1. CHER-LOB: Preoperative chemotherapy plus trastuzumab, lapatinib or both in HER2 positive operable breast cancer. Preliminary safety report with focus on cardiac tolerability.
Valentina Guarneri1, Antonio Frassoldati1, Katia Cagossi2 , Alberto Bottini3, Luigi Cavanna4, Andrea Michelotti5, Gordana Jovic1,
Federico Piacentini1, Cristina Oliva6, PierFranco Conte1
1From the 1Department of Oncology and Hematology, Modena University Hospital, Italy and from The Divisions of Medical Oncology of: 2Ramazzini Hospital, Carpi; 3Istituti Ospitalieri, Cremona; 4Hospital of Piacenza, 5S. Chiara University Hospital, Pisa, Italy; 6Oncology Medicine Development Center, GlaxoSmithKline, Greenford, UK
INTRODUCTION
RESULTS
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.
TOXICITY
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
PRELIMINARY CARDIAC EVALUATION
Hematological toxicity per cycle (G2)
Weekly paclitaxel
FEC G2 G3 G4
Leukopenia
1.5%
0.75% -
48.2%
3.7%
Neutropenia
44.4%
25.9%
14.8%
Anemia
2.25%
Thrombocytopenia
Febrile neutropenia
Evaluable pts
Mean LVEF (range)
Baseline 14
62% (54-74%)
After 12 weeks 8
61% (58-71%)
After 24 weeks 7
61% (60-63%)
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
PATIENTS AND METHODS
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%
Recommended surgery w/o PS: Mastectomy
Breast Conserving
69%
31%
Histology: Ductal
Lobular
Other
77%
15% 8%
Histologic Grade: G1 G2 G3 NA
ER and/or PgR +
ER and PgR -
71%
29%
Non-hematological toxicity per cycle
Weekly paclitaxel
FEC G1 G2 G3
Nausea
6.6%
2.2% -
14.7%
Vomiting
3.7%
1.5%
5.9%
2.9%
Mucositis/stomatitis
5.2%
8.8%
Diarrhoea
16.3%
7.4%
Skin toxicity (rash)
11.1%
14%
26.5%
Nail changes
11.7%
Neuropathy sensory
Hepatotoxicity: GT
Tachycardia
0.7%
Pulmonary (dyspnea)
Hypersensitivity reaction
STUDY PLAN
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 R A N D O M I Z T
Lapatinib 1000 mg/daily
Lapatinib 1500 mg/daily C E B P S Y U G *
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 
Arm A
Arm B
Arm C
LVEF %
Baseline
12 weeks
24 weeks
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
CONCLUSIONS
Lapatinib compliance
Permanent lapatinib discontinuation
Lapatinib dose reduction
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
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
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
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
PARTICIPATING INSTITUTIONS
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)
Supported by GlaxoSmithKline