-0.98; P = .04) 82 vs 111 events Pts at Risk, n
ZOL: 519 502 No ZOL: 522 509 0 482 475 448 441 422 401 190 177 29 26 0 0

(95% CI: 0.78-1.21; P = .81) 161 vs 165 events 0.4 Pts at Risk, n 0.2 1162 1131 1078 1020 0
No ZOL: 1156 1123 0 1076 1032 ZOL: 955 963 466 446 71 60 0 0

6 12 18 24 30 36 42 48 54 60 66 72 78 84

6 12 18 24 30 36 42 48 54 60 66 72 78 84

Time From Randomization (Mos)

Time From Randomization (Mos)

Coleman RE, et al. N Engl J Med. 2011;365:1396-1405.

Treatment Effects on First IDFS Recurrence Outside Bone by Menopausal Status

Menopausal Group Odds Ratio

Pre, Peri and unknown menopause

HR: 1.32 (95% CI: 1.09-1.59)

> 5 yrs postmenopause

HR: 0.70 (95% CI: 0.54-0.92)
TOTAL: 6% +/- 8 Z = .79, P = .43

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

21 (heterogeneity) = 14.00; P = < .001 Adjusted for imbalances in ER, lymph node status, and T stage. by menopausal status or age No significant differences in bone recurrence

SABCS 2011

Conclusions
In this population of patients, primarily treated with adjuvant chemotherapy
No effect of zoledronate on breast cancer outcome in the unselected overall population Suggestion of improved outcome in pts with >5 years of menopause, due to recurrence outside bone

Unplanned subset analysis of interest but not sufficient to influence patient care
Variable results in 7 published trials Bisphosphonates should be used to prevent or treat bone loss in patients with breast cancer Bisphosphonates should not be used only for the purpose of preventing breast cancer recurrence

Ongoing studies are evaluating the impact of denosumab on breast cancer outcome in women with early stage disease
D-Care, ABCSG-18 UCSF phase II trial in pts with DTCs

RTOG 9804: Does Good Risk DCIS Always Need Radiation?

Common disease, low long-term risk Primary goal of treatment is to prevent invasive IBTR Clearly variable risk exist based on biology, age, extent of disease We have transitioned from mastectomy to lumpectomy and radiation with essentially equivalent outcomes
Does everyone need radiation?
McCormick et al, #1004

RTOG 9804: Eligibility and Schema

No palpable mass, low or intermediate grade, < 2.5 cm, margins > 3 mm
Age 1. < 50 2 50 Final Path Margins 1. Negative (re-excision) 2. 3-9 mm 3. 10 mm Mammographic/Pathologic Size of Primary 1. 1 cm 2. > 1 cm to 2.5 cm Nuclei Grade 1. Low 2. Intermediate Tamoxifen Use 1. No 2. Yes

N=585
Arm 1 Observation
tamoxifen, 20 mg per day for 5 years

Results at 5 years
Local failure in ipsilateral breast 3.2 vs 0.4% HR 0.14, p=0.0022 15 vs 2 events DFS Identical HR 0.84, p=0.48

Arm 2 Radiation therapy to

the whole breast, tamoxifen, 20 mg per day for 5 years

McCormick et al, #1004

Summary
In patients with good risk DCIS, the addition of radiation
Added little to local control Added nothing to survival

Use of genomic tests, such as the GH DCIS score, may help refine treatment decisions Longer follow-up of this trial will be interesting.

