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• What’s 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 don’t 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

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

• Blocks downstream HER2 signaling to inhibit proliferation of tumor cells

• Flags HER2-positive tumor cells for destruction via antibody-dependent cell-mediated cytotoxicity

• Inhibits HER2 shedding

aDM1 is 25–500 fold more potent than taxane in cytotoxic assays.

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

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

Potent antimicrotubule agent is released once inside the HER2-positivetumor cell

T-DM1 binds to the HER2 protein on cancer cells

• Targeted intracellular delivery of a potent antimicrotubule agent, DM1

• Spares normal tissue from toxicity of free DM1• Trastuzumab-like activity by binding to HER2HER2

• 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

Phase II Randomized International Open Label Studyb

1:1

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

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

+ Docetaxel 75 or 100 mg/m2 q3w

(n=70)

Crossover toT-DM1 (optional)

PDa

T-DM13.6 mg/kg q3w IV

(n=67)PDa

aPatients were treated until PD or unacceptable toxicity.bThis was a hypothesis generating study; the final PFS analysis was to take place after 72 events had occurred. Hurvitz et al, ESMO 2011

Time (months)Time (months)

PFS by Investigator P

rop

ort

ion

pro

gre

ssi

on

-fre

e P

rop

ort

ion

pro

gre

ssi

on

-fre

e

1.0

0.8

0.6

0.4

0.2

0.0

1.0

0.8

0.6

0.4

0.2

0.00 2 4 6 8 10 12 14 16 18 200 2 4 6 8 10 12 14 16 18 20

Number of patients at risk

T+D 70 66 63 53 43 27 12 4 2 2 0T-DM1 67 60 51 46 42 35 22 15 6 3 0

Number of patients at risk

T+D 70 66 63 53 43 27 12 4 2 2 0T-DM1 67 60 51 46 42 35 22 15 6 3 0

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

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

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

MedianPFS, mos

Hazard ratio 95% CI

Log-rank P value

9.214.2

0.594 0.364– 0.968

0.0353

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

N=137

Crossover allowed to TDM1Significantly less toxicity with TDM1, better patient

reported outcomes

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

• 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

1:1

HER2+ (central) HER2+ (central) LABC or MBC LABC or MBC

(N=980)(N=980)

•Prior taxane and Prior taxane and trastuzumab trastuzumab

•Progression on Progression on metastatic tx or metastatic tx or within 6 mos of within 6 mos of adjuvant txadjuvant tx

PDT-DM1 3.6 mg/kg q3w IV

Capecitabine 1000 mg/m2 orally bid, days 1–14, q3w

+ Lapatinib

1250 mg/day orally qd

PD

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

496 404 310 176 129 73 53 35 25 14 9 8 5 1 0 0

495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0

Cap + Lap

T-DM1

No. at risk 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

Unstratified HR=0.66 (P<0.0001).

Subroup analysis:TDM1 superior regardless of line of therapy (1-3) and HR status

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

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

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

Cap + Lap (n=488)

T-DM1 (n=490)

All-grade AE, n (%) 477 (97.7) 470 (95.9)

Grade ≥3 AE, n (%) 278 (57.0) 200 (40.8)

AEs leading to treatment discontinuation (for any study drug), n (%)

52 (10.7) 29 (5.9)

AEs leading to death on treatment, n (%)a 5 (1.0) 1 (0.2)

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

7 (1.6)

8 (1.7)

• 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)

Stage I BCHER2+N=500

Ra

nd

om

ize

3:1

Trastuzumab emtansine q 3 weeks x 17N=375

Paclitaxel + Trastuzumab weekly x 12 Trastuzumab every 3 weeks x 13

N=125

3

1

Two Questions• Can lapatinib overcome trastuzumab

resistance?– Doesn’t 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

1 2

Downstream signaling pathways

Cell proliferation Cell survival

21 1 2

TrastuzumabT

LapatinibL L L L L L

Primary Outcome: PFS

RandomizeMA.31/ EGF108919: Metastatic Disease

Sample Size: ~ 600 (536 centrally confirmed HER2+ patients) )

