Neo-adjuvant Treatment SABCS 2011 - GBECAM · Neo-adjuvant Treatment SABCS 2011 Carlos H. Barrios, MD Instituto do Câncer HMD Faculdade de Medicina PUCRS Porto Alegre, Brazil

Neo-adjuvant

TreatmentTreatment

SABCS 2011

Carlos H. Barrios, MDInstituto do Câncer HMD

Faculdade de Medicina PUCRSPorto Alegre, Brazil

Response to the Same DrugsDiffers by Subtype

Modified PAM50 subtyping in 360 patients treated with neo-adjuvant anthracycline/taxane chemotherapy (no Trastuzumab)

Overall pCR rate = 22%

Classification Residual disease pCR

Basal-like 47 (58%) 34 (42%)

Claudin-low 29 (67%) 14 (33%)

HER2-enriched 31 (63%) 18 (37%)

Luminal A 110 (98%) 2 (2%)

Luminal B 56 (85%) 10 (15%)

Normal-like 13 (76%) 4 (24%)

Perou C, et al. 2011

TRYPHAENA - Study design

HER2-positive EBC centrally confirmed(n = 225)

FEC

SURG

SURG

Docetaxel

Cycles 1 ‒3 4‒6

PertuzumabPertuzumab

Pertuzumab + trastuzumab

FECDocetaxel

B

A

(n = 225)GERY

GERY

Pertuzumab+ trastuzumab

Carboplatin

Docetaxel

Pertuzumab + trastuzumabC

Study dosing q3w:− FEC: 500 mg/m2, 100 mg/m2, 600 mg/m2− Carboplatin: AUC 6− Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintena nce− Pertuzumab: 840 mg loading dose, 420 mg maintenance− Docetaxel: 75 mg/m2 (escalating to 100 mg/m2 if to lerated, in Arms A and B only)

Schneeweiss A, et al. Cancer Res. 2011;71(24 Suppl):Abstract S5-6.

TRYPHAENA: Study endpoints

• Primary endpoint :– Cardiac safety

• Symptomatic LVSD (grade ≥3)• LVEF declines (≥10 percentage points and below 50%)

• Secondary endpoints :• Secondary endpoints :– Toxicity– pCR (defined as the absence of invasive tumor residues in the

breast at surgery; remaining in situ lesions allowed; ypT0/is)• Study was not powered for formal comparison between arms

– Clinical response rate– Rate of breast-conserving surgery


TRYPHAENA

Cardiac Events During Neo-adjuvant Treatment

FEC+H+P x3→→→→ T+H+P x3

n = 72

FEC x3 →→→→ T+H+P x3

n = 75

TCH+P x6

n = 76

Symptomatic LVSD (grade ≥3),n (%) 0 (0.0) 2 (2.7) 0 (0.0)n (%) 0 (0.0) 2 (2.7) 0 (0.0)

LVSD (all grades), n (%) 4 (5.6) 3 (4.0) 2 (2.6)

LVEF decline ≥10% points and below 50%, n (%) 3 (4.2) 4 (5.3) 3 (3.9)


TRYPHAENA: pCR Rates

Pat

holo

gic

com

plet

e re

spon

se (%

)

ypT0/is100

90

80

70

60

50

61.666.2

57.3

Pat

holo

gic

com

plet

e re

spon

se (%

)

FEC+H+P x3→→→→ T+H+P x3(n = 73)

FEC x3→→→→ T+H+P x3(n = 75)

TCH+P x6(n = 77)

50

40

30

20

10

0


TRYPHAENApCR Rates per HR Status

Pat

holo

gic

com

plet

e re

spon

se (%

)ER- and PR-negative ER- and/or PR-positive

79.4

65.0

83.8

ypT0/is100

90

80

70

60

Pat

holo

gic

com

plet

e re

spon

se (%

)

46.2 48.6 50.0

FEC+H+P x3→→→→ T+H+P x3(n = 73)

FEC x3→→→→ T+H+P x3(n = 75)

TCH+P x6(n = 77)

50

40

30

20

10

0


TRYPHAENA: Summary

• Combination of trastuzumab and pertuzumab with anthracycline containing chemotherapy is feasible

• Cardiac toxicity is similar for concomitant or sequential administration of the two monoclonal antibodies with anthracyclines (as judged from early cardiac events)

• pCR rates higher than in NeoSphere suggest role for the longer 6-cycles treatment duration and/or for use with combination chemotherapy

• pCR rates consistently higher for ER negative tumors

• TRYPHAENA supports the ongoing APHINITY study (NCT01358877), a phase III trial to evaluate pertuzumab and trastuzumab plus standard chemotherapy in the adjuvant setting


Dual HER2 blockade alone or with chemotherapy (or with more chemotherapy?)

