A Randomized Phase III Trial Comparing Nanoparticle-Based ... · A joint study of the AGO Breast and the German Breast Group (GBG) Abstract S2-07 . Initial Study Design y 12 weeks

A Randomized Phase III Trial Comparing

Nanoparticle-Based (nab) Paclitaxel With

Solvent-Based Paclitaxel as Part of

Neoadjuvant Chemotherapy for Patients

With Early Breast Cancer

GBG 69 - GeparSepto

Untch M, Jackisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C,

Eidtmann H, Wiebringhaus H, Kümmel S, Hilfrich J, Warm M, Paepke S, Just M,

Hanusch C, Hackmann J, Blohmer J-U, Clemens M, Costa S-D , Gerber B,

Nekljudova V, Loibl S, von Minckwitz G

A joint study of the AGO Breast and the German Breast Group (GBG)

Abstract S2-07

Initial Study Design

Su

rgery

12 weeks 12 weeks

N = 1200

R

*Centrally confirmed:

- Subtypes HER 2/ HR

- Ki 67

- SPARC

Paclitaxel

80 mg/m2

weekly

nab-Paclitaxel

150 mg/ m2

weekly

Epirubicin 90 mg/m2

Cyclophosphamide

600 mg/m2

If HER2 positive:

Trastuzumab 8 mg/kg (loading

dose) followed by 6 mg/kg

Pertuzumab (absolute dose per

application) 840 mg (loading

dose) followed by 420 mg

If HER2 positive:

Trastuzumab

If HR positive:

Tamoxifen,

Aromatase

inhibitors

accorrding to

AGO Guidelines

Core biopsy

Co

re b

iop

sy*

(b

efo

re s

tud

y e

ntr

y)

Arm A

Arm B

Core biopsy

optional

Core biopsy

optional

Untch M, et al. Presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio,

Texas. Abstract S2-07.

R*

Final Study Design (After 400 Patients Recruited)

Su

rgery

12 weeks 12 weeks

N = 1200

*Centrally confirmed:

- Subtypes HER 2/ HR

- Ki67

- SPARC

Paclitaxel

80 mg/ m2

weekly

nab-Paclitaxel

125 mg/ m2

weekly

Epirubicin 90 mg/m2

Cyclophosphamide

600 mg/m2

If HER2 positive:

Trastuzumab 8 mg/kg (loading dose)

followed by 6 mg/kg

Pertuzumab (absolute dose per

application) 840 mg (loading dose)

followed by 420 mg

If H

ER

2 p

osit

ive:

Tra

stu

zu

mab

acco

rdin

g to

AG

O G

uid

elin

es

Core biopsy

Co

re b

iop

sy*

(a

fte

r a

nti

-HE

R2

tre

atm

en

t /

be

fore

stu

dy e

ntr

y) Arm A

Arm B

Core biopsy

optional

Core biopsy

optional

R*

Co

re b

iop

sy*

(b

efo

re s

tud

y e

ntr

y)

N = 60 (HER2 positive)

6 weeks

* Randomizations carried out simultaneously



Endpoints Primary endpoint:

• pCR (ypT0 ypN0)

– No invasive or in situ disease in breast or lymph nodes

Secondary endpoints:

• Other pCR definitions:

– No invasive disease in breast or lymph nodes

– No invasive disease in breast

• Toxicity and compliance

• pCR rates by SPARC (Secreted protein acidic and rich in cysteine

protein expression, NCL-O-NECTIN; 1: 100;Novocastra)



Selected Hematological Toxicities

Adverse

events (AE) Grade

Paclitaxel

N (%)

N = 598

Nab-paclitaxel

N (%)

N = 606 P value

Anemia Any 526 (88.3) 560 (92.4) .019

3-4 6 ( 1.0) 15 ( 2.5) .076

Neutropenia Any 485 (81.5) 528 (87.3) .007

3-4 368 (61.8) 366 (60.5) .636

Febrile

neutropenia 25 ( 4.2) 28 ( 4.6) .779



Non-Hematological Toxicities

AE Grade

Paclitaxel

N (%)

