Debu Tripathy, MD

Professor of Medicine

University of Southern California

Norris Comprehensive Cancer Center

ASCO and San Antonio Updates

30th Annual Miami Breast

Cancer Conference

March 7-10, 2013

Breakthroughs in 2012-2013

Sentinel Nodes after Neoadjuvant Therapy

Not as accurate, but can still be useful

Radiation – when is less OK?

Hypofractionation and omission for low risk DCIS

Adjuvant Therapy Refinements

5 vs 10 years of tamoxifen, comparisons of 3rd

generation regimens, therapy for local recurrences

Advanced Breast Cancer

HER2+ - new options; CDK inhibitors; first line chemo

Emerging genomic picture of breast cancer

New therapeutic targets

ACOSOG Z1071 Trial – Design 1° Endpoint: False Neg Rate cN1 w/ 2 SNLs Examined

Boughey JC, et al. SABCS 2012, Abstr S2-1

● cT0-4 cN1-2 M0 ● Node FNA or core biopsy +

● Any preoperative chemotherapy ● Enrolled N = 756

Underwent surgery with SLN

identification and ALND

SLN + ALND N = 687

SLN ID’ed N = 637 (92.7%)

Dual tracer encouraged

Node + 255 (40%) Node - 382 (60%)

SLN+ 326 SLN- 56 False Neg Rate 12.6%

• 78 with 1 SLN False negative rate 31.5%

• 310 with ≥ 3 SLNs False negative rate 9.1%

• Dual tracer False negative rate 10.8%

• Clip False negative rate 10.8%

• No Clip False negative rate 13.5%

Axillary imaging

used only if axillary

physical exam was

“unclear” N=662

N=360

N=715

N=592 N=123

SENTINA Trial - Design

Kuehn T, et al. SABCS 2012, Abstr S2-2

SENTINA Trial – SLN Detection Rate

Kuehn T, et al. SABCS 2012, Abstr S2-2

SENTINA Trial - False Negative Rate

Kuehn T, et al. SABCS 2012, Abstr S2-2

+/- Radiation for Low Risk DCIS: RTOG 9804

McCormick B, et al. ASCO 2012, Abstr 1004

Lumpectomy for

• DCIS Gr 1, 2

• < 2 cm

• > 3mm margin

N = 636

62% received Tam

Radiation (50, 50.4 or 42.5 cGy over 25,

28 or 16 fractions) (N = 287)

Observation (N = 298)

0

1

2

3

4

5

Ipsilateral Contralateral

5.0

2.8

0.7

3.7

% L

oc

al F

ailu

re

No XRT

XRT

• 33% failures

invasive

• No difference

in survival

• Difference in

Gr 1/2, not Gr

3/4 toxicities

Median Follow up = 6.46 years

UK START Trials – 10 Year Follow-up

Haviland JS, et al. SABCS 2012, Abstr S1-4

UK START Trial B – Patients Free of Physician- Judged Marked to Moderate Skin Effects

Haviland JS, et al. SABCS 2012, Abstr S1-4

UK START Trial B – Local-Regional Relapse

Haviland JS, et al. SABCS 2012, Abstr S1-4

40 cGy in 15 fractions/3 weeks is now standard in UK for all

patients with invasive breast cancer (NICU Guidance 2009)

ATLAS Trial ~5 vs. ~10 Years of Tamoxifen

Davies C, et al. SABCS 2012, Abstr S1-2

Recurrence Cancer Mortality

Cumulative Event 5 years 10 years HR P value

Endometrial cancer 1.6% 3.1% 1.74 0.0002

Endometrial cancer mortality 0.2% 0.4% 1.49 0.26

Longer Periods of Tamoxifen: Estimates of Benefit

Davies C, et al. SABCS 2012, Abstr S1-2

AZURE Trial: Is Adjuvant Benefit Divergent Based On Age or Estrogen Levels?

Marshall H, et al.

