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Harbeck N.,Ludwig Maximilians University of Munich | Huang C.-S.,National Taiwan University Hospital | Hurvitz S.,University of California at Los Angeles | Hurvitz S.,Translational Research in Oncology | And 18 more authors.
The Lancet Oncology | Year: 2016

Background: Trastuzumab resistance is a key therapeutic challenge in metastatic breast cancer. We postulated that broader inhibition of ErbB receptors with afatinib would improve clinical outcomes compared with HER2 inhibition alone in patients who had progressed on previous trastuzumab treatment. LUX-Breast 1 compared afatinib plus vinorelbine with trastuzumab plus vinorelbine for such patients with HER2-positive metastatic breast cancer. Methods: We did this open-label trial at 350 hospitals in 41 countries worldwide. We enrolled female patients with HER2-overexpressing metastatic breast cancer who had progressed on or following adjuvant trastuzumab or first-line treatment of metastatic disease with trastuzumab. Participants were randomly assigned (2:1) to receive oral afatinib (40 mg/day) plus intravenous vinorelbine (25 mg/m2 per week) or intravenous trastuzumab (2 mg/kg per week after 4 mg/kg loading dose) plus vinorelbine. Randomisation was done centrally and stratified by previous trastuzumab treatment (adjuvant vs first-line treatment), hormone receptor status (oestrogen receptor and progesterone receptor positive vs others), and region. The primary endpoint was progression-free survival, assessed in the intention-to-treat population. This trial is closed to enrolment and is registered with ClinicalTrials.gov, NCT01125566. Findings: Between Aug 26, 2010, and April 26, 2013, we enrolled 508 patients: 339 assigned to the afatinib group and 169 assigned to the trastuzumab group. Recruitment was stopped on April 26, 2013, after a benefit-risk assessment by the independent data monitoring committee was unfavourable for the afatinib group. Patients on afatinib plus vinorelbine had to switch to trastuzumab plus vinorelbine, afatinib monotherapy, vinorelbine monotherapy, or receive treatment outside of the trial. Median follow-up was 9·3 months (IQR 3·7-16·0). Median progression-free survival was 5·5 months (95% CI 5·4-5·6) in the afatinib group and 5·6 months (5·3-7·3) in the trastuzumab group (hazard ratio 1·10 95% CI 0·86-1·41; p=0·43). The most common drug-related adverse events of grade 3 or higher were neutropenia (190 [56%] of 337 patients in the afatinib group vs 102 [60%] of 169 patients in the trastuzumab group), leucopenia (64 [19%] vs 34 [20%]), and diarrhoea (60 [18%] vs none). Interpretation: Trastuzumab-based therapy remains the treatment of choice for patients with HER2-positive metastatic breast cancer who had progressed on trastuzumab. Funding: Boehringer Ingelheim. © 2016 Elsevier Ltd.

Mackey J.R.,University of Alberta | Ramos-Vazquez M.,Centro Oncologico Of Galicia Jose Antonio Quiroga Y Pineiro | Lipatov O.,Republican Clinical Oncology Dispensary | McCarthy N.,ICON Cancer Care Wesley | And 15 more authors.
Journal of Clinical Oncology | Year: 2015

Purpose: Currently, antiangiogenic strategies in metastatic breast cancer have demonstrated modest improvements in progression-free survival (PFS) but not improved quality or duration of survival, warranting evaluation of new agents in a placebo-controlled setting. Ramucirumab is a human immunoglobulin G1 antibody that binds vascular endothelial growth factor receptor-2 and blocks ligand-stimulated activation. The ROSE/TRIO-012 trial evaluated ramucirumab with docetaxel in unresectable, locally recurrent, or metastatic breast cancer. Patients and Methods: In this double-blind, placebo-controlled, randomized, multinational phase III trial, 1,144 patients with human epidermal growth factor receptor 2 (HER2) -negative breast cancer who had not received cytotoxic chemotherapy in the advanced setting were randomly assigned at a two-to-one ratio to receive docetaxel 75 mg/m2 plus ramucirumab 10 mg/kg or docetaxel 75 mg/m2 plus placebo once every 3 weeks. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria. Patients were stratified by previous taxane therapy, visceral metastasis, hormone receptor status, and geographic region. An independent data monitoring committee oversaw the trial. The primary end point was investigator-assessed PFS. Results: Median PFS in patients treated with ramucirumab plus docetaxel was 9.5 months, compared with 8.2 months in patients who received placebo plus docetaxel (hazard ratio [HR], 0.88; P = .077). Median overall survival was 27.3 months in patients who received ramucirumab plus docetaxel, compared with 27.2 months in patients who received placebo plus docetaxel (HR, 1.01; P = .915). Toxicities seen at significantly higher rates in patients receiving ramucirumab included fatigue, hypertension, febrile neutropenia, palmar-plantar erythrodysesthesia syndrome, and stomatitis. Conclusion: Addition of ramucirumab to docetaxel in HER2-negative advanced breast cancer did not meaningfully improve important clinical outcomes. © 2014 by American Society of Clinical Oncology.

