Preoperative Chemotherapy Plus Trastuzumab

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30

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JOURNAL OF CLINICAL ONCOLOGY

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Preoperative Chemotherapy Plus Trastuzumab, Lapatinib, or Both in Human Epidermal Growth Factor Receptor 2–Positive Operable Breast Cancer: Results of the Randomized Phase II CHER-LOB Study Valentina Guarneri, Antonio Frassoldati, Alberto Bottini, Katia Cagossi, Giancarlo Bisagni, Samanta Sarti, Alberto Ravaioli, Luigi Cavanna, Giovanni Giardina, Antonino Musolino, Michael Untch, Laura Orlando, Fabrizio Artioli, Corrado Boni, Daniele Giulio Generali, Patrizia Serra, Michela Bagnalasta, Luca Marini, Federico Piacentini, Roberto D’Amico, and PierFranco Conte See accompanying editorial on page 1909; listen to the podcast by Dr Burstein at www.jco.org/podcasts Author affiliations appear at the end of this article. Submitted September 6, 2011; accepted January 3, 2012; published online ahead of print at www.jco.org on April 9, 2012. Supported by GlaxoSmithKline, Verona, Italy (lapatinib and financial support). Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical Trials repository link available on JCO.org. Corresponding author: PierFranco Conte, MD, Department of Oncology, Hematology and Respiratory Diseases, University Hospital, via del Pozzo 71, 41100 Modena, Italy; e-mail: [email protected]. © 2012 by American Society of Clinical Oncology 0732-183X/12/3016-1989/$20.00 DOI: 10.1200/JCO.2011.39.0823

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Purpose This is a noncomparative, randomized, phase II trial of preoperative taxane-anthracycline in combination with trastuzumab, lapatinib, or combined trastuzumab plus lapatinib in patients with human epidermal growth factor receptor 2 (HER2) –positive, stage II to IIIA operable breast cancer. The primary aim was to estimate the percentage of pathologic complete response (pCR; no invasive tumor in breast and axillary nodes). Patients and Methods In the three arms, chemotherapy consisted of weekly paclitaxel (80 mg/m2) for 12 weeks followed by fluorouracil, epirubicin, and cyclophosphamide for four courses every 3 weeks. The patients randomly assigned to arm A received a 4-mg loading dose of trastuzumab followed by 2 mg weekly; in arm B patients received lapatinib 1,500 mg orally (PO) daily; and in arm C, patients received trastuzumab and lapatinib 1,000 mg PO daily. Results A total of 121 patients were randomly assigned. Diarrhea and dermatologic and hepatic toxicities were observed more frequently in patients receiving lapatinib. No episodes of congestive heart failure were observed. The rates of breast-conserving surgery were 66.7%, 57.9%, and 68.9% in arms A, B and C, respectively. The pCR rates were 25% (90% CI, 13.1% to 36.9%) in arm A, 26.3% (90% CI, 14.5% to 38.1%) in arm B, and 46.7% (90% CI, 34.4% to 58.9%) in arm C (exploratory P ⫽ .019). Conclusion The primary end point of the study was met, with a relative increase of 80% in the pCR rate achieved with chemotherapy plus trastuzumab and lapatinib compared with chemotherapy plus either trastuzumab or lapatinib. These data add further evidence supporting the superiority of a dual-HER2 inhibition for the treatment of HER2-positive breast cancer. J Clin Oncol 30:1989-1995. © 2012 by American Society of Clinical Oncology

INTRODUCTION

The human epidermal growth factor receptor 2 (HER2) is overexpressed in 15% to 20% of breast cancer, and it is associated with a highly aggressive behavior. The availability of the anti-HER2 monoclonal antibody trastuzumab has significantly improved the prognosis of patients with HER2positive breast cancer both in early and advanced disease stages.1-6

However, not all patients equally benefit from trastuzumab therapy, and multiple pathways can contribute to the intrinsic or acquired resistance to HER2 blockade.7 Lapatinib is a small molecule, dual inhibitor of the tyrosine kinase activity of epidermal growth factor receptor and HER2, currently approved in patients with HER2positive advanced breast cancer who have experienced treatment failure with trastuzumab therapy.8-12 By blocking two different domains of © 2012 by American Society of Clinical Oncology

Information downloaded from jco.ascopubs.org and provided by at Novartis Global on January 21, 2016 from 213.194.46.58 Copyright © 2012 American Society of Clinical Oncology. All rights reserved.