80

100

(Neo-Sphere, Neo-Altto, Tryphaena)

63%

pC

R R

ate

Dual HER2

blockade

+

Taxane

Dual HER2

blockade

+

Taxane

50%

20

40

60

Dual HER2

blockade alone

Dual HER2

blockade alone

17%

Dual HER2 blockade

+Taxane

+Other agent(anthrac., carbo)

63%

%p

CR

Ra

te

Neo ALTTO

N=450

Regimen pCR

Trastuzumab

+ Lapatinib

+ Docetaxel

51%

Neo-Sphere

N=417

Regimen pCR

Trastuzumab

+ Pertuzumab17%

Trastuzumab

+ Pertuzumab

+ Docetaxel

46%

Tryphaena

N=225

Regimen pCR

Trastuzumab

+ Pertuzumab

+ Doce/Carbo

66%

Strategy

Combo MTA

Combo MTA +

Chemotherapy

Neo-adjuvant Anti-HER2 MTA in Breast Cancer

+ Docetaxel

Trastuzumab

+ Paclitaxel29%

Lapatinib

+ Paclitaxel25%

+ Docetaxel

Trastuzumab

+ Docetaxel29%

Pertuzumab

+ Docetaxel24%

+ Doce/Carbo

Trastuzumab

+ Pertuzumab

FEC-Docetax

Sequential

Concomitant

57%

62%

Combo MTA +

Chemotherapy

Trastuzumab +

Chemotherapy

Single MTA +

Chemotherapy

Hormone Receptor Negative Disease

62%

80

100

80%

% p

CR

Ra

tes

Dual HER2 blockade alone or with chemotherapy

(Neo-Sphere, Neo-Altto, Tryphaena)

Dual HER2

blockade

+

Taxane

62%

20

40

60

Dual HER2

blockade alone

29%

Dual HER2

blockade

+

Taxane

+

other agent(Anthra, Carbo)

% p

CR

Ra

tes

80

100 These somewhat « less impressive »results could still translate

into excellent DFS rates (?)

Hormone Receptor Positive Disease

Dual HER2 blockade alone or with chemotherapy

(Neo-Sphere, Neo-Altto, Tryphaena, Chang’s Trial)

% p

CR

Ra

tes

7.2

Trastuzumab

+

Pertuzumab

+

Taxane

26%

20

40

60

Dual HER2

blockade alone

6%

Trastuzumab

+

Lapatinib

+

Taxane

42%

Trastuzumab

+

FEC

and

Taxane

47%

Trastuzumab

+

Pertuzumab

+

Docetaxel

+

Carboplatin

21%

50%

Trastuzumab

+ Lapatinib

+ A.I.

Trastuzumab

+ Lapatinib

+ A.I.

% p

CR

Ra

tes

Neo-adjuvant pertuzumab (P) and trastuzumab (H):

Biomarker analyses of a 4-arm randomized Phase II study

(NeoSphere) in patients (pts) with

HER2-positive breast cancer (BC)

