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Efficacy and safety of trastuzumab, lapatinib, and paclitaxel neoadjuvant treatment with or without prolonged exposure to anti-HER2 therapy, and with or without hormone therapy for HER2-positive primary breast cancer: a randomised, five-arm, multicentre, open-label phase II trial.

ABSTRACT: BACKGROUND:Dual blockade of HER2 promises increased pathological complete response (pCR) rate compared with single blockade in the presence of chemotherapy for HER2-positive (+) primary breast cancer. Many questions remain regarding optimal duration of treatment and combination impact of endocrine therapy for luminal HER2 disease. METHODS:We designed a randomised phase II, five-arm study to evaluate the efficacy and safety of lapatinib and trastuzumab (6 weeks) followed by lapatinib and trastuzumab plus weekly paclitaxel (12 weeks) with/without prolongation of anti-HER2 therapy prior to chemotherapy (18 vs. 6 weeks), and with/without endocrine therapy in patients with HER2+ and/or oestrogen receptor (ER)+ disease. The primary endpoint was comprehensive pCR (CpCR) rate. Among the secondary endpoints, pCR (yT0-isyN0) rate, safety, and clinical response were evaluated. RESULTS:In total, 215 patients were enrolled; 212 were included in the full analysis set (median age 53.0 years; tumour size = T2, 65%; and tumour spread = N0, 55%). CpCR was achieved in 101 (47.9%) patients and was significantly higher in ER- patients than in ER+ patients (ER- 63.0%, ER+ 36.1%; P = 0.0034). pCR with pN0 was achieved in 42.2% of patients (ER- 57.6%, ER+ 30.3%). No significant difference was observed in pCR rate between prolonged exposure groups and standard groups. Better clinical response outcomes were obtained in the prolongation phase of the anti-HER2 therapy. No surplus was detected in pCR rate by adding endocrine treatment. No major safety concern was recognised by prolonging the anti-HER2 treatment or adding endocrine therapy. CONCLUSIONS:This study confirmed the therapeutic impact of lapatinib, trastuzumab, and paclitaxel therapy for each ER- and ER+ subgroup of HER2+ patients. Development of further strategies and tools is required, particularly for luminal HER2 disease.

SUBMITTER: Masuda N

PROVIDER: S-EPMC5996004 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Efficacy and safety of trastuzumab, lapatinib, and paclitaxel neoadjuvant treatment with or without prolonged exposure to anti-HER2 therapy, and with or without hormone therapy for HER2-positive primary breast cancer: a randomised, five-arm, multicentre, open-label phase II trial.

Masuda N N Toi M M Yamamoto N N Iwata H H Kuroi K K Bando H H Ohtani S S Takano T T Inoue K K Yanagita Y Y Kasai H H Morita S S Sakurai T T Ohno S S

Breast cancer (Tokyo, Japan) 20180214 4

<h4>Background</h4>Dual blockade of HER2 promises increased pathological complete response (pCR) rate compared with single blockade in the presence of chemotherapy for HER2-positive (+) primary breast cancer. Many questions remain regarding optimal duration of treatment and combination impact of endocrine therapy for luminal HER2 disease.<h4>Methods</h4>We designed a randomised phase II, five-arm study to evaluate the efficacy and safety of lapatinib and trastuzumab (6 weeks) followed by lapatin ...[more]

PMID: 29445928

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Project description:BackgroundNeoadjuvant dual human epidermal growth factor receptor (HER2) blockade with trastuzumab and pertuzumab plus paclitaxel leads to an overall pathologic complete response (pCR) rate of 46%. Dual HER2 blockade with ado-trastuzumab emtansine (T-DM1) and lapatinib plus nab-paclitaxel has shown efficacy in patients with metastatic HER2-positive breast cancer. To test neoadjuvant effectiveness of this regimen, an open-label, multicenter, randomized, phase II trial was conducted comparing T-DM1, lapatinib, and nab-paclitaxel with trastuzumab, pertuzumab, and paclitaxel in patients with early-stage HER2-positive breast cancer.MethodsStratification by estrogen receptor (ER) status occurred prior to randomization. Patients in the experimental arm received 6 weeks of targeted therapies (T-DM1 and lapatinib) followed by T-DM1 every 3 weeks, lapatinib daily, and nab-paclitaxel weekly for 12 weeks. In the standard arm, patients received 6 weeks of trastuzumab and pertuzumab followed by trastuzumab weekly, pertuzumab every 3 weeks, and paclitaxel weekly for 12 weeks. The primary objective was to evaluate the proportion of patients with residual cancer burden (RCB) 0 or I. Key secondary objectives included pCR rate, safety, and change in tumor size at 6 weeks. Hypothesis-generating correlative assessments were also performed.ResultsThe 30 evaluable patients were well-balanced in patient and tumor characteristics. The proportion of patients with RCB 0 or I was higher in the experimental arm (100% vs. 62.5% in the standard arm, p = 0.0035). In the ER-positive subset, all patients in the experimental arm achieved RCB 0-I versus 25% in the standard arm (p = 0.0035). Adverse events were similar between the two arms.ConclusionIn early-stage HER2-positive breast cancer, the neoadjuvant treatment with T-DM1, lapatinib, and nab-paclitaxel was more effective than the standard treatment, particularly in the ER-positive cohort.Trial registrationClinicaltrials.gov NCT02073487 , February 27, 2014.