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the HER2 receptor, the combination of trastuzumab and lapatinib is a promising strategy to enhance HER2 inhibition.13,14 In heavily pretreated patients, the combination of trastuzumab and lapatinib significantly prolonged progression-free and overall survival as compared with lapatinib alone, with a good safety profile.15,16 There is a strong biologic and clinical rationale to test the trastuzumab/ lapatinib combination earlier in patients with HER2-positive breast cancer. Preoperative or neoadjuvant chemotherapy is the standard treatment for locally advanced and inflammatory breast cancer, and it is currently adopted for treatment of larger primary tumors to increase the chance for breast conservation.17 Moreover, the neoadjuvant setting permits an in vivo evaluation of treatment efficacy and allows identification of subgroups of patients with different prognosis. In particular, irrespectively of tumor biology and disease stage at diagnosis, patients achieving a pathologic complete response (pCR) have a better outcome, and pCR is now an accepted surrogate end point of treatment efficacy.18-23 In the preoperative setting, the combination of trastuzumab with sequential chemotherapy with taxanes and anthracyclines resulted in an impressive rate of pCR.24-27 On these premises, we designed this phase II randomized study to evaluate activity and safety of chemotherapy plus either trastuzumab or lapatinib or combination of chemotherapy with both trastuzumab and lapatinib as preoperative therapy for HER2-positive operable breast cancer. PATIENTS AND METHODS Study Design This is a noncomparative, phase IIb, randomized study in which patients with HER2-positive primary breast cancer stages II to IIIA were randomly assigned to receive chemotherapy plus trastuzumab (arm A), chemotherapy plus lapatinib (arm B), or chemotherapy plus combined trastuzumab and lapatinib (arm C). Although randomization was used to allocate patients to arms A, B, and C, no comparisons among treatment regimens were planned. The purpose of randomization was to reduce bias owing to patient selection into treatment arms. The primary end point was the percentage of pCR, defined as complete disappearance of invasive tumor in breast and axillary lymph nodes. Residual ductal carcinoma in situ (DCIS) only was included in the pCR category. Secondary aims included the percentage of clinical objective responses in the breast, the percentage of breast-conserving surgery, the safety profile of

these combinations, the time to treatment failure from start of primary therapy, the percentage of inhibition of intermediate and final biomarkers of the proliferative and apoptosis pathways induced by the different combinations, and the correlation between gene expression at diagnosis and pathologic response. The correlative biologic studies are still in progress, and they will be reported separately. The protocol was approved by the local human investigation committees of participating institutions. Patients Patients were eligible if they met the following criteria: previously untreated, infiltrating primary breast cancer of more than 2.0 cm in largest clinical diameter, HER2 positivity (either immunohistochemistry 3⫹ or fluorescent in situ hybridization amplification), age 18 to 65 years, Eastern Cooperative Oncology Group performance status of 0 to 1, availability of tumor tissue for biologic and molecular examination before starting primary treatment, left ventricular ejection fraction (LVEF) within the institutional range of normal, normal organ and marrow function (leukocytes ⱖ 3,000/␮L, absolute neutrophil count ⱖ 1,500/␮L, platelets ⱖ 100,000/␮L, total bilirubin ⱕ 1.5 times the upper limit of normal, and AST and ALT ⱕ 2.5 times the upper limit of normal), ability to swallow and retain oral medication, adequate contraception methods for women of childbearing potential, and written informed consent. Study Procedures At diagnosis, patients underwent a complete workout staging, including chest radiogram, abdominal ultrasonography, and bone scan for patients with clinically enlarged axillary lymph nodes to exclude distant metastases. The local extent of disease was evaluated by mammography, breast ultrasonography, and clinically by caliper. A core-needle biopsy was performed to establish the diagnosis and the biomarker analyses. Randomization was performed centrally at the trial office of the Department of Oncology, Hematology, and Respiratory Diseases, Modena University Hospital, Modena, Italy. Randomization sequence was generated using R software (http://cran.r-project.org). A dedicated web site, with restricted access through password, was used for randomization. On verification of patient’s eligibility, investigators were immediately notified of the allocated treatment. The chemotherapy regimen consisted of weekly paclitaxel 80 mg/m2 for 12 weeks followed by four courses of fluorouracil 600 mg/m2, epirubicin 75 mg/m2, and cyclophosphamide 600 mg/m2 administered every 3 weeks. Patients randomly assigned to arm A received concomitant trastuzumab (4mg/kg loading dose followed by 2 mg/kg weekly for 26 weeks). Patients randomly assigned to arm B received concomitant lapatinib (1,500 mg orally [PO] daily for 26 weeks). Patients randomized to arm C received concomitant trastuzumab (4-mg/kg loading dose followed by 2 mg/kg weekly) plus lapatinib 1,000 mg PO daily for 26 weeks (Fig 1). Corticosteroids and histaminereceptor blockers were administered before paclitaxel. Antiemetics were administered according to local guidelines.