EXPERIMENTAL ARM

24 Weeks: Lapatinib

plus Taxane

Until PD:

Lapatinib

STANDARD ARM

24 Weeks: Trastuzumab

plus Taxane

Until PD:

Trastuzumab

Gelmon et al, LBA671, ASCO 2012

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

Progression Free Survival Centrally-confirmed HER2+ Analysis

TTAX/TLTAX/L

TTAX/T LTAX/L

Serious Adverse Events

LTAX/L(Total SAE reports = 136)

TTAX/T(Total SAE reports = 78)

EVENT Total Number*

Number post amendment **

EVENT Total Number*

Number post amendment **

Diarrhea 32 25 Diarrhea 5 3

Febrile Neutropenia

17 7 Febrile Neutropenia

7 6

* Included as one of the adverse event terms within a single SAE report** ** Protocol Amendment after first 189 patients were randomized mandated

primary GCSF prophylaxis for patients on docetaxel and lapatinib

• Discontinuation rates significantly higher for lapatinib arm

Gelmon et al, LBA671, ASCO 2012

Neo-Altto(N=455)

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

GeparQuinto(N=615)

Pertuzumab + trastuzumab: improved pCR (NeoSphere, Tryphaena)

NSABP B-41 Schema (n=529)

Operable Breast Cancer HER-2 neu Positive

T > 2 cm

R

AC→ WP + T

AC→ WP + L1250

AC→ WP + T + L 750

SURGERY

Tissue for Biomarkers

Trastuzumab for a total of

1 year

Endpoints: pCR, cardiac events, DFS, OSWP: d 1, 8, 15 q 28 d x 4

WP=Weekly Paclitaxel

Tissue for Biomarkers

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)

ALTTOS

urg

ery

1 year

Lapatinib

LapatinibTrastuzumab

Trastuzumab

Paclitaxel weekly or TCH

+/- Anthracycline

containingCT

Lapatinib Trastuzumab

Closed due to futility

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 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?

OsteoporosisOsteoporosis

Observational Studies of Bisphosphonate Use and Breast Cancer Incidence

Author Study Design

Patient Cases (% bisphosphonate)

Control Subjects (%

bisphosphonate)

Breast Cancer

Association

Rennert Case-control

1822 (10.5%) 2207 (14.8%) OR 0.72 (0.57-0.90)

Newcomb Case-control

2336 (4.4%) 2975 (6.2%) OR 0.67 (0.51-0.89)

Chlebowski Cohort 154, 768 women, 2816 (1.8%) bisphosphonate users, 5,092 breast

cancer cases

HR 0.68 (0.52-0.88)

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

Shepherd LE et al, ASCO 2012, #501

• 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

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%)

Stephen Paget1855–1926

'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 SecondaryGrowths in Cancer of the Breast.

The Lancet. 1889

The seed and soil hypothesis

AZURE: Study Design

Standard therapyStandard therapy

Standard therapy +Zoledronic acid 4 mgStandard therapy +

Zoledronic acid 4 mg

3,360 Breast Cancer

PatientsStage II/III

3,360 Breast Cancer

PatientsStage II/III

Zoledronic acid treatment duration 5 years

Accrual September 2003 - February 2006

RR

6 doses 8 doses 5 dosesQ3-4 weeks Q 3 months Q 6 months 6 doses 8 doses 5 dosesQ3-4 weeks Q 3 months Q 6 months

Months 6 30 60

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

No difference in disease free or

invasive disease free survival (IDFS)

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

AZURE: Invasive DFS and OS by Menopausal Status

0

Time From Randomization (Mos)

1.0

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

0.8

0.6

0.4

0.2

0

Pro

port

ion

Aliv

e an

d in

vasi

ve D

isea

se F

ree

IDFS: Pre, Peri, and Unknown Menopause

Adjusted HR: 1.15(95% CI: 0.97-1.36; P = .11)288 vs 256 events

Pts at Risk, nZOL:

No ZOL:1162 1088 996 919 829 393 57 0

1156 1092 995 920 853 388 47 0

0

Time From Randomization (Mos)