L Gianni, G Bianchini, A Kiermaier, G Bianchi, Y.-H Im, T Pienkowski,

L Roman, M-C Liu, L-M Tseng, J Ratnayake, T Szado, G Ross, P Valagussa

on behalf of the ‘NeoSphere’ study investigators

NeoSphere: Biomarker analyses on overall population

Assay method Biomarker Sample Size

IHC HER2 mem H-score 416

HER3 mem H-score 377

IGF1R mem H-score 339

PTEN cyt H-score 373

PTEN nuc H-score 373

pAKT cyt H-score 299

pAKT nuc H-score 299pAKT nuc H-score 299

qRT-PCR HER2/HER3-CR 384

HER3-CR 384

HER2-CR 387

EGFR-CR 377

FISH c-myc 275

ELISA (serum) sHER2 (ng/mL) 381

Amphiregulin (pg/mL) 384

TGF-alpha (pg/mL) 384

EGF (pg/mL) 384

Mutational analyses PI3K mutation 273

Summary of NeoSphere biomarker analyses

• HER2 expression (H-score) associated with sensitivity to

pertuzumab

• PI3K mutations in exon 9 linked to lack of sensitivity to HER2-

directed Mab’s

• Intrinsic differences between HER2+ tumors based on hormone • Intrinsic differences between HER2+ tumors based on hormone

receptor status

• No predictive role for truncated forms of the HER2 receptor

including p95HER2

• So far none of the analyses provided clinically useful assays for

patient and/or regimen selection in addition or alternative to the

conventional assessment of HER2 by IHC or FISH

2

GEPAR-TRIO trial

Neoadjuvant chemotherapy adapted by interim

response improves overall survival of primary breast

cancer patients

Results of the GeparTrio trial.

Gunter von Minckwitz, Jens Uwe Blohmer, Serban Dan Costa, Carsten Denkert, Holger Eidtmann, Wolfgang

Eiermann, Bernd Gerber, Claus Hanusch, Jörn Hilfrich, Jens Huober, Christian Jackisch, Manfred Kaufmann,

Sherko Kümmel, Stefan Paepke, Andreas Schneeweiss, Michael Untch, Dirk Michael Zahm, Keyur Mehta, Sibylle

Loibl

Courtesy of G. von Minckwitz. SABCS 2011

Core Biopsy:

Uni/bilateral BC cT2-4a-d

Core Biopsy:


NC

Son

ogra

phy

NX

TACx6

R

Gepar-Trio Trial Design

N=2072

Response-guidedArms

N=622

cT2-4a-dcN0-3size ≥ 2 cm*


CR/PR

Son

ogra

phy

TACx8

TACx6

R

*low risk patients were excluded (T2 + ER/PR pos. + cNO + G1/2 + > 35 yrs)von Minckwitz et al, JNCI 100: 542, 2008von Minckwitz et al. JNCI 100; 552, 2008

Conventional Arms

N=1390N=1390

GEPAR-TRIO: Study Population

Characteristic Conventional Response-guided

(%) (%)

Age < 40 years 16.9 18.2

cT> 40 mm 60.5 61.5cT> 40 mm 60.5 61.5

cT4a-c 9.0 8.7

cT4d 4.6 4.3

cN + 55.3 54.7

Lobular type 13.8 13.1

Grade 3 41.0 35.1

HR-negative 36.8 34.4

HER2-positive 30.5 29.1


GEPAR-TRIO: Short Term Efficacy (pCR = ypT0 ypN0)

Non-ResponderN=604

ResponderN=1344

P=0.73P=0.2730%

6.06.0

20%

0

TAC-NXTACx6

23.5

TACx6 TACx8

21.0

5.3

10%

von Minckwitz et al, JNCI 100: 542, 2008von Minckwitz et al. JNCI 100; 552, 2008

PRIMARY CONCLUSIONNo difference in pCR among the arms !

Core Biopsy:


Core Biopsy:


NC

Son

ogra

phy

NX

TACx6

R

Gepar-Trio Trial Design

N=2072

Response-guidedArms

N=622



CR/PR

Son

ogra

phy

TACx8

TACx6

R

*low risk patients were excluded (T2 + ER/PR pos. + cNO + G1/2 + > 35 yrs)von Minckwitz et al, JNCI 100: 542, 2008von Minckwitz et al. JNCI 100; 552, 2008

Conventional Arms

N=1390N=1390

DFS and OS after Conventional (TACx6) vs. Response-guided Rx (TACx8/TAC-NX)

Median follow up 62 months


PATIENT SELECTION ACCORDING TO RESPONSE AFTER TACX2 !!!(independent of pCR or not)

Response-guided arms: better DFS and OS

DFS: Responding and Non-responding Patients

TACx6 vs. TACx8(responding)

TACx6 vs. TACx8(responding)