NSABP B-38 Schema

(n=4894, med FU 5.3 yrs)
Stratification: # nodes, HR status + or neg, Surgery and RT

TAC q 3 wk

All arms pegfilgrastim or filgrastim

AC q 2 wk

P q 2 wk

N+
AC q 2 wk PG q2 wk

ER positive: hormonal therapy for 5 yrs after chemo 80% ER+ 65% 1-3+ nodes

Swain et al, LBA#1000

P = paclitaxel 175 mg/m2 G = gemcitabine 1000 mg/m2

NSABP B-38 Disease-Free Survival

Disease-Free Survival
0.8 0.4 0.6 1.0

Treat

Events

P-value* (vs ACPG)

TAC 1610 327 ACP 1618 294 ACPG 1613 320

0 1 2

0.410 0.388

0.0

0.2

# at risk
1610 1618 1613 1532 1554 1533 1424 1452 1453

Years since Randomization

1331 1348 1350 1217 1240 1244 719 754 730

* Stratified log-rank test adjusting for randomization factors

Survival, Toxicity and Conclusions

Overall survival no different between arms More deaths on treatment in the TAC arm than AC/P or AC/PG (13/5/7, p=0.2) Addition of gemcitabine did not improve outcome DD AC/P similar to TAC
More FN, anemia, diarrhea, less neuropathy with TAC

This trial started in 2004 and completed accrual in 2007

About 10 years from initial planning to negative results We can no longer do large trials testing therapy based solely on extent of disease

CALGB 40502 - NCCTG N063H - CTSU 40502

An Open Label Phase III Trial of Firstline Therapy for Locally Recurrent or Metastatic Breast Cancer
N = 900 (planned)
Strata: Adj taxanes ER/PR status Exp 1 nab-paclitaxel 150 mg/m2 weekly + bevacizumab 10 mg/kg q 2 wks2

Control

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

ixabepilone 16 mg/m2 weekly + bevacizumab 10 mg/kg q 2 wks3

mg/m2

Restage q 2 cycles until disease progression

Exp 2

All chemotherapy was given on a 3 week on, one week off schedule Patients could discontinue chemotherapy and continue bevacizumab alone after 6 cycles if stable or responding disease
1. Miller et al, N Engl J Med, 2007 2. Gradishar et al, J Clin Oncol, 2009 3. Dickson et al, Proc ASCO 2006.

CALGB 40502 Progression-Free Survival By Treatment Arm

1 Proportion Progression-Free
Comparison HR 1.19 1.53 P-value 0.12 < 0.0001 95% CI

0.8

nab vs. pac ixa vs. pac

Pac 0.96-1.49
1.24-1.90 Ixa

Nab

0.4

0.6

paclitaxel nab-paclitaxel ixabepilone

0.0
0
Agent paclitaxel nab-Paclitaxel ixabepilone

0.2

10
N 283 271 245

20
Median PFS 10.6 9.2 7.6

30

Months From Study Entry

CALGB 40502 Overall Survival

1 Proportion Alive
paclitaxel Pac nab-paclitaxel Nab ixabepilone Ixa

0.4
Comparison

0.6

0.8

HR 1.02 1.28

P-value 0.92 0.10

95% CI 0.75-1.38 0.95-1.72

0.2 0.0
0

nab vs. pac ixa vs. pac

10
Agent paclitaxel nab-paclitaxel ixabepilone

20
N 283 271 245

30
Median OS 26 27 21

Months From Study Entry

Dose Reductions by Cycle 3 duction

45%
60 50

All Cause Cumulative Discontinuation by Cycle

40

Percent

paclitaxel nab-paclitaxel ixabepilone

30

15%

15%

20

10

nab Pac pac ixa nab Ixa

Cycle 3 Cycle 3

Cycle number

Sensory Neuropathy
Arm nab
(N = 258)

Other AEs Grade 3+

nab
(N = 258)

pac
(N = 262)

ixa
(N = 237)

Grade 3+ Leukopenia

17%
p = 0.0004

7% 18% 8% 9% 4% 2%

3%
p = 0.042

25%
p=0.012

Neutropenia Hypertension

47%
p = 0.0001

7%
p = 0.0002

7% 16%
p = 0.010

11% 15%
p = 0.036

pac
(N = 262)

16% 25%
p=0.022

Fatigue Pain Motor neuropathy

ixa
(N = 237)