N = 598

Nab-paclitaxel

N (%)

N = 606 P value

Fatigue Any 465 (77.8) 502 (82.8) .030

3-4 28 (4.7) 36 (5.9) .369

Diarrhea Any 264 (44.1) 310 (51.2) .015

3-4 17 (2.8) 20 (3.3) .739

Rash Any 138 (23.1) 201 (33.2) <.001

3-4 4 (0.7) 7 (1.2) .547

Hand-foot syndrome Any 105 (17.6) 168 (27.7) <.001

3-4 6 (1.0) 14 (2.3) .112

Peripheral sensory

neuropathy*

Any 390 (65.2) 511 (84.3) <.001

3-4 16 (2.7) 62 (10.2) <.001

Myalgia Any 145 (24.2) 189 (31.2) .008

3-4 0 (0.0) 3 (0.5) .249



* Nab-paclitaxel 125mg/m2 - grade 3-4 peripheral sensory neuropathy: 6 (5.5%)

Primary Endpoint (pCR: ypT0 ypN0)

P = .001



pCR in Stratified Subgroups

Parameter Subgroup pCR (%) P value

SPARC SPARC negative 28.8 vs 37.7 .003

SPARC positive 29.8 vs 48.3 .074

Ki67 Ki67≤20% 19.6 vs 26.1 .137

Ki67>20% 33.1 vs 44.0 .001

Biological

subtype

HER2-, HR+ 12.0 vs 16.0 .183

HER2-, HR- 25.7 vs 48.2 <.001

HER2+, HR+ 50.0 vs 56.4 .275

HER2+, HR- 66.7 vs 74.6 .371

HER2 HER2- 17.7 vs. 27.0 <.001

HER2+ 54.1 vs 61.8 .120

HR status HR- 36.1 vs. 56.1 <.001

HR+ 25.6 vs. 29.9 .169



40% 49%

0%

10%

20%

30%

40%

50%

60%

paclitaxel nab-paclitaxel

Secondary Endpoints pCR Rates According to

Other Definitions

pCR (ypT0 /is ypN0) pCR (ypT0/ is ypN0/+)

34% 43%

0%

10%

20%

30%

40%

50%

60%

paclitaxel nab-paclitaxel

P = .004 P = .002



Conclusion • Primary study endpoint was reached:

Nab-paclitaxel increased significantly the pCR rate

compared to paclitaxel (odds ratio [OR] 1.53; P < .001)

• This effect was seen in all subgroups, especially in

patients with triple-negative tumors (OR 2.69)

• Nab-paclitaxel 150mg/m2 weekly was associated with a

higher rate of sensory neuropathy than paclitaxel

• Long term follow-up is needed to validate if the increase

in pCR rate translates into a better disease-free survival

and overall survival



Mutational Analysis of CALGB 40601

(Alliance), a Neoadjuvant Phase III

Trial of Weekly Paclitaxel (T) and

Trastuzumab (H) With or Without

Lapatinib (L) for HER2-Positive

Breast Cancer

Hoadley KA, Barry WT, Pitcher BN, Parker JS, Wilkerson MD,

Singh B, Irvin W Jr, Henry NL, Tolaney SM, Dang C, Krop IE,

Berry DA, Mardis ER, Perou CM, Winer EP, Hudis CA, Carey LA

On behalf of the Alliance for Clinical Trials in Oncology

Abstract S3-06

Specific Aims

• Evaluate the mutational landscape of 181 HER2-

positive pretreatment tumors from the CALGB

40601 trial

• Correlate mutations in 9 genes with pCR to

chemotherapy plus HER2 targeting

– Focus primarily on three genes

TP53

PIK3CA

HER2

Hoadley KA, et al. Presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio,


CALGB 40601 (Alliance), A Neoadjuvant Phase III Trial of Weekly Paclitaxel (wT) and