Randomly assigned (N = 121)

Allocated to (n = 36) intervention (n = 36) Received allocated intervention

(n = 39) Allocated to intervention (n = 39) Received allocated intervention

(n = 46) Allocated to intervention (n = 46) Received allocated intervention

Analyzed for safety (n = 36)*



Analyzed Excluded from analysis

(n = 38) Analyzed (n = 1) Excluded from analysis (informed consent withdrawn)

(n = 45) Analyzed (n = 1) Excluded from analysis (major protocol violation)

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(n = 36) (n = 0)

© 2012 by American Society of Clinical Oncology

Fig 1. CONSORT diagram. (*) All patients who have received at least one dose of study medication were included in the safety analysis.



Preoperative Trastuzumab and Lapatinib in HER2ⴙ Operable BC

Criteria for dose modifications were as follows: chemotherapy doses were reduced at 75% of the projected dose in case of grade 4 neutropenia lasting more than 3 days or grade 4 thrombocytopenia lasting more than 5 days after prior course. Paclitaxel was discontinued until recovery in case of sensory-motor neurologic toxicity ⱖ grade 2. Lapatinib dose was held until recovery and then reduced by 250 mg in case of grade 3 or prolonged grade 2 nonhematologic toxicities. Lapatinib was permanently discontinued for any grade 4 toxicity. No dose adjustment was foreseen for trastuzumab. LVEF was evaluated before study entry and repeated after 12 weeks and at the completion of treatment. Management of cardiac toxicity was as follows: (1) New York Heart Association class III/IV cardiac dysfunctions resulted in permanent treatment discontinuation; (2) absolute LVEF decrease of ⱖ 10% below the lower limit of normal resulted in trastuzumab and/or lapatinib being held until recovery and permanently discontinued if recovery did not occur after 8 weeks with trastuzumab and 2 weeks with lapatinib; (3) absolute LVEF decrease of ⱕ 10% below the lower limit of normal resulted in treatment continuing as planned, with LVEF evaluation every 4 weeks. The breast clinical objective response was evaluated by comparing the largest tumor diameter before and after therapy, as assessed by ultrasonography, according to RECIST criteria. Surgery was planned within 5 weeks after the last chemotherapy administration. Treatment after surgery was left to treating physician discretion. The recommendations included 5 years of hormonal therapy for patients with hormone receptor–positive tumors, radiation therapy according to local guidelines, and trastuzumab for up to 1 year of anti-HER2 therapy. Regular follow-up, including clinical examination, blood chemistry, carcinoembryonic antigen, CA 15-3, chest radiogram liver ultrasound, and mammography, was planned up to 5 years. An independent data monitoring committee periodically evaluated the occurrence of adverse events, as well as patient outcomes. Pathology Assessment Clips or ink were used to mark the tumor bed before start of preoperative therapy to facilitate the surgeons and the pathologists. pCR was defined according to the preferred definition of pCR, which consists of the absence of residual invasive cancer within both the breast and lymph nodes.28 The presence of residual DCIS was included in the definition of pCR.