Mackey J.R.,Cross Cancer Institute | Pienkowski T.,Center of Oncology of Poland | Crown J.,Dublin City University | Sadeghi S.,University of California at Los Angeles | And 15 more authors.
Annals of Oncology | Year: 2016

Background: The optimal regimen for adjuvant breast cancer chemotherapy is undefined. We compared sequential to concurrent combination of doxorubicin and cyclophosphamide with docetaxel chemotherapy in women with nodepositive non-metastatic breast cancer. We report the final, 10-year analysis of disease-free survival (DFS), overall survival (OS), and long-term safety. Patients and methods: A total of 3298 women with HER2 nonamplified breast cancer were randomized to doxorubicin and cyclophosphamide every 3 weeks for four cycles followed by docetaxel (AC→T) every 3 weeks for four cycles or docetaxel, doxorubicin, and cyclophosphamide (TAC) every 3 weeks for six cycles. The patients received standard radiotherapy and endocrine therapy and were followed up for 10 years with annual clinical evaluation and mammography. Results: The 10-year DFS rates were 66.5% in the AC→T arm and 66.3% in the TAC arm (P = 0.749). OS was 79.9% in the AC→T arm and 78.9% in the TAC arm (P = 0.506). TAC was associated with higher rates of febrile neutropenia, although G-CSF primary prophylaxis greatly reduced this risk. AC→T was associated with a higher rate of myalgia, hand-foot syndrome, fluid retention, and sensory neuropathy. Conclusion: This 10-year analysis of the BCIRG-005 trial confirmed that the efficacy of TAC was not superior to AC→T in women with node-positive early breast cancer. The toxicity profiles differ between arms and were consistent with previous reports. The TAC regimen with G-CSF support provides shorter adjuvant treatment duration with less toxicity. Trial Registration: ClinicalTrials.gov Identifier NCT00312208. © The Author 2016.

Fresco R.,Translational Research in Oncology | Spera G.,Translational Research in Oncology | Meyer C.,Translational Research in Oncology | Cabral P.,University of the Republic of Uruguay | Mackey J.R.,University of Alberta
Oncologist | Year: 2015

Background. Medical imaging is commonly required in breast cancer (BC) clinical trials to assess the efficacy and/or safety of study interventions. Despite the lack of definitive epidemiological data linking imaging radiation with cancer development in adults, concerns exist about the risks of imaging radiation-induced malignancies (IRIMs) in subjects exposed to repetitive imaging.We estimated the imaging radiation dose and IRIM risk in subjects participating in BC trials. Materials and Methods. The imaging protocol requirements in 10 phase III trials in the adjuvant and advanced settings were assessed to estimate the effective radiation dose received by a typical and fully compliant subject in each trial. For each study, the excess lifetime attributable cancer risk (LAR) was calculated using the National Cancer Institute’s Radiation Risk Assessment Tool, version 3.7.1. Dose and risk calculations were performed for both imaging intensive and nonintensive approaches to reflect the variability in imaging performed within the studies. Results. Thetotal effective imaging radiationdosewas 0.4-262.2 mSvinadjuvanttrialsand26-241.3mSvinmetastatic studies.The dose variability resulted fromdiffering protocol requirements and imaging intensity approaches,with computed tomography,multigated acquisition scans, and bone scans as the major contributors. The mean LAR was 1.87-2,410/100,000 in adjuvant trials (IRIM: 0.0002%-2.41% of randomized subjects) and 6.9-67.3/100,000 in metastatic studies (IRIM: 0.007%-0.067% of subjects). Conclusion. IRIMs are infrequent events. In adjuvant trials, aligning the protocol requirements with the clinical guidelines’ surveillance recommendations and substituting radiating procedures with equivalent nonradiating ones would reduce IRIM risk. No significant risk has been observed in metastatic trials, and potential concerns on IRIMs are not justified. © AlphaMed Press 2015.

Hecht J.R.,University of California at Los Angeles | Bang Y.-J.,Seoul National University | Qin S.K.,Peoples Liberation Army Cancer Center | Chung H.C.,Yonsei University | And 20 more authors.
Journal of Clinical Oncology | Year: 2016

Purpose: To evaluate the efficacy of adding lapatinib to capecitabine and oxaliplatin (CapeOx) in patients with previously untreated human epidermal growth factor receptor 2 (HER2) -amplified advanced gastroesophageal adenocarcinoma. Patients and Methods: Patients with HER2-positive advanced gastroesophageal adenocarcinoma were randomly assigned at a one-to-one ratio to CapeOx plus lapatinib 1,250mg or placebo daily. Primary end point was overall survival (OS) in patientswith centrally confirmed HER2 amplification in the primary efficacy population. Results: A total of 545 patients were randomly assigned, and 487 patients comprised the primary efficacy population. Median OS in the lapatinib and placebo arms was 12.2 (95% CI, 10.6 to 14.2) and 10.5 months (95% CI, 9.0 to 11.3), respectively, which was not significantly different (hazard ratio, 0.91; 95% CI, 0.73 to 1.12). Median progression-free survival in the lapatinib and placebo arms was 6.0 (95% CI, 5.6 to 7.0) and 5.4 months (95% CI, 4.4 to 5.7), respectively (hazard ratio, 0.82; 95% CI, 0.68 to 1.00; P = .0381). Response rate was significantly higher in the lapatinib arm: 53% (95% CI, 46.4 to 58.8) compared with 39% (95% CI, 32.9 to 45.3) in the placebo arm (P = .0031). Preplanned exploratory subgroup analyses showed OS in the lapatinib arm was prolonged in Asian and younger patients. No correlation was observed between HER2 immunohistochemistry status and survival. There were increased toxicities in the lapatinib arm, particularly diarrhea. Conclusion: Addition of lapatinib to CapeOx did not increase OS in patients with HER2-amplified gastroesophageal adenocarcinoma. There were clear differences in the effect of lapatinib depending on region and age. Future studies could examine this correlation. © 2016 by American Society of Clinical Oncology. All rights reserved.

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