Trastuzumab (H) With or Without Lapatinib (L) for HER2-Positive Breast Cancer

Research

tissue

Research

tissue

Clinical

stage II-III

HER2+

R

wT+H+L x 16 weeks

wT+H x 16 weeks

wT+L x 16 weeks

S

U

R

G

E

R

Y

Recommended:

Dose-dense AC

→ H x 34 weeks

Carey L, J Clin Oncol. 2013;31(Suppl): Abstract 500.



Primary Endpoint: ASCO 2013 • In-breast pCR to dual therapy (THL) versus single (TH)

– 56% versus 45% (P = .12)




T

H

L

T

H

T

L

P = .12 THL vs TH

P = .12 TH vs TL

56%

46%

37%

pCR by Intrinsic Subtype (All Arms, n = 265)




Other subtypes:

3 Claudin-low (0% pCR)

14 basel-like (35% pCR)

Excluded “normal” (n = 6)

70%

80%

34% 36% 37%

40%

71%

38% 41%

52%

9%

22%

Pe

rce

nta

ge

Consort

• Exome subset pCR Rate = 45% (51% THL, 47% TH, 34% TL)

• Consistent with overall study population




THL (n = 118)

Evaluable for pCR

(n = 116)

TH (n = 120)

Evaluable for

pCR (n = 117)

TL (n = 67)

Evaluable for

pCR (n = 62)

Randomized (305)

Analysis n = 295

For analysis

(n = 103)

Excluded

(n = 13)

RNAseq

265/295

90%

For analysis

(n = 104)

Excluded

(n = 13)

For analysis

(n = 58)

Excluded

(n = 4)

For analysis

(n = 67)

Excluded

(n = 36)

For analysis

(n = 70)

Excluded

(n = 34)

For analysis

(n = 44)

Excluded

(n = 14)

DNAseq

181/295

68%

Excluded samples:

Withdrew consent n = 2

No biospecimen n = 7

Inadequate RNA n = 12

RNAseq failure n = 9

Excluded samples:

No DNA consent n = 42

No normal sample n = 25

Consent pending n = 14

DNAseq failed n = 3

Selected Mutated Genes




% M

uta

ted

56%

20%

9%

4% 4% 2% 2% 1% 1%

# Samples

TP53 Mutations by pCR and Subtype

Troester MA, et al. BMC Cancer. 2006;6:276. Carey L, J Clin Oncol. 2013;31(Suppl): Abstract 500.



OR: 3.67;

P<.001

*

OR: 5.23;

P = .007

*

Wild type Mutant

Total, n 181 57 58 51 9 4 2

# TP53

mutant

102

(56%)

50

(88%)

18

(31%)

25

(49%)

7

(78%)

2

(50%)

0

(0%)

• TP53 mutation gene expression signature (Troester, et al) previously show to be correlated with

pCR (Carey, et al) was also highly correlated with the TP53 exome-based mutation calls (P<.001)

PIK3CA Mutations

PIK3CA mutation not correlated with pCR



Subtype Wildtype Mutant

Basal-like 8 1 (11%)

Claudin-low 2 0 (0%)

HER2-E 43 14 (25%)

Luminal A 51 4 (7%)

Luminal B 35 16 (31%)

Normal-like 3 1 (25%)

93% of mutations were in exons 9 and 20

No pCR pCR

Wildtype 77 (53%) 68 (47%)

Mutant 22 (61%) 14 (39%)

P value = .5

No

. M

uta

tio

ns

17

0

p.E545K

p.E542K

p.H1047L/R

0 200 400 600 800 1068 aa

Helical

domain

Kinase

domain

HER2/ERBB2 Mutations

• 2/8 HER2 mutations were detected at variant allele

frequencies (VAF) greater than 10%



8 mutations in 7 patients ERBB2

p.L755S p.V777L

# M

uta

tio

ns

Rec.. Furin-like Rec.. GF_..