R A N D O M I Z A T I O N

C O R E B I O P S Y

HER2+ operable breast cancer Paclitaxel 80 mg/m2 once weekly

RESULTS

From August 2006 to November 2010, 121 patients from 12 institutions were randomly assigned; 36 patients were allocated to arm A, 39 to arm B, and 46 to arm C (Fig 2). After the second safety report of the independent data monitoring committee, the protocol was amended to reduce lapatinib doses to 1,250 mg PO daily in arm B and to 750 mg daily in arm C because of the occurrence of grade 3 diarrhea in 20% of patients in arm B and in 41% of the patients in arm C. Among the 85 patients randomly assigned to lapatinib-containing arms, 35 patients started according to the initial protocol doses, and the following 50 patients started therapy on lapatinib amended doses. The safety analyses include all randomly assigned patients. Two patients were excluded from efficacy analysis because of informed

A

B

S U R G E R Y

Lapatinib continuous daily dose

Fig 2. CHER-LOB (Chemotherapy, Herceptin and Lapatinib in Operable Breast cancer) study plan. HER2, human epidermal growth factor receptor 2; LVEF, left ventricular ejection fraction.

C Lapatinib continuous daily dose Fluorouracil 600 mg/m2 Epirubicin 75 mg/m2 Cyclophosphamide 600 mg/m2 every 3 weeks

www.jco.org

Statistical Analysis The study used Simon’s two-stage design in each arm. The calculation was based on the assumption of an expected pCR with chemotherapy plus single anti-HER2 agents of 40%. The lowest limit of therapeutic effect considered to be of interest was a pCR of 20%, which is what we expected the rate of pCR with chemotherapy alone to be. The combination of chemotherapy plus dual anti-HER2 (trastuzumab and lapatinib) was considered worthwhile if a pCR ⱖ 60% was obtained (a 50% increase over the expected pCR rate with single anti-HER2 treatment). Setting ␣ ⫽ 10% and ␤ ⫽ 10%, the resulting sample sizes were 37 patients for arms A and B and 46 patients for arm C, totaling 120 patients. A formal comparison of the three arms was not foreseen. However, an exploratory comparison between the combined two single anti-HER2 arms and the dual anti-HER2 arms was carried out. For such analysis, the relative risk was used as a measure of association, and its relative 95% CI was also reported. The relative risk was calculated as the ratio of the pCR rate among patients allocated to arm C to the pCR rate among patients allocated to arms A and B. Toxicities were graded according to the NCI Common Terminology Criteria for Adverse Events version 3.0 and reported as cumulative incidence.

Trastuzumab 4 mg/kg Loading dose → 2 mg/kg once weekly

LVEF



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Compliance With Treatment and Toxicity The majority of patients allocated to arms B and C required lapatinib dose reduction: 80% and 54% before and after the protocol amendment, respectively, for patients randomly assigned to arm B, and 55% and 34% before and after the amendment, respectively, for arm C. Twelve patients in arm B and eight patients in arm C permanently discontinued lapatinib. The mean days on lapatinib for patients with permanent discontinuation were 65 days (range, 13 to 150 days) in arm B and 75 days (range, 10 to 155 days) in arm C of the 182 planned days. Seventeen patients (43.6%) in arm B and 25 patients (54%) in arm C required lapatinib interruptions: The mean days on lapatinib for these patients were 158 days (range, 118 to 179 days) in arm B and 161 days (range, 129 to 179 days) in arm C. Nonhematologic toxicities worse than grade 1 are summarized in Table 2. As expected, diarrhea, dermatologic toxicities, and hepatic toxicities were observed more frequently in patients receiving lapatinib. Hepatic toxicity consisted of transient increases in liver function tests, with no patients with Hy’s law criteria.29 Grade 4 neutropenia occurred in 39%, 36%, and 41% in arms A, B, and C, respectively. Febrile neutropenia occurred in one patient in arm A, three patients in arm B, and one patient in arm C. No relevant cardiac safety issues have emerged. An asymptomatic decrease in the LVEF below the limit of normal was observed in one patient in arm A. No patient had symptoms of congestive heart failure (Fig 3).