1.0

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

0.8

0.6

0.4

0.2

0

Pro

port

ion

Aliv

e

OS: Pre, Peri, and Unknown Menopause

Adjusted HR: 0.97(95% CI: 0.78-1.21; P = .81)161 vs 165 events

Pts at Risk, nZOL:

No ZOL:1162 1131 1078 1020 955 466 71 0

1156 1123 1076 1032 963 446 60 0

0

Time From Randomization (Mos)

1.0

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

0.8

0.6

0.4

0.2

0

Pro

port

ion

Aliv

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d in

vasi

ve D

isea

se F

ree

IDFS: > 5 Yrs Postmenopausal

Adjusted HR: 0.75(95% CI: 0.59-0.96; P = .02)116 vs 147 events

Pts at Risk, nZOL:

No ZOL:519 490 447 418 393 177 25 0

522 482 431 396 368 156 21 0

0

Time From Randomization (Mos)

1.0

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

0.8

0.6

0.4

0.2

0

Pro

port

ion

Aliv

e

OS: > 5 Yrs Postmenopausal

Adjusted HR: 0.74(95% CI: 0.55-0.98; P = .04)82 vs 111 events

Pts at Risk, nZOL:

No ZOL:519 502 482 448 422 190 29 0

522 509 475 441 401 177 26 0

N=2318 N=1041

Adjusted for imbalances in ER, lymph node status, and T stage.

HR: 0.70 (95% CI: 0.54-0.92)

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

Treatment Effects on First IDFS Recurrence Outside Bone by Menopausal Status

Odds Ratio

21 (heterogeneity) = 14.00; P = < .001

1.0 1.2 1.4 1.6 1.8 2.00.2 0.4 0.6 0.8

Pre, Peri and unknown menopause

> 5 yrs postmenopause

Menopausal Group

TOTAL: 6% +/- 8Z = .79, P = .43

No significant differences in bone recurrence by menopausal status or age

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

McCormick et al, #1004

No palpable mass, low or intermediate grade, < 2.5 cm, margins > 3 mm

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

N=585

Arm 1Observation ± tamoxifen,

20 mg per day for 5 years

 Arm 2Radiation therapy to

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

Age1. < 502 ≥ 50Final Path Margins1. Negative (re-excision)2. 3-9 mm3. 10 mmMammographic/Pathologic Size of Primary1. ≤ 1 cm2. > 1 cm to ≤ 2.5 cm Nuclei Grade1. Low2. IntermediateTamoxifen Use1. No2. Yes

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.

AC q 2 wk P q 2 wk

N+N+AC q 2 wk PG q2 wk

TAC q 3 wkAll arms pegfilgrastim or filgrastim

ER positive: hormonal therapy for 5 yrs after chemo

80% ER+65% 1-3+ nodes

NSABP B-38 Schema (n=4894, med FU 5.3 yrs)

Stratification: # nodes, HR status + or neg, Surgery and RT

Swain et al, LBA#1000P = paclitaxel 175 mg/m2G = gemcitabine 1000 mg/m2

# at risk1610 1532 1424 1331 1217 7191618 1554 1452 1348 1240 7541613 1533 1453 1350 1244 730

NSABP B-38 Disease-Free Survival

* 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

- -

Control

Exp 11

Exp 2

N = 900 (planned)

Strata:Adj taxanesER/PR status

-

nab-paclitaxel 150 mg/m2 weekly + bevacizumab 10 mg/kg q 2 wks2

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

Restage q 2 cycles until

disease progression

CALGB 40502 - NCCTG N063H - CTSU 40502An Open Label Phase III Trial of Firstline Therapy for Locally Recurrent or Metastatic Breast Cancer