TACx6 vs. TAC-NX(non responding)

TACx6 vs. TAC-NX(non responding)


LONGER IS BETTERLONGER IS BETTER CHANGING IS BETTER CHANGING IS BETTER

Breast Cancer Phenotypes (St. Gallen definition*)

Phenotype Definition Conventional Response-

guided(%) (%)

Luminal A HR+, HER2-, G1/2 34.4 37.1

Luminal B (HER2-) HR+, HER2-, G3 13.5 12.8

Luminal B (HER2+) HR+, HER2+ 17.3 17.8

HER2+ (non-luminal) HR-, HER2+ 11.7 10.4

Triple-negative HR-, HER2- 23.1 22.0

Missing N=181 N=227


GEPAR-TRIO: pCR Rates by Subtype

25

30

35

40

pCR (%)

0

5

10

15

20

25

Luminal A (N=572) Luminal B (HER2-) (N=211)

Luminal B (HER2+) (N=281)

HER2+ (non-luminal) (N=178)

Triple-negative N=362)


DFS in Luminal A tumors (ER+, HER2-, G1/2)

by pCRby pCR by treatment by treatment


DFS in Luminal B tumors (ER+, HER2-, G3)



DFS in Luminal B tumors (HER2+)



pCR prognostic in Luminal B overall but not in Luminal B HER2+(without anti-HER2 therapy)(this needs an explanation)

DFS in HER2+ (non-luminal) tumors



DFS in Triple Negative Tumors



Gepar-Trio

• Early assessment of clinical response as a surrogate of efficacy is a provocative finding and needs confirmation

• Response-guided therapy has two different regimens (TAC-NX and TCx8) that are analyzed in conjunction

• Even though the distribution in both groups seemed adequate, definition of molecular sub-groups was retrospective (needs more information)

• Different predictive/prognostic results for pCR according to molecular sub-groups needs confirmation/validation.

vs p=0.295

pCRpCR

n= 662 HER2+ with trastuzumabn= 3060 HER2 negativen= 665 HER2+; no trastuzumab



Log-rankvs p=0.058vs p=0.134

No pCRNo pCR

pCR as Surrogate for OS in HER2+

vs p=0.295vs p=0.384

Loibl S, Von Minckwitz G, Blohmer J, et al. pCR as a surrogate in HER2-positive patients treated with trastuzumab.

Cancer Research. 2011;71(24 suppl 3). Abstract S5-4.

Arm N Events

HER2 + w/trast 481 35

HER2 + w/o trast 546 75

HER2 Negative 2606 310

Arm N Events

HER2 + w/trast 181 1

HER2 + w/o trast 119 9

HER2 Negative 454 14

vs p=0.134

Virtually no deaths in pts reaching pCR with a trastuzumab-containing regimen !!

pCR HER2+ without Trastuzumab seems to do worse than pCR with Trastuzumab

HER2+ patients with no pCR require new alternatives

Moving Forward

• Changing a clinical research paradigm?

• Neo-adjuvant trials have advantages:

– Smaller, faster trials can guide larger definitive trials

– Embedded tissue-based studies key to selection strategies– Embedded tissue-based studies key to selection strategies

– Needs an effective multidisciplinary model.

• Different subtypes respond differently to the same drugs – be

careful about generalizing the results.

• Information on long term outcome (DFS, OS) is essential !!!

(ex.: Luminal A, Luminal B HER2+ or not, pCR HER2 positive w and w/out Trastuzumab)

Moving Forward

• Recognize that metastasis are complex

– Distant disease may be similar but not the same as the

primary

– Importance of the microenvironment

– Impact of time and therapy (i.e. the disease evolves with – Impact of time and therapy (i.e. the disease evolves with

time and is forced to change with therapy)

• Tissue-based studies are key (many questions)

– Need to biopsy metastases?

– When to biopsy?

– Serial biopsies (early and late pts) to guide/optimize

therapy?

Documents

Neo-adjuvant Treatment SABCS 2011 - GBECAM · Neo-adjuvant Treatment SABCS 2011 Carlos H. Barrios, MD Instituto do Câncer HMD Faculdade de Medicina PUCRS Porto Alegre, Brazil