ASCO 2012, Abstr 503

Standard therapy

Standard therapy +

Zoledronate 4 mg

Stage II/III

Breast Cancer

N = 3,360

R

6 doses 8 doses 5 doses

Q3-4 wks Q 3 mos Q 6 mos

Months 6 30 60

Subset being Compared Hazard Ratio (95% CI)* P - Value†

≤ 50 years of age (N=1626) 1.16 (0.95-1.42) 0.04

> 50 years of age (N=1733) 0.85 (0.70-1.03)

Bone: pre, peri and unknown menopause 0.86 (0.63-1.17) 0.70

Bone: > 5 years post menopause 0.96 (0.59-1.57)

Other: pre, peri and unknown menopause 1.32 (1.09-1.59) 5 years post menopause 0.70 (0.54-0.92)

* Invasive disease-free recurrence on zoledronate vs placebo † Heterogeneity between specified patient subgroups

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 2.0 0.2 0.4 0.6 0.8

Pre, Peri and unknown menopause

> 5 yrs postmenopause

Menopausal Group

TOTAL: 6% +/- 8

Z = .79, P = .43

Marshall H, et al. ASCO 2012, Abstr 503

CALOR* Trial: Adjuvant Chemotherapy for Local-Regional Recurrence (median f/u 5 years)

Early Stage Breast Cancer

• Loco-regional recurrence

• Rendered free of disease

with surgery

Chemotherapy (N=85) (4-6 months multi-agent

recommended)

Observation (N=77)

Chemo Observ P value

Disease-Free Survival @ 5 years 69% 57% 0.0455

ER-Negative 67% 35% 0.007

ER-Positive 70% 69% 0.87

Overall Survival @ 5 years 88% 76% 0.02

ER-Negative 79% 69% 0.12

ER-Positive 94% 80% 0.12

Hormonal, radiation and trastuzumab allowed for both arms

Aebi S, et al. SABCS 2012, Abstr S3-2 * IBCSG 27-02, NSABP B-37, BIG 1-02

41%

59%

Adjuvant Chemotherapy Options

CMF AC

AC Paclitaxel

CEF

FEC100

FEC50

Dose dense AC Paclitaxel

CAF AC Docetaxel

A/E CMF

FEC100 Paclitaxel/ Docetaxel

Arrows indicated direct comparisons from randomized trials Benefits not drawn to scale

TC

AC weekly paclitaxel

FAC

TAC x 6

A+ Docetaxel TAC x 4

AC q 2 wk P q 2 wk

N+ AC q 2 wk PG q2 wk

TAC q 3 wk All 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)

Swain S, et al, ASCO 2012, LBA#1000

P = paclitaxel 175 mg/m2

G = gemcitabine 1000 mg/m2

# at risk 1610 1532 1424 1331 1217 719

1618 1554 1452 1348 1240 754

1613 1533 1453 1350 1244 730

0 1 2 3 4 5

0.0

0

.2

0.4

0

.6

0.8

1

.0

Years since Randomization

Dis

ease-F

ree S

urv

ival

Treat N Events P-value* (vs ACPG)

TAC 1610 327 0.410

ACP 1618 294 0.388

ACPG 1613 320

NSABP B-38

Disease-Free Survival

* Stratified log-rank test adjusting for randomization factors Swain S, et al, ASCO 2012, LBA#1000

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

o More FN, anemia, diarrhea, less neuropathy with TAC

Swain S, et al, ASCO 2012, LBA#1000

HERA 2-Year Trial: Study Design

Study Sites: Global (33

countries)

Primary endpoint

• Disease-free survival:

o 1-year trastuzumab vs.

observation

o 2-year trastuzumab vs.

observation

Secondary endpoint

• Disease-free survival

o 1-year trastuzumab vs.