0 200 400 600 800 1000 1255 aa

p.G727A

10

0

Kinase_Tyr

• HER2-E with V777L

– THL Arm

– Preclinically predicted

sensitive to lapatinib

– Achieved pCR

• Luminal A with L755S

– TL Arm

– Preclinically predicted

resistant to Lapatinib

– No pCR

HER2/ERBB2 Mutations



Bose R, et al. Cancer Discovery. 2013;3(2):224-237.

Conclusions

• TP53 was the most frequently mutated gene (56% overall)

– TP53 mutations were associated with increased pCR

– TP53 mutations were correlated with a higher overall

somatic mutation rate

• Mutations in PIK3CA and the lower frequency mutations in

GATA3, MALAT1, ERBB2, TRPS1, MAP3K1, AKT1, MAP2K4

were not associated with pCR

• Activating HER2 mutations were uncommon but V777L and

L755S behaved as predicted from preclinical studies

• Studies to simultaneously use genomic signatures,

somatic mutations, and clinical variables for pCR

predictions are underway



Neoadjuvant Chemotherapy With or Without

Bevacizumab or Everolimus: Survival Analysis

of the HER2-Negative Cohort of the

GeparQuinto Study (GBG 44)

Gerber B, Loibl S, Untch M, Eidtmann H, Rezai M, Fasching PA,

Tesch H, Eggemann H, Schrader I, Kittel K, Hanusch C, Huober J,

Solbach C, Jackisch C, Kunz G, Blohmer J-U, Hauschild M, Fehm T,

Nekljudova V, von Minckwitz G

Abstract P3-11-01

Background • The GeparQuinto study showed that adding

bevacizumab (Bev) to 24 weeks of anthracycline-

taxane-based chemotherapy increases pathologic

complete response (pCR, breast and axilla) rates from

14.9% to 18.4% (P = .04) and in TNBC patients from

27.9% to 39.3% (P = .003)1

• No difference in pCR rate was observed with

everolimus (Eve) and paclitaxel in patients who had no

early response to neoadjuvant chemotherapy2

1. Von Minckwitz G, et al. N Engl J Med. 2012;366(4):299-309. 2. Huober J, et al. Eur J Cancer. 2013;49(10):2284-2293.

Gerber B, et al. Presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio,

Texas. Abstract P3-11-01.

Objectives

• Secondary objectives of GeparQuinto were:

– DFS

– OS



Materials and Methods

• Patients with HER2-negative tumors were randomized to

neoadjuvant treatment

– 4x epirubicin/cyclophosphamide (EC; E 90 mg/m2, C 600

mg/m2 q3w) followed by

– 4x Docetaxel (T; 100 mg/m2 q3w)

– ± Bevacizumab (15 mg/kg q3w) before surgery

• Patients not clinically responding to EC ± Bev were randomized

to weekly paclitaxel (80 mg/m2) ± everolimus (5 mg/day)

• Patients with hormone receptor-positive tumors received

endocrine treatment after surgery; no Bev or Eve were given

post surgery



DFS and OS After Neoadjuvant Anthracycline-Taxane Based

Chemotherapy ± Bevacizumab

Overall, 3-year DFS was 80.8% and 3-year OS was 89.7%. Outcome was

not different for patients receiving bevacizumab compared to patients

receiving chemotherapy alone overall and in subgroups.