10%
p = 0.010

4% 6%
p = 0.021

10%
p = 0.0003

Summary and interpretation

Neither weekly nab-paclitaxel or ixabepilone are superior to weekly paclitaxel Weekly paclitaxel appears to offer better progression-free survival than ixabepilone Hematologic toxicity was greater with nabpaclitaxel; sensory neuropathy was greater in both experimental arms compared to paclitaxel Paclitaxel is a reasonable choice in a similar setting 100 mg/m2 is the most appropriate dose for weekly nab-paclitaxel

Study Design: Role of Maintenance Therapy

Prospective, phase III, multi-center, randomized study Enroll period: 2007.05 2010.09
PD 324 MBC patients with no prior chemotherapy 6 cycles of PG PG regimen
Paclitaxel 175 mg/m2 Day 1 Gemcitabine 1,250 mg/m2 Day 1 & 8 every 3 weeks

Off the study

till PD

CR/PR/SD N=231

N=115
Observation till PD

Stratification 1. Visceral diseases 2. Prior adjuvant taxane 3. Response(CR/PR vs. SD) 4. HR(+) vs. HR(-)

N=116

Primary Endpoint; PFS from Randomization Secondary Endpoints; OS, Toxicities, QoL, and Response Duration

Im et al, #1003

75% HR positive, ~20% received hormone therapy in the metastatic setting

 Subgroup analysis
Primary benefit in HR negative (n=59), and in premenopausal women

Toxicity
More toxicity in the maintenance arm > cycle 6 QOL similar between the two arms

Interpretation complicated by lack of use of hormone therapy in the control arm

This should not change our general management of patients in this setting For hormone receptor negative disease, better to continue at least a low dose of chemotherapy

Other Interesting Data

Targeting the androgen receptor in ER/PR negative disease (Gucalp et al, #1006, TBCRC)
12% of screened patients were AR+ Treated with bicalutamide 150 mg/day

26 patients
Median age 66 15% visceral metastases Median 1 prior chemotherapy regimen for MBC

24% clinical benefit rate (5/24)

Disease in LN, breast and bone, one GI

A larger trial is planned

Summary
New HER2 directed therapy provides increased efficacy without significant toxicity
Adjuvant and neoadjuvant trials are ongoing or planned

Zoledronate may improve outcome in subsets of women with early stage breast cancer and high bone turnover
This is not practice changing The current recommendation is to use potent bisphosphonates to treat osteoporosis, or osteopenia in high risk women

Radiation appears to add little benefit to patients with low risk DCIS treated with BCT

Summary (2)
Early stage disease
Gemcitabine does not add to DD AC/P but increases toxicity Approach to clinical trials needs to change
Its all about biology and understanding the drivers of disease

Metastatic disease
Paclitaxel is the preferred microtubule targeting agent in 1st line MBC Maintenance chemotherapy may provide benefit, but this is likely to be in HR negative or resistant disease More studies targeting the androgen receptor are warranted

Phase 1b Study: all BC

PLX3397 oral daily dosing Eribulin: 1.4 mg/m2 iv, day 1 and 8 Each cycle of treatment lasts 21 days First Cohort = 600 mg/day 3-6 patients

KOMEN Promise Grant: Can inhibition of macrophages Second Cohort = 800 mg/day reverse chemotherapy 3-6 patients resistance?
Phase II Primary Endpoint: PFS at 12 weeks

Third Cohort = 1000 mg/day 3-6 patients

Biopsy for immune profiling

Lead in period of 5-7d with PLX3397 at MTD oral daily dosing (day -7/5 to day 0) Add Eribulin 1.4 mg/m2 iv day 1 and 8 Each cycle of treatment lasts 21 days

Phase II Study: Metastatic TNBC

Starting Day 1

PI: Hope S. Rugo, UCSF, Lisa Coussens, OHSU, Shelley Hwang, Duke.