2-year trastuzumab

o Overall survival

Study Details Study Design

Nodal status, adjuvant chemotherapy regimen, hormone receptor status and endocrine therapy,

age, region

Observation

(n = ~1700)

HER2-positive invasive EBC

(N ~ 5000)

Stratification

Randomization

1 years trastuzumab

8 mg/kg → 6 mg/kg

3-weekly schedule

(n ~ 1700)

2 year trastuzumab

8 mg/kg → 6 mg/kg

3-weekly schedule

(n ~ 1700)

Arm 2 Arm 1 Arm 3

Surgery + (neo)adjuvant chemotherapy ± radiotherapy

Piccart-Gebhart MJ, et al. SABCS 2012, Abstr S5-2

Dis

ea

se-f

ree s

urv

ival

(%)

Years from randomization

89.1%

86.7% 81.0%

81.6%

75.8%

76.0%

100

80

60

40

20

0

0 1 2 3 4 5 6 7 8 9

No. at risk

Trastuzumab 2 years 1553 1553 1442 1361 1292 1223 1153 1051 633 194

Trastuzumab 1 year 1552 1552 1413 1319 1265 1214 1180 1071 649 205

Trastuzumab 1 year

Trastuzumab 2 years

Pts Events HR (2 vs 1) 95% CI p-value

2 years 1553 367 0.99 (0.85-1.14) 0.86

1 year 1552 367

HERA 2-Year Trial: DFS Results

Gelber R et al. ESMO 2012 Piccart-Gebhart MJ, et al. SABCS 2012, Abstr S5-2

Cardiac Events

Primary or

secondary = EF

< 50% or ≥ 10%

below baseline,

but not NYHA III

or IV heart failure

Piccart-Gebhart MJ, et al. SABCS 2012, Abstr S5-2

PHARE Trial: Study Design

HER2-positive EBC

(N ~ 3500)

Trastuzumab x 6 mos

Any chemo adjuvant regimen

Chemotherapy and trastuzumab timing: sequential vs. concurrent, Hormonal therapy,

Recruiting center

Stratification

No further

trastuzumab 6 months

trastuzumab

Study Sites: France (~150

sites)

Primary endpoint

(non-inferiority)

• Disease-free survival

o 6 months of

trastuzumab vs. 1 year

of trastuzumab

Surgery + (neo)adjuvant chemotherapy ± radiotherapy

Study Details Study Design

Arm 1 Arm 2

≈50% sequential

≈50% concurrent

Randomization

Pivot X, et al. SABCS 2012, Abstr S5-3

0.00

0.25

0.50

0.75

1.00

Pro

ba

bili

ty

1690 1586 1353 939 526 23H 6m1690 1613 1390 980 544 18H-12m

At risk

0 12 24 36 48 60Months

H-12m H-6m

PHARE Study: Disease Free Survival

* Cox model stratified by ER status and concomitant chemotherapy

95.5 91.2 87.8 84.9

97.0 93.8 90.7 87.8

Events HR 95%CI

p-value

H 12m 176

H 6m 219 1.28 (1.05 – 1.56) 0.29

Pivot X et al. ESMO 2012 Pivot X, et al. SABCS 2012, Abstr S5-3

Equivalent

Superior

Non Inferior

Inferior

A

B

C

D

E

.85 1 1.15 1.3 1.45 1.6 HR

Primary Endpoint Scenarios

PHARE trial

Pivot X, et al. SABCS 2012, Abstr S5-3

Trial did not meet non-inferiority endpoint

Longer follow-up and other trial results needed for final

conclusions

EMILIA Trial: T-DM1 vs. Capecitabine + Lapatinib

Progression-Free Survival by Independent (IRC) and Investigator (INV) 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:

Unstratified HR by independent review=0.66 (P

Overall Survival: T-DM1 vs. Capecitabine + Lapatinib

496 469 438 364 296 242 195 155 129 97 74 52 31 17 7 3 2 1 0

495 484 461 390 331 277 220 182 149 123 96 67 46 29 16 5 2 0 0

Cap + Lap

T-DM1

No. at risk: Time (mos)

