Neoadjuvant chemotherapy and targeted therapy: when pCR matters?

XII Michelangelo Foundation Seminar

when pCR matters? The NSABP Experience

N. Wolmark, Pittsburgh, USA

Neoadjuvant therapy in early BC: >50 Years

a hopeless heresy or a feasible paradigm shift?

MilanNorman Wolmark

Oct 12, 2012

Neoadjuvant TherapyTherapy

B-18Duration: 88 -93ACCRUAL: 1,523

B-27Duration: 95 -00ACCRUAL: 2,411ACCRUAL: 2,411

B-40Her2 Neg

BevpCR endpoint’’’’07-’’’’10; N=1206

B-41Her2 Pos

H and LapatanibpCR endpoint‘‘‘‘07-’’’’11; N=522

P E R S P E C T I V E

The FDA may grant accelerated approval on the basis of a surrogate end point …For neoadjuvant

June 2012: Tatiana Prowell and Richard Pazdur

basis of a surrogate end point …For neoadjuvant breast cancer we propose that the rate of pCR be used as this surrogate.

Patricia Cortazar , Meta-analysis: N=13,125Optimal def pCR; def N0; pCR correlation with outcome; ∆ pCR; enriched population; subtype def(molecular); pCR and targeted agents

Operable Breast CancerOperable Breast Cancer

StratificationStratification• Age• Age

NSABP BNSABP B --1818Neoadjuvant vs. Adjuvant ACNeoadjuvant vs. Adjuvant AC

•• Obj Clinical Response: Obj Clinical Response: 80%80%•• pCR: pCR: 13%13%•• Increase in lumpectomy Increase in lumpectomy

rate: rate: 68% vs. 60%68% vs. 60%

88-93; N=1523

• Clinical Tumor Size• Clinical Tumor Size• Clinical Nodal Status• Clinical Nodal Status

OperationOperation

AC x 4AC x 4 OperationOperation

AC x 4AC x 4

rate: rate: 68% vs. 60%68% vs. 60%•• Downstaging of (+) axillary Downstaging of (+) axillary

nodes: nodes: 58% vs. 40%58% vs. 40%•• No difference No difference inin DFS DFS andand SS**•• Significant Significant correlationcorrelation

between between pCR pCR andand survivalsurvival

Seq tam for women ≥≥≥≥50 yrs. only

Outcome: pre v postOutcome: pre v post

70

80

90

100N Ev HR PN Ev HR P

Post 751 311Post 751 311Pre 742 308Pre 742 308 .99 0.90 .99 0.90

% A

live

% A

live

NSABP BNSABP B --18: Overall Survival 18: Overall Survival

30

40

50

60

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

% A

live

% A

live

YearsYears

J Clin Oncol 2008J Clin Oncol 2008Goldie-Coldman Hypothesis Refuted

Treatment by AgeInteractionInteraction

SS

70

80

90

100

<50yrs<50yrs

70

80

90

100

≥≥50yrs50yrs

QualitativeTreatment by Age

Interaction

30

40

50

60

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

N Ev HR PPost 388 167

Pre 381 139 .81 0.06

30

40

50

60

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

N Ev HR PPost 363 148Pre 361 171 1.23 0.07

Interactionp=0.01

Should We Revisit the Concept of Should We Revisit the Concept of Neoadjuvant vs. Adjuvant Chemo?Neoadjuvant vs. Adjuvant Chemo?

OR OR

•• Are there subsets Are there subsets in in which one which one

•• Is neoadjuvant chemo = adjuvant Is neoadjuvant chemo = adjuvant chemo in all patient?chemo in all patient?

•• Are there subsets Are there subsets in in which one which one approach may be superior to the approach may be superior to the other?other?

NeoadjuvantNeoadjuvant >> AdjuvantAdjuvant : Triple Negative, : Triple Negative, HERHER--2 +, 2 +, HighHigh --Risk Risk ER + (<50) ER + (<50)

Adjuvant Adjuvant > > NeoadjuvantNeoadjuvant : : LowLow --Risk ER+ (Risk ER+ (>>50)50)