DFS OS 100 -

90 -

80 -

70 -

60 -

50 -

40 -

30 -

20 -

10 -

0 -

100 -

90 -

80 -

70 -

60 -

50 -

40 -

30 -

20 -

10 -

0 -

Logrank P = .7837

EC-T 195/969 events

ECB-TB 202/956

Logrank P = .8422

EC-T 118/969 events

ECB-TB 116/956

DFS, months OS, months

Pro

po

rtio

n D

isea

se

Fre

e

Pro

po

rtio

n A

live

0 12 24 36 48 60 72 0 12 24 36 48 60 72

EC-T 969 831 696 585 322 78 0

ECB-TB 956 844 700 579 339 77 0

EC-T 969 859 751 629 352 88 0

ECB-TB 956 863 749 651 372 84 0

DFS After Neoadjuvant Anthracycline-Taxane Based Chemo ± Bev

According to pCR

Survival analysis according to pCR showed that patients with a pCR had

a worse DFS if they received bevacizumab as part of their neoadjuvant

therapy (P = .062). OS was not different.



1.0 –

0.8 –

0.6 –

0.4 –

0.2 –

0.0 –

DFS, months

Su

rviv

al

Pro

ba

bilit

y

Logrank P<.0001

EC-T, no pCR 825 698 378 486 267 67 0

EC-T, pCR 144 133 118 99 55 11 0

ECB-TB, no pCR 780 680 558 459 282 66 0

ECB-TB, pCR 176 164 142 120 57 11 0

0 12 24 36 48 60 72

HR 95% CI P value

pCR vs no pCR EC-T 0.274 (0.145, 0.519) <.001

pCR vs no pCR ECB-TB 0.551 (0.360, 0.845) .006

ECB-TB vs EC-T, pCR 2.02 (0.965, 4.22) .062

ECB-TB vs EC-T, no pCR 0.989 (0.805, 1.22) .919

Conclusions

• The use of 24 weeks of neoadjuvant

bevacizumab containing therapy did not

improve DFS and OS

• Patients achieving pCR had a trend for worse

DFS if treated with bevacizumab compared to

patients treated without bevacizumab



S0800 – Nab-Paclitaxel, Doxorubicin,

Cyclophosphamide, and Pegfilgrastim With or

Without Bevacizumab in Treating Women With

Inflammatory or Locally Advanced Breast

Cancer (NCI CDR0000636131)

Nahleh ZA, Barlow WE, Hayes DF, Schott AF, Gralow JR, Perez EA,

Sikov WM, Chennuru S, Mirshahidi H, Vidito S, Lew DL, Pusztai L,

Livingston RB, Hortobagyi GN

Abstract P3-11-16

Background • Locally advanced breast cancer (LABC), either

inflammatory (IBC) or noninflammatory, remains a

challenge despite progress in multimodality treatment.

• Standard anthracycline-taxane neoadjuvant combination

chemotherapy for HER2-negative IBC and LABC generally

yields poor pathologic complete response rates (pCR rate

approx 10%) and long term survival rates less than 40%.

• S0800 sought to compare bevacizumab in combination

with weekly nab-paclitaxel followed by dose-dense

doxorubicin and cyclophosphamide (AC) to nab-paclitaxel

and AC alone as neoadjuvant treatment for patients with

HER2 negative IBC and LABC

Nahleh ZA, et al. Presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio,


Low J, et al. J Clin Oncol. 2004;22(20):4067-4074. Kleer CG, et al. Breast Cancer Res. 2000;2(6):423-429. Shirakawa K, et al. Breast Cancer Res.

2003;5(3):136-139. Wedam S, et al. J Clin Oncol. 2006;24(5):769-777. Jain R. Nat Med. 2001;7(9):987-999. Sweeney CJ, et al. Cancer Res.

2001;61(8):3369-3372. Desai N, et al. Clin Cancer Res. 2006;12(4):1317-1324. Müller BG, et al. Pharm Res. 1996;13(1):32-37. Kim YW, et al. J Korean

Med Sci. 1998;13(6):652-657. Van den Eynden GG, et al. Breast Cancer Res Treat. 2006:95(3):219-228. Volk LD, et al. Neoplasia. 2011;13(4):327-338.

Link JS, et al. Clin Breast Cancer. 2007;7(10):779-783.