Table 1. Patient and Tumor Characteristics Arm A (CT ⫹ trastuzumab)

Arm B (CT ⫹ lapatinib)

Arm C (CT ⫹ trastuzumab⫹ lapatinib)

Characteristic

No.

No. of patients Age, years Mean Range Premenopausal status Clinical stage IIA IIB IIIA Mammographic T size, cm Median Range Mastectomy recommended upfront Histology Ductal Lobular/other Histologic grade 1/2 3 NA Hormone receptor expression both ER and PgR ⱖ 10% ER ⱖ 10%/PgR ⬍ 10% ER ⬍ 10%/PgR ⱖ 10% both ER and PgR ⬍ 10%

36

39

46

50 34-65 17 47.2

49 34-68 15 38.5

49 26-65 19 41.7

11 19 6

13 19 7

14 23 9

%

No.

30.6 52.8 16.7

3 1-9.6

%

No.

33.3 48.7 17.9 3 1.5-5

%

30.4 50 19.6 3.5 1-9

22

61

21

53.8

25

54.3

32 4

88.9 11.1

36 3

92.3 7.7

43 3

93.5 6.5

8 24 4

22.2 66.7 11.1

6 25 8

15.4 64.1 20.5

9 28 9

19.5 60.9 19.5

12 8 1 15

33.3 22.2 2.7 41.7

14 9 1 15

35.9 23.1 2.5 38.5

20 8 0 18

43.5 17.4

Surgery and Responses Overall, approximately 90% of the patients experienced a clinical objective response as assessed by palpation and/or ultrasonography. One hundred eighteen patients underwent surgery. The rates of breast-conserving surgery (BCS) were 66.7%, 57.9%, and 68.9% for patients randomly assigned to arms A, B, and C, respectively. A conversion from mastectomy to BCS was achieved in 61.9%, 42.8%, and 60% of the patients randomly assigned to arms A, B, and C, respectively. A pCR in breast and axillary nodes was observed in 25% (90% CI, 13.1% to 36.9%) of the patients receiving chemotherapy plus trastuzumab (arm A), in 26.3% (90% CI, 14.5% to 38.1%) of the patients receiving chemotherapy plus lapatinib (arm B), and in 46.7% (90% CI, 34.4% to 58.9%) of the patients receiving chemotherapy plus both

39.1

Abbreviations: CT, chemotherapy; ER, estrogen receptor; NA, not available; PgR, progesterone receptor.

consent withdrawal (one patient in arm B) and major protocol violation (one patient in arm C). Patient and tumor characteristics are summarized in Table 1. No imbalances in terms of patient characteristics were observed across the three arms. The majority of the patients had tumor stage at diagnosis IIB (50%, 49%, and 51% in arms A, B, and C, respectively). At diagnosis, approximately half of the patients were judged as candidates for mastectomy.

Table 2. Grade ⬎ 1 Nonhematologic Toxicity Arm A (CT ⫹ trastuzumab) Grade 2

Grade 3

Grade 4

Adverse Event

No.

%

No.

%

No.

Nausea and vomiting Diarrhea Hepatic toxicityⴱ Dermatologic toxicity Mucositis Abdominal pain Fatigue Peripheral neuropathy (sensory) Hypersensitivity reaction

14 2 — 1 1 4 5 — 1

38.8 5.5

2 1 1 2 — — 2 — —

5.5 2.7 2.7 5.5

— — 1 — 1 — — — —

2.7 2.7 11.1 13.8 2.7

5.5

Arm B (CT ⫹ lapatinib)

%

2.7 2.7

Grade 2

Grade 3

Arm C (CT ⫹ trastuzumab ⫹ lapatinib)

Grade 4

Grade 2

Grade 3

Grade 4

No.