pCR and OutcomepCR = ypT0/is ypNx

Absence of invasive cancer in the breast ±±±± DCIS; ±±±± nodal involvement

70

80

90

100

Survival and pCRSurvival and pCR

86

66 ∆ 20%

30

40

50

60

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

N Ev HR No pCR 599 265pCR 86 14 .32 P <0.0001

OPERABLE BREAST CANCER

B-27

Age, T, cN12’’’’95-12’’’’00N=2411MTF=10 yrs

OPERATION

AC AC→→→→Txt*

OPERATION

AC

OPERATION

Txt*100mg/m² x 4; concom Tam for all

pCRpCR

Path Complete Response

40%

12.9

0%

20%

AC AC>T

pCR

JCO Nov ‘‘‘‘03

Path Complete Response

40%

12.9

26.1

0%

20%

AC AC>T

pCR

P < 0.001P < 0.001

JCO Nov ‘‘‘‘03

OutcomeOutcome

70

80

90

100

SurvivalSurvival

40

50

60

70

0 1 2 3 4 5 6 7 8

N Ev RR PAC 784 192AC→T 783 182 .93 0.46 ACSx→ T 777 189 .97 0.76

Doubling of pCR did not improve clinical outcome

15% 85%

AC arm

Extrapolation of B -18 and B -27 5 yr Survival

30% 70%

AC->T arm

pCR90% 5YS 75% 5YS

5YS = 77.25%

pCR90% 5YS 75% 5YS

5YS = 79.50%

pCR in B -27 was not a robust predictor for survival

pCR and OutcomepCR and Outcome

80

90

100

Survival and pCRSurvival and pCR

pCR93

80

40

50

60

70

0 1 2 3 4 5 6 7 8

No pCR

80

pCR v no pCRHR 0.36 P <.0001

Heterogeneous group includes subsets with good prognosis who may have ▼▼▼▼benefit from chemoRx

B-27 DFSno pCR and Nodes (1881)

0

1-3

#N %0 471-3 324-9 1610+ 5

4-9

10+

B-27 Affymetrix GeneChip analysis of FPET

50 gene Risk Prediction IndexNCI Reviewing the State of the Science Mar 2007

B-27 No pCR50 gene Risk Prediction Index

0.6

0.6

0.8

0.8

1.0

1.0

surv

ival

surv

ival highhigh --risk (n=163)risk (n=163)

lowlow--risk (n=163)risk (n=163)

00 2020 4040 6060 8080 100100

0.0

0.0

0.2

0.2

0.4

0.4

0.6

0.6

Time (months)Time (months)

surv

ival

surv

ival highhigh --risk (n=163)risk (n=163)

Paik NCI SOS Mar 2007

0.6

0.8

1.0

surv

ival

pCR (16)

No-pCR (147 )

B-27 pCR (50 gene)Low Risk

Time (months)

0.0

0.2

0.4

0.6

surv

ival

0 20 40 60 80 100

Paik NCI SOS Mar 2007

0.6

0.8

1.0

surv

ival

pCR (34)

no-pCR (125)

B-27 pCRHigh Risk

0.0

0.2

0.4su

rviv

al

0 20 40 60 80 100Time (months)

Ki67<10 (173 )

surv

ival

surv

ivalB-27 No pCR

Ki67

Ki67>10 (102)

HR 3.0; p=.0009

YearsYears

surv

ival

surv

ival

Paik, MD. Susan G Komen Award Lecture, SABCS 2010

E/PR+ N- patients(Paik, Wolmark: NEJM, 2004; JCO, 2006))

Oncotype DX

Preoperative Targeted Preoperative Targeted AgentsAgentsAgentsAgents

NOAH Trial: LABC Her2+NOAH Trial: LABC Her2+

EFS

Gianni L, et al; Lancet 2010

N Ev HR PT 117 36 .58 0.013

NoT 118 51

0 42 mo

Techno GBG N=217 JCO ‘‘‘‘11

NSABP BNSABP B --4141Her PosHer Pos

Paclitaxel/wk +Paclitaxel/wk +TrastuzumabTrastuzumab

SSuurr

AC X 4AC X 4

Paclitaxel/wk +Paclitaxel/wk +AC X 4AC X 4

OOppeerraa T T

uurrggeerryy

RPaclitaxel/wk +Paclitaxel/wk +

LapatinibAC X 4AC X 4aabbllee

BBCC

Paclitaxel/wk +Paclitaxel/wk +Lapatinib +

TrastuzumabTrastuzumabAC X 4AC X 4

T T mmaabb

pCR ∆ 22% (42→64%) ‘‘‘‘07-’’’’11; N=522 Tmab 2mg qW; Lnib 1250 qD; 750 w Tmab

NSABP B -41pCR Breast

P=0.095

P=0.99

ASCO 12

NSABP B -41pCR Breast by Hormone Receptor Status

P=0.23

P=0.96

P=0.49

P=0.71

N=100N=122 N=108 N=71N=55 N=63

HR+ HR–

P=0.96

NSABP/GBG/GNE B -5x (Her2+)

Neo-adjuvant Her2-directed Therapy

Residual Tumor

SURGERY N=1484 HR .753y IDFS

T-DM1

Residual Tumor

(Breast or Nodes)

H

3y IDFS