Project description:CALGB 40601 was activated as a 3-arm study (paclitaxel + trastuzumab + lapatinib [THL], paclitaxel + trastuzumab [TH] and paclitaxel + lapatinib [TL]). In December 2010, twoneoadjuvant studies were presented at the Cancer Therapy and Research Center-American Association for Cancer Research (CTRC-AACR) San Antonio Breast Cancer Symposium that affected the scientific and practical enthusiasm for the TL arm. For this reason the CALGB 40601 has been amended to omit the TL treatment arm (arm 3). In the Geparquinto trial, patients with HER2-positive breast cancer received epirubicin/cyclophosphamide followed by docetaxel combined either with trastuzumab (EC-DOC-H) or lapatinib (EC-DOC-L) neoadjuvantly, then trastuzumab for a total of 12 months adjuvantly [34]. Pathologic complete response (pCR) in breast and axilla was the primary endpoint. Among 620 patients randomized, there was a higher pCR rate (31% vs 22%) and lower toxicity with fewer discontinuations (10% vs 16%) among patients on the trastuzumab arm than the lapatinib arm. The first results of the NeoALTTO trial were similar [35]. Approximately 450 women with HER2-positive breast cancer received a lead-in phase of 6 weeks of biologic therapy withlapatinib (L), trastuzumab (H), or both, then paclitaxel was added for an additional 12 weeks prior to surgery. All drugs were given at doses similar to CALGB 40601. Postoperative adjuvant therapy included additional chemotherapy and biologic therapy, however, the presentation focused solely on the primary endpoint of pCR in the breast at surgery; no longterm outcomes were presented. There were more grade > 3 adverse events in the lapatinib arm compared with the trastuzumab arm, including diarrhea (23% vs 2%), hepatic abnormalities (13% vs 1%), and neutropenia (16% vs 3%). The only death occurred in the combined biologic (LH) arm. Failure to complete treatment as planned was higher in the L (34%) and LH arms (39%) that in the H arm (u%). PCR was highest with LH-paclitaxel (51%), followed by H-paclitaxel (30%), and L-paclitaxel (25%). Based on the inferior results and higher toxicity of the investigational lapatinib arms of these studies and in discussion with CTEP, in January 2011 it was decided to amend CALGB 40601 to omit Arm 3 (TL). Those patients on this arm will complete protocol therapy as perthe original study design. In CALGB 40601, it is recommended that all patients receive trastuzumab adjuvantly for 1 year, hence all of the patients including those previously randomized to the TL neoadjuvant arm, will be able to receive the known benefit of trastuzumab. After local IRB approval of Update #5, the remainder of the patients will be enrolled and randomized to Arm 1 (THL) and Arm 2 (TH) in a 2:1 fashion. Given that TH isthe standard regimen, and is also clearly the best tolerated, we will continue that arm of thestudy as the comparator, with THL as the only investigational arm.

Project description:BackgroundStudies testing the addition of lapatinib to neoadjuvant trastuzumab + chemotherapy reported an increase in pathologic complete response (pCR), with, nevertheless, discordant results in terms of survival, mainly due to suboptimal power. We here leverage the meta-analytic approach to resolve these inconsistencies.MethodsWe conducted a meta-analysis of randomized phase II/III studies testing lapatinib + trastuzumab in combination with neoadjuvant chemotherapy for human epidermal growth factor receptor (HER2)-positive early breast cancer (BC). Recurrence-free survival (RFS) and overall survival (OS) were adopted as survival endpoints. Pooled hazard ratios (HR) were obtained for the effect of lapatinib + trastuzumab versus trastuzumab, pCR versus no-pCR in the whole study populations and pCR versus no-pCR according to hormone receptor status.ResultsFour phase II/III randomized trials were included in the meta-analysis (CALGB 40601, Cher-LOB, NSABP-B41, NeoALTTO) for an overall population of 1410 patients receiving neoadjuvant chemotherapy in association with either trastuzumab, lapatinib or their combination. RFS was significantly improved with dual HER2 blockade as compared to trastuzumab [HR 0.62, 95% confidence interval (CI) 0.46-0.85]. Dual blockade also led to significantly improved OS (HR 0.65, 95% CI 0.43-0.98). For all treatments combined, patients achieving pCR had better RFS and OS than those with residual disease (HR 0.45, 95% CI 0.34-0.60, and HR 0.32, 95% CI 0.22-0.48, for RFS and OS, respectively). In patients with hormone receptor-negative tumors, pCR was associated with 65% and 73% relative reduction of risk of relapse and death, respectively. Patients with hormone receptor-positive tumors also experienced improved RFS if they achieved pCR; however, the benefit was smaller than that in hormone receptor-negative disease.ConclusionFindings from this meta-analysis further validate the role of pCR as a strong predictor of outcome in patients with HER2-positive BC, especially in hormone receptor-negative disease. Moreover, we provide robust evidence that dual blockade with lapatinib + trastuzumab in combination with neoadjuvant chemotherapy prolongs OS, suggesting that the role of lapatinib could be reconsidered in the early setting.

Dataset Information

Efficacy and safety of trastuzumab, lapatinib, and paclitaxel neoadjuvant treatment with or without prolonged exposure to anti-HER2 therapy, and with or without hormone therapy for HER2-positive primary breast cancer: a randomised, five-arm, multicentre, open-label phase II trial.

Publications

Efficacy and safety of trastuzumab, lapatinib, and paclitaxel neoadjuvant treatment with or without prolonged exposure to anti-HER2 therapy, and with or without hormone therapy for HER2-positive primary breast cancer: a randomised, five-arm, multicentre, open-label phase II trial.

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