Background • The rationale for using bevacizumab in S0800 is based on

the proposed role of angiogenesis in improving flow and

oxygenation and enhancing the delivery of chemotherapy

agents (vascular pruning hypothesis)5, and the

proapoptotic effect with certain classes of

chemotherapeutic agents, particularly taxanes1,5

• S0800 used nab-paclitaxel as the taxane backbone based

on several potential advantages in locally advanced

vascular tumors2-7



Low J, et al. J Clin Oncol. 2004;22(20):4067-4074. Kleer CG, et al. Breast Cancer Res. 2000;2(6):423-429. Shirakawa K, et al. Breast Cancer Res.

2003;5(3):136-139. Wedam S, et al. J Clin Oncol. 2006;24(5):769-777. Jain R. Nat Med. 2001;7(9):987-999. Sweeney CJ, et al. Cancer Res.

2001;61(8):3369-3372. Desai N, et al. Clin Cancer Res. 2006;12(4):1317-1324. Müller BG, et al. Pharm Res. 1996;13(1):32-37. Kim YW, et al. J Korean

Med Sci. 1998;13(6):652-657. Van den Eynden GG, et al. Breast Cancer Res Treat. 2006:95(3):219-228. Volk LD, et al. Neoplasia. 2011;13(4):327-338.

Link JS, et al. Clin Breast Cancer. 2007;7(10):779-783.

Methods • Prospective randomized phase II SWOG trial in women with HER2-

negative in inflammatory or locally advanced breast cancer IBC

(AJCC stages IIB, IIIA, IIIB, or IIIC).

• Randomization to either:

– Arm 1: (n = 100)

Bevacizumab 10 mg/kg IV D1 q2w x 12 weeks +

nab-paclitaxel 100 mg/m2 IV D1 every week for 12 weeks

Followed by AC every 14 days X 6 + pegfilgrastim (n = 100)

– Arm 2: (n = 50)

nab-paclitaxel followed by AC + pegfilgrastim

– Arm 3: (n = 50)

AC + pegfilgrastim followed by nab-paclitaxel

• Randomization stratified by HR status and disease (IBC/not IBC)

• Primary endpoint: pCR, defined as no evidence of invasive tumor at the

primary tumor site and axillary lymph nodes in the surgical specimen



pCR Rates by Randomized Treatment



Perc

en

tag

e W

ith

pC

R

21

36

28

59

18

25

14

30

22

37

Overall Survival by Randomized Treatment



Overa

ll S

urv

ival

Months Since Randomization

No bevacizumab (n = 122, 13 deaths)

Bevacizumab (n = 96, 8 deaths)

Stratified log-rank P = .59

Number at risk

No bevacizumab 112 110 71 24 2

Bevacizumab 96 92 61 12 2

1.00 –

0.75 –

0.50 –

0.25 –

0.00 –

0 12 24 36 48

Grade 3/4 Adverse Events



Nab-PAC+BEV→AC+PEG-G

n = 92

Nab-PAC+BEV with AC+PEG-G arms

n = 108

Adverse event No. No.

Any grade 3-4 62 (67%) 70 (65%)

ARDS 1 0

Diarrha 3 2

Dyspnea 3 1

Enterocolitis infectious 0 2

Hand-foot syndrome 1 2

Heart failure 0 1

Hematologic events

(including, anemia, febrile

neutropenia)

