CHER-LOB: PREOPERATIVE CHEMOTHERAPY PLUS TRASTUZUMAB, LAPATINIB OR BOTH IN HER2-POSITIVE OPERABLE BREAST CANCER – PRELIMINARY SAFETY REPORT WITH FOCUS ON CARDIAC TOLERABILITY

(1)

CHER-LOB: Preoperative chemotherapy plus trastuzumab, lapatinib or both in HER2

positive operable breast cancer.

Preliminary safety report with focus on cardiac tolerability.

_{Preliminary safety report with focus on cardiac tolerability.}

Valentina Guarneri

1

1 , Antonio Frassoldati

_{, Antonio Frassoldati}

1

1 , Katia Cagossi

_{, Katia Cagossi}

2

2 , Alberto Bottini

_{, Alberto Bottini}

3

3 , Luigi Cavanna

_{, Luigi Cavanna}

4

4 , Andrea Michelotti

_{, Andrea Michelotti}

5

5 , Gordana Jovic

_{, Gordana Jovic}

1

1 ,

_,

Federico Piacentini

1

1 , Cristina Oliva

_{, Cristina Oliva}

6

6 , PierFranco Conte

_{, PierFranco Conte}

1

1 1From the

1From the

11

_{Department of Oncology and Hematology, Modena University Hospital, Italy and from The}

_{Divisions of Medical Oncology of:}

22

Ramazzini Hospital, Carpi;

_{Ramazzini Hospital, Carpi;}

33

Istituti Ospitalieri, Cremona;

_{Istituti Ospitalieri, Cremona;}

44

Hospital of Piacenza,

_{Hospital of Piacenza,}

55

S. _S.

Chiara University Hospital, Pisa, Italy;

66

Oncology Medicine Development Center, GlaxoSmithKline, Greenford, UK

_{Oncology Medicine Development Center, GlaxoSmithKline, Greenford, UK}

RESULTS

KEY INCLUSION CRITERIA

• Histologically confirmed infiltrating primary BC of >2.0 cm in largest clinical diameter

• HER2 positive tumor (either IHC 3+ or FISH+)

• Availability of tumor tissue for biological and molecular examination • Age >18, < 65 years

• ECOG PS 0-1

• Normal organ and marrow function

• LVEF within the institutional range of normal

• Adequate contraception (women of child-bearing potential) • Ability to swallow and retain oral medication

• Written informed consent

ENDPOINTS

Primary

• % of pCR in the breast and axillary nodes Secondary

• % of clinical objective responses (CR+ PR measured by USG) in the breast

• % of conservative surgery • safety profile

• time to treatment failure from start of primary therapy

• inhibition of intermediate and final biomarkers of the proliferative and the apoptotic pathways induced by the treatment

• correlation between tumor gene expression at diagnosis and pathological response

PATIENTS AND METHODS

CONCLUSIONS

Non-hematological toxicity per cycle

Weekly paclitaxel FEC

G1 G2 G3 G1 G2 G3 Nausea 6.6% 2.2% - 14.7% 14.7% -Vomiting 3.7% 1.5% - 5.9% 14.7% 2.9% Mucositis/stomatitis 5.2% - - 8.8% - -Diarrhoea 16.3% 7.4% 3.7% 8.8% 2.9% -Skin toxicity (rash) 11.1% 14% - 2.9% 26.5% -Nail changes - - - 11.7% - -Neuropathy sensory 5.9% - - - - -Hepatotoxicity: GT - 1.5% 2.9% 5.9% - -Tachycardia 0.7% - - - - -Pulmonary (dyspnea) 0.7% - - - - -Hypersensitivity reaction - - 0.7% - -

-Overall patient and tumor characteristics

Median age, yrs (range) 47 (27;66) Postmenopausal status: Yes

No 36%64% Mean T mammographic size, cm (range) 3.85 (2;9) Clinical stage: IIA

IIB IIIA

21.5% 57% 21.5% Recommended surgery w/o PS: Mastectomy

Breast Conserving 69%31% Histology: Ductal Lobular Other 77% 15% 8% Histologic Grade: G1 G2 G3 NA 8% 8% 69% 15% ER and/or PgR + ER and PgR - 71%29%

Hematological toxicity per cycle (

G2)

Weekly paclitaxel FEC

G2 G3 G4 G2 G3 G4 Leukopenia 1.5% 0.75% _- _48.2% _3.7% -Neutropenia - 0.75% _- _{44.4% 25.9% 14.8%} Anemia 2.25% - - - - -Thrombocytopenia - - - -Febrile neutropenia - - -

-STUDY PLAN

STUDY PLAN

INTRODUCTION

SAMPLE SIZE

• The sample size has been estimated by using the two-stage Simon’s design

• Assuming a 50% increase in the pCR rate for the CT+T+L arm vs CT+T or CT+L, in the first stage 52 patients will be enrolled; in case we observe 4 pCR in CT+T and CT+L arms each and 8 pCR in CT+T+L arm, additional 68 patients will be enrolled, for a total of 120 patients

