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