43 40

Hypercalcemia 0 1

Hypertension 8 3

Nausea 5 10

Pain 2 4

Respiratory failure 1 1

Sepsis 2 1

Thromboembolic event 1 2

Conclusions • Compared with combination anthracycline-taxane neoadjuvant

chemotherapy, the Bev/Nab-paclitaxel/AC regimen significantly

improved pCR rate overall, especially for triple-negative breast

cancer (TNBC) patients

• The observed pCR rate in ER-negative disease (59%) suggests

that the addition of bevacizumab to this chemotherapy backbone

may improve outcome in this subset and justifies further testing

of such an approach

• Similar findings were noted with the addition of bevacizumab in

GeparQuinto and CALGB40602 in women with TNBC

• Grade 3 and 4 toxicities were common but did not differ by

treatment arm

• This regimen using the weekly nab-paclitaxel backbone could be

a good choice for TNBC/IBC neoadjuvant treatment



TBCRC023: A Randomized Multicenter Phase II

Neoadjuvant Trial of Lapatinib, Trastuzumab,

With or Without Endocrine Therapy for

12 Weeks vs 24 Weeks in Patients With HER2

Overexpressing Breast Cancer

Rimawi MF, Niravath PA, Wang T, Rexer B, Forero A, Wolff AC, Nanda

R, Storniolo AM, Krop I, Goetz MP, Nangia JR, Jiralerspong S,

Pavlick AC, Gutierrez C, Schiff R, Hilsenbeck SG, Osborne CK,

on behalf of TBCRC

Abstract S6-02

Targeting HER2 Pathway

Rimawi MF, et al. Presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio,


Arpino G, et al. J Natl Cancer Inst. 2007;99(9):694-705. Rimawi MF, et al. Clin Cancer Res. 2011;17(6):1351-1361.

TBCRC 006



Rimawi MF, et al. J Clin Oncol. 2013;31(14):1726-1731.

Path CR

(ypT0-is)

Residual

CA≤ 1cm

Total 17 (27%) 14 (22%)

ER+ 8 (21%) 13 (33%)

ER- 9 (36%) 1 (4%)

N = 64

Median tumor

Size = 6 cm

Surgery Lapatinib + trastuzumab

(Plus estrogen deprivation if ER+)

12 weeks

Stage

II/III

HER2+

breast

cancer

Hypothesis

• In HER2-positive breast cancer, longer

treatment with anti-HER2 therapy and

endocrine therapy, if tumors are also

ER-positive, will result in higher pCR

rate.



TBCRC023 Schema



1:2

randomization

Lapatinib + trastuzumab

(Plus estrogen deprivation if ER+)cc

HER2+

breast

cancer

Biopsy Biopsy Biopsy

Week

1

Week

12

Week

1

Week

12

Week

24

Study Endpoints

• Primary endpoint

– Pathologic complete response (pCR) in the

breast (ypT0-isypNx)

• Secondary endpoints

– Safety and tolerability

– Time to first recurrence

– Overall survival



Toxicity

No grade 4 toxicity



Grade 3

toxicity

12 week

N (%)

24 week

N (%)

Elevated LFT - 5 (9%)

Diarrhea - 1 (2%)

Mucositis - 1 (2%)

Anemia 1 (3%) -

Renal calculi (SAE) 1 (3%) -

Pathologic Response

Path CR

(ypT0-is)

12 weeks

(n = 33)

24 weeks

(n = 61)

Overall 4 (12%) 17 (28%)

ER-positive 2 (9%) 13 (33%)

ER-negative 2 (20%) 4 (18%)



Pathologic Response



Perc

en

tag

e

35%

13%

18%

9% 33% 18% 20%

Conclusions

• TBCRC023 did not meet its primary endpoint of

increasing pCR to 45%. This was mainly due to lower

than expected pCR in both arms.

• However, the study demonstrated a twofold numeric

increase in pCR in the 24 weeks arm over the 12 week

arm. That increase was more than threefold in the

ER-positive subgroup.

• This is the first trial to show that longer treatment

with dual anti-HER2 therapy in combination with

endocrine therapy, and without chemotherapy, leads

to a meaningful increase in pCR rate in ER-positive

and HER2-positive breast cancer.



Documents

A Randomized Phase III Trial Comparing Nanoparticle-Based ... · A joint study of the AGO Breast and the German Breast Group (GBG) Abstract S2-07 . Initial Study Design y 12 weeks