%

No.

%

No.

%

No.

%

No.

%

No.

7 6 6 15 3 3 3 1 1

17.9 15.3 15.3 38.5 7.7 7.7 7.7 2.5 2.5

2 13 5 5 1 5 3 1 1

5.1 33.3 12.8 12.8 2.5 12.8 7.7 2.5 2.5

1 1 — 1 — — — — —

2.5 2.5

15 12 8 16 3 9 5 — 2

32.6 26.1 17.4 34.8 6.5 19.6 10.8

5 16 2 5 — 3 4 — 2

10.8 34.8 4.3 10.8

— — 2 — — — — — —

2.5

4.3

6.5 8.7 4.3

%

4.3

Abbreviation: CT, chemotherapy. ⴱ No patients with Hy’s law criteria.

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Arm A Arm B Arm C

80

LVEF (%)

70

60

50

40 Baseline

12−13 Weeks

End of Therapy

Fig 3. Left ventricular ejection fraction (LVEF) per treatment arm. Box plots of LVEF at baseline, after 12 to 13 weeks, and at the end of therapy. Length of whiskers are at 1.5 interquartile range. The white lines within the boxes represent median values. Dots are the outlier values (ⱖ 3 times above the third quartile; ⱕ 3 times below the first quartile).

trastuzumab and lapatinib (arm C). We also carried out an exploratory analysis to compare the pCR rates of the dual anti-HER2 blockade versus the combination of the two single-agent arms (arm C v arms A and B), resulting in a significant difference favoring the chemotherapy plus both trastuzumab and lapatinib arm (risk ratio, 1.81; P ⫽ .019). The rate of node negativity at surgery was 72.2%, 71%, and 84.4% in arms A, B, and C, respectively. We also evaluated the rate of near-pCR, defined as the presence of infiltrating residual disease of less than 5 mm and node negativity (ypT1aN0). The combined rates of pCR plus near pCR were 41.6% in arm A, 36.8% in arm B, and 68.8% in the chemotherapy plus trastuzumab and lapatinib (arm C; Table 3). As expected, the pCR rate was higher in case of hormone receptor negativity (41.3% v 28.8%). DISCUSSION

Preoperative therapy represents the ideal model to study new treatment strategies because the achievement of a pCR is a reliable

predictor of long-term outcomes. The aim of the CHER-LOB (Chemotherapy, Herceptin and Lapatinib in Operable Breast cancer) study was to evaluate the activity and safety of the combination of two anti-HER2 agents in combination with anthracycline-based sequential chemotherapy. Chemotherapy plus trastuzumab and lapatinib induced a pCR rate of 46.7%, which represents a relative increase of 80% in the pCR rate achieved with the same chemotherapy plus either trastuzumab or lapatinib. Recently, other preoperative trials in HER2positive disease have been reported. The Geparquinto study is a head-to-head comparison between lapatinib and trastuzumab administered with sequential epirubicin plus cyclophosphamide ⫻ 4 followed by docetaxel ⫻ 4.30 In this study, the pCR rate, defined as no residual invasive or noninvasive tumor cells in any resected specimens of the breast and axillary nodes (ypT0, ypN0, without DCIS), significantly favored trastuzumab (31.3% v 21.7%; P ⬍ .05). However, different from our study, the lapatinib dose was 1,250 mg reduced to 1,000 mg PO daily because of toxicity. The differences in the lapatinib doses, as well as differences in inclusion criteria and definition of pCR, might account for these different results. Moreover, our study has not the power to compare lapatinib/ chemotherapy versus trastuzumab/chemotherapy; therefore, we can neither confirm nor reject the results from larger studies. In the NeoSphere phase II randomized trial, patients with HER2positive operable or locally advanced breast cancer were randomly assigned to four courses of preoperative docetaxel plus trastuzumab, docetaxel plus trastuzumab plus pertuzumab, trastuzumab plus pertuzumab, or docetaxel plus pertuzumab. The primary aim was the breast pCR rate, which was significantly higher for the dual anti-HER2 combination plus chemotherapy (45.8% v 29% for docetaxel plus trastuzumab and 24% for docetaxel plus pertuzumab). Of interest, the combination of the two anti-HER2 antibodies without chemotherapy induced a 16.8% rate of breast pCR.31 In the Neo-ALTTO phase III study, in which the primary end point was the pCR rate (defined as complete disappearance of infiltrating tumor in the breast), a significant increase was observed for dual anti-HER2 blockade plus paclitaxel (51.3%) as compared with paclitaxel plus trastuzumab (29.5%) or lapatinib (24.7%).32 As a secondary aim, the total pCR rate was also evaluated (breast and axillary nodes) and confirmed the superiority of dual anti-HER2 blockade. These results are consistent with those observed in our CHERLOB trial.