Pro

po

rtio

n s

urv

ivin

g

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

78.4% 64.7%

51.8%

85.2%

Median (mos) No. events

Cap + Lap 25.1 182

T-DM1 30.9 149

Stratified HR=0.68 (95% CI, 0.55, 0.85)

P < 0.001 Efficacy stopping boundary P=0.0037 or HR=0.73

Verma S, et al. NEJM 2012

- -

Control

Exp 1

Exp 2

N = 900

(planned)

Strata:

Adj taxanes

ER/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

CALGB 40502 - NCCTG N063H - CTSU 40502 An Open Label Phase III Trial of First Line 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

• Restage every 2 cycles until disease progression

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. Rugo H, et al. ASCO 2012, Abstr CRA 1002

Months From Study Entry

Pro

po

rtio

n P

rog

ressio

n-F

ree

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 40502

Progression-Free Survival By Treatment Arm

Paclitaxel

Nab-paclitaxel

Ixabepilone

Agent N Median PFS

Paclitaxel 283 10.6

Nab-Paclitaxel 271 9.2

Ixabepilone 245 7.6 Rugo H, et al. ASCO

2012, Abstr CRA 1002

Eribulin vs. Capecitabine in Earlier Lines for MBC

Kaufman P, et al. SABCS 2012, Abstr S6-6

MBC or unresect LABC

• < 3 cm chemo lines

(< 2 for MBC)

• Prior anthra/taxane

Eribulin 1.4 mg/m2 d 1, 8 q 3 wk

Capecitabine 1250 mg/m2 bid d1-14 q 3 wk

PFS (IR)

Erib 4.1 mo

Cape 4.2 mo

ORR (IR)

Erib 11%

Cape 12%

Eribulin vs. Capecitabine OS HR by Subsets

Kaufman P, et al. SABCS 2012, Abstr S6-6

Rb as Master-Regulator of the R-point

Finn RS, et al. SABCS 2012, Abstr S1-6

Randomized Phase 2 Design Postmenopausal, ER+/HER2-, No Prior Therapy for MBC

N = 66

1:1

Part 1

ER+, HER2–

BC

R

A

N

D

O

M

I

Z

A

T

I

O

N

PD 0332991

125 mg QDa +

Letrozole

2.5 mg QD

Letrozole

2.5 mg QD

Part 2

N = 99

1:1

ER+, HER2–

BC with

CCND1 amp

and/or

loss of p16

R

A

N

D

O

M

I

Z

A

T

I

O

N

PD 0332991

125 mg QDa +

Letrozole

2.5 mg QD

Letrozole

2.5 mg QD

Stratification Factors

• Disease Site (Visceral vs Bone only vs Other)

• Disease-Free Interval (>12 vs ≤12 mo from end of

adjuvant to recurrence or de novo advanced disease)

Finn RS, et al. SABCS 2012, Abstr S1-6

Progression-Free Survival PD 991 + LET

(n = 84)

LET

(n = 81)

Number of Events (%) 21 (25) 40 (49)

Median PFS, months

(95% CI)

26.1

(12.7, 26.1)

7.5

(5.6, 12.6)

Hazard Ratio

(95% CI)

0.37

(0.21, 0.63)

P value

HER2 Somatic Mutations in 25 Patients

• 8 publications, total of 1499 patients (estimated incidence of 1.7%)

• 20% of mutations at AA 309 or 310

• 80% of mutations from 755-781

Bose R, et al. SABCS 2012, Abstr S5-6

HER2 Mutations Differentially Activate HER2 Signaling

Bose R, et al. SABCS 2012, Abstr S5-6

Colony formation of HER2 Mutants inhibited by HER1/2 Kinase Inhibitor Neratinib

Bose R,

et al.

SABCS

2012

Abstr S5-6

Multi-center

Phase II

Trial with

Neratinib Planned

• Please view the SABCS Poster Display during the Welcome Reception from 6-7 pm in the Exhibit Hall

• Discussion to follow at 7pm in the General Session Room moderated by Drs. Pat Borgen and Hope Rugo.