CARDIAC EVALUATION

• Only those patients with normal LVEF (as measured by echocardiography or MUGA scan) are eligible for the study

• After baseline, LVEF measurement is repeated after 12 weeks (prior to start FEC), and at the end of treatment

• More frequent LVEF evaluations should be performed when clinically indicated

• A >15% absolute decrease from baseline in LVEF

(asymptomatic or symptomatic), that is below the lower limit of normal is considered a SAE

STATUS OF THE TRIAL

• 19 pts have been randomized: 6 in arm A, 6 in arm B, and 7 in arm C • Number of evaluable paclitaxel doses: 135

• Number of evaluable FEC cycles: 34 • Mean duration of treatment

– Arm A: 20.2 (range 3-26) weeks – Arm B: 18.5 (range 11-26) weeks – Arm C: 20.3 (range 6-26) weeks

Lapatinib compliance

Permanent lapatinib discontinuation 0

Lapatinib dose reduction 0

Temporary lapatinib interruption 9

Mean duration of lapatinib interruption, dd (range) 7.6 (1;14)

Reasons for lapatinib interruption: Skin toxicity (G2) Dyspnea (G1) Diarrhoea (G3) Increase of GT (G3) Nausea/Vomiting (G3) Neutropenia (G4) Fever 2 1 1 1 2 1 1

PRELIMINARY CARDIAC EVALUATION

Evaluable pts Mean LVEF (range)

Baseline 14 62% (54-74%)

After 12 weeks 8 61% (58-71%)

After 24 weeks 7 61% (60-63%)

TOXICITY

• This is the first report of the combination of anthracycline-based chemotherapy, trastuzumab and lapatinib as primary systemic therapy for HER2+ operable breast cancer

• Hematological and non-hematological toxicities are mild and manageable

• Taking into account the potential for cardiac toxicity of these agents, a careful monitoring of cardiac safety is planned • These very preliminary data are encouraging on the safety of these combinations

• Study accrual is ongoing

PARTICIPATING INSTITUTIONS

Supported by GlaxoSmithKline

• Modena, Italy (Coordinating Center PI PF Conte ) • Carpi (MO), Italy (PI K Cagossi)

• Piacenza, Italy (PI L Cavanna) • Cremona, Italy (PI A Bottini) • Reggio Emilia, Italy (PI C Boni) • Pisa, Italy (PI A Michelotti)

• Forlì, Italy (PI D Amadori) • Rimini, Italy (PI A Ravaioli) • Parma, Italy (PI A Ardizzoni) • Perugia, Italy (PI LCrinò)

• Candiolo, Italy (PI M Aglietta) • Varese, Italy (PI G Giardina)

• Ancona, Italy (PI S Cascinu) • Treviglio, Italy (PI S Barni) • Pavia, Italy (PI M Danova) • Berlin, Germany (PI M Untch) • Newcastle, UK (PI M Verril)

• Warsaw, Poland (PI C. Szczylik)

• Chemotherapy plus trastuzumab represents the standard treatment for HER2+ breast cancer patients

• In the preoperative setting, the combination of trastuzumab with sequential chemotherapy including taxane and anthracycline resulted in an impressive rate of pathologic complete responses (pCR).

• However, intrinsic or acquired resistance to trastuzumab has been reported in both early and advanced breast cancer

• Lapatinib, a dual inhibitor of the TK activity of EGFR and erbB2, can induce a more effective blockade of the proliferative stimulation

• The combination of trastuzumab and lapatinib is under development because of the potential additive effect of a combined blockade of the outer and inner part of the HER2 receptor, with promising safety and activity data

• On these premises, we have designed a phase II randomized trial to evaluate activity and safety of chemotherapy plus lapatinib, trastuzumab, or both as preoperative therapy for HER2positive operable breast cancer.

LV

E

F

%

Baseline 12 weeks 24 weeks

Arm A Arm B Arm C • No episodes of CHF

• No decline in mean LVEF

• No patient experienced a significant LVEF decline (>15%) • No patient had a LVEF value below the LLN at any point

R A N D O M I Z A T I O N Lapatinib 1000 mg/daily Lapatinib 1500 mg/daily C O R E B I O P S Y S U R G E R Y * TXL 80 mg/m2 Trastuzumab 2 mg/kg

*Surgery within 2 weeks after the last trastuzumab/lapatinib dose

5 FU 600 mg/m2 Epi 75 mg/m2 CTX 600 mg/m2

EGFR, HER2

pTEN, pAKT, pMAPK TUNEL Test, Ki 67 Gene expression

EGFR, HER2

pTEN, pAKT, pMAPK TUNEL Test, Ki 67