Table 3. Surgery and Pathologic Response Arm A (CT ⫹ trastuzumab; 36 evaluable patients) Surgery and Response Type of surgeryⴱ Mastectomy BCS Conversion rate from mastectomy to BCS Response pCR rate (breast and axillary nodes) Node negativity at surgery pCR ⫹ near pCR rate (ypt1a,N0)

Arm B (CT ⫹ lapatinib; 38 evaluable patients)

Arm C (CT ⫹ trastuzumab ⫹ lapatinib; 45 evaluable patients)

No.

%

No.

%

No.

%

12 24

33.3 66.7 61.9

15 22

39.5 57.9 42.8

14 31

31.1 68.9 60

9 26 15

25 72.2 41.6

10 27 14

26.3 71 36.8

21 38 31

46.7 84.4 68.8

Abbreviations: BCS, breast-conserving surgery; CT, chemotherapy; pCR, pathologic complete response. ⴱ One patient in arm B was withdrawn from the study before surgery because of toxicity and was included in the efficacy analysis.

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The pCR rate in our chemotherapy plus trastuzumab arm was lower than expected (expected 40%, observed 25%). Apart from treatment efficacy, other parameters can influence the rate of pCR, such as the tumor size (median tumor size in CHER-LOB was 3 cm) and the percentage of hormone-receptor positive disease (60.3% in CHERLOB). As a matter of fact, however, the efficacy of weekly paclitaxel, fluorouracil, epirubicin, and cyclophosphamide plus anti-HER2 treatments was confirmed by the rate of BCS, which ranged from 58% to 69%; the percentage of nodal negativity ranging from 70% in the chemotherapy plus single anti-HER2 agents to 84% in the chemotherapy plus dual anti-HER2 agents; and the rates of pCR plus near pCR (yT1aN0) ranging from 37% to 69%. The rate of BCS as well as the rate of conversion from mastectomy to BCS was slightly inferior in the lapatinib arm (58% and 43%, respectively, v 67% to 69% and 62% to 60% in the two trastuzumabcontaining arms). Breast conservation depends on several parameters, such as breast size, tumor location, presence of DCIS, contraindication to radiation therapy, and patient willingness. Therefore, these differences in BCS cannot only be attributed to differences in treatment activity. Different from NeoSphere and Neo-ALTTO, our CHER-LOB trial has also provided useful information on cardiac safety of anthracyclines administered concomitantly with anti-HER2 agents. In line with prior reports, our data confirm that appropriate patient selection and monitoring allows for the use of anthracycline-based chemotherapy concomitantly with trastuzumab, lapatinib, or both without any relevant clinical or instrumental cardiac toxicity.19,21One patient only in the chemotherapy plus trastuzumab arm developed an asymptomatic decrease of LVEF below the limit. However, the incidence of symptomatic events is generally in the rate of 2% to 3%; therefore, because of the limited sample size, our data do not support the use of an anthracycline plus anti-HER2 agents outside of clinical trials. Despite of the dosage reduction for lapatinib after the independent data monitoring committee recommendations, the compliance was still suboptimal, mainly because of diarrhea and skin toxicities. However, the majority of the adverse events resolved with appropriate measures, and the incidence of severe ones were prevented by dose reduction and proactive management. Appropriate training for doctors and patients in the management of adverse events is a priority to improve tolerability and compliance. Of interest, even if the majority of patients required lapatinib dose adjustment and/or temporary inREFERENCES 1. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpress HER2. N Engl J Med 344:783-792, 2001 2. Marty M, Cognetti F, Maraninchi D, et al: Randomised phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: The M77001 study group. J Clin Oncol 23:4265-4274, 2005 3. Piccart-Gebhart MJ, Procter M, LeylandJones B, et al: Trastuzumab after adjuvant chemotherapy in HER-2 positive breast cancer. N Engl J Med 353:1659-1672, 2005 1994