• 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

paclitaxel 90 mg/m2 weekly + bevacizumab 10 mg/kg q 2 wks1

1. Miller et al, N Engl J Med, 2007 2. Gradishar et al, J Clin Oncol, 2009 3. Dickson et al, Proc ASCO 2006.

Months From Study Entry

Pro

port

ion

Pro

gres

sion

-Fre

e

0 10 20 30

0.0

0.2

0.4

0.6

0.8

1

PacNabIxa

Comparison HR P-value 95% CI

nab vs. pac 1.19 0.12 0.96-1.49

ixa vs. pac 1.53 < 0.0001 1.24-1.90

CALGB 40502Progression-Free Survival By Treatment Arm

paclitaxelnab-paclitaxelixabepilone

Agent N Median PFS

paclitaxel 283 10.6

nab-Paclitaxel 271 9.2

ixabepilone 245 7.6

Months From Study Entry

Pro

port

ion

Aliv

e

0 10 20 30

0.0

0.2

0.4

0.6

0.8

1

PacNabIxa

CALGB 40502Overall Survival

Comparison

HR P-value 95% CI

nab vs. pac 1.02 0.92 0.75-1.38

ixa vs. pac 1.28 0.10 0.95-1.72

Agent N Median OS

paclitaxel 283 26

nab-paclitaxel 271 27

ixabepilone 245 21

Dose Reductions by Cycle 3

Cycle 2 Cycle 3

Dose reduction

Fre

quency (

%)

010

20

30

40

50

nab Pac Ixa nab Pac Ixa

Cycle 3

45%

15% 15%

ixanab pac

All Cause Cumulative Discontinuation by Cycle

Arm Grade 3+

nab (N = 258)

25%p=0.012

pac (N = 262)

16%

ixa (N = 237)

25%p=0.022

Sensory Neuropathy nab

(N = 258)pac

(N = 262)ixa

(N = 237)

Leukopenia 17% p = 0.0004

7% 3% p = 0.042

Neutropenia 47%p = 0.0001

18% 7%p = 0.0002

Hypertension 7% 8% 11%

Fatigue 16% p = 0.010

9% 15% p = 0.036

Pain 10%p = 0.010

4% 4%

Motor neuropathy

10%p = 0.0003

2% 6% p = 0.021

Other AEs – Grade 3+

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 nab-paclitaxel; 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

324 MBC patients with

no prior chemotherapy

PD

CR/PR/SDCR/PR/SD

Off the study

Observation till PD

till PD

6 cycles of PG

Stratification

1. Visceral diseases2. Prior adjuvant taxane3. Response(CR/PR vs. SD)4. HR(+) vs. HR(-)

RRPG regimenPaclitaxel 175 mg/m2 Day 1Gemcitabine 1,250 mg/m2 Day 1 & 8 every 3 weeks

Prospective, phase III, multi-center, randomized studyEnroll period: 2007.05 – 2010.09

Primary Endpoint; PFS from Randomization

Secondary Endpoints; OS, Toxicities, QoL, and Response Duration

Im et al, #1003

N=231

N=116

N=115

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 BCPLX3397 oral daily dosing

Eribulin: 1.4 mg/m2 iv, day 1 and 8Each cycle of treatment lasts 21 days

PLX3397 oral daily dosingEribulin: 1.4 mg/m2 iv, day 1 and 8

Each cycle of treatment lasts 21 days

First Cohort = 600 mg/day3-6 patients

First Cohort = 600 mg/day3-6 patients

Second Cohort = 800 mg/day3-6 patients

Second Cohort = 800 mg/day3-6 patients

Third Cohort = 1000 mg/day3-6 patients

Third Cohort = 1000 mg/day3-6 patients

Phase II Study: Metastatic TNBC

Lead in period of 5-7d with PLX3397 at MTD oral daily dosing (day -7/5 to day 0)

Phase II Study: Metastatic TNBC

Lead in period of 5-7d with PLX3397 at MTD oral daily dosing (day -7/5 to day 0)

Starting Day 1Add Eribulin 1.4 mg/m2 iv day 1 and 8Each cycle of treatment lasts 21 days

Starting Day 1Add Eribulin 1.4 mg/m2 iv day 1 and 8Each cycle of treatment lasts 21 days

Biopsy for immune profiling

Biopsy for immune profiling

PI: Hope S. Rugo, UCSF, Lisa Coussens, OHSU, Shelley Hwang, Duke. Clinical trial sites: UCSF, Vanderbilt (Mayer), Duke (Blackwell)

KOMEN Promise Grant:Can inhibition of

macrophages reverse chemotherapy resistance?

Phase II Primary Endpoint:PFS at 12 weeks