terruption, treatment efficacy was not affected, and the pCR rate was even slightly higher in the chemotherapy plus lapatinib arm. In conclusion, the CHER-LOB study is a phase II randomized study aimed at identifying the best anti-HER2 treatment in terms of pCR rate in operable breast cancer. The data from this trial add further evidence supporting the superiority of a dual-HER2 inhibition for the treatment of patients with HER2-positive breast cancer. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Michela Bagnalasta, GlaxoSmithKline (C); Luca Marini, GlaxoSmithKline (C) Consultant or Advisory Role: PierFranco Conte, GlaxoSmithKline, Roche (C) Stock Ownership: Luca Marini, GlaxoSmithKline Honoraria: PierFranco Conte, GlaxoSmithKline, Roche Research Funding: PierFranco Conte, GlaxoSmithKline Expert Testimony: None Other Remuneration: None

AUTHOR CONTRIBUTIONS Conception and design: Valentina Guarneri, Antonio Frassoldati, Michela Bagnalasta, Luca Marini, PierFranco Conte Financial support: Michela Bagnalasta, Luca Marini Provision of study materials or patients: Valentina Guarneri, Antonio Frassoldati, Alberto Bottini, Katia Cagossi, Giancarlo Bisagni, Samanta Sarti, Alberto Ravaioli, Luigi Cavanna, Giovanni Giardina, Antonino Musolino, Michael Untch, Laura Orlando, Fabrizio Artioli, Corrado Boni, Daniele Giulio Generali, Federico Piacentini Collection and assembly of data: Alberto Bottini, Katia Cagossi, Giancarlo Bisagni, Samanta Sarti, Alberto Ravaioli, Luigi Cavanna, Giovanni Giardina, Antonino Musolino, Michael Untch, Laura Orlando, Fabrizio Artioli, Corrado Boni, Daniele Giulio Generali, Patrizia Serra, Federico Piacentini Data analysis and interpretation: Valentina Guarneri, Roberto D’Amico, PierFranco Conte Manuscript writing: All authors Final approval of manuscript: All authors

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Affiliations Valentina Guarneri, Antonio Frassoldati, Federico Piacentini, Roberto D’Amico, and PierFranco, Modena University Hospital, Modena; Alberto Bottini and Daniele Giulio Generali, AO Istituti Ospitalieri di Cremona, Cremona; Katia Cagossi and Fabrizio Artioli, Ramazzini Hospital, Carpi; Giancarlo Bisagni and Corrado Boni, Arcispedale Santa Maria Nuova, Reggio Emilia; Samanta Sarti and Patrizia Serra, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola; Alberto Ravaioli, Ospedale Infermi, Rimini; Luigi Cavanna, Hospital of Piacenza, Piacenza; Giovanni Giardina, Ospedale di Circolo e Fondazione Macchi, Varese; Antonino Musolino, University Hospital of Parma, Parma; Laura Orlando, Antonio Perrino Hospital, Brindisi; Michela Bagnalasta and Luca Marini, GlaxoSmithKline, Verona, Italy; and Michael Untch, Helios Klinikum Berlin-Buch, Berlin, Germany. ■ ■ ■

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