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Ian E Krop - One of the best experts on this subject based on the ideXlab platform.
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Trastuzumab Emtansine versus capecitabine plus lapatinib in patients with previously treated her2 positive advanced breast cancer emilia a descriptive analysis of final overall survival results from a randomised open label phase 3 trial
Lancet Oncology, 2017Co-Authors: Véronique Diéras, Ian E Krop, David Miles, Sunil Verma, Mark D Pegram, Manfred Welslau, Jose Baselga, K L Blackwell, Silke Hoersch, Jin XuAbstract:Summary Background The antibody–drug conjugate Trastuzumab Emtansine is indicated for the treatment of patients with HER2-positive metastatic breast cancer previously treated with Trastuzumab and a taxane. Approval of this drug was based on progression-free survival and interim overall survival data from the phase 3 EMILIA study. In this report, we present a descriptive analysis of the final overall survival data from that trial. Methods EMILIA was a randomised, international, open-label, phase 3 study of men and women aged 18 years or older with HER2-positive unresectable, locally advanced or metastatic breast cancer previously treated with Trastuzumab and a taxane. Enrolled patients were randomly assigned (1:1) via a hierarchical, dynamic randomisation scheme and an interactive voice response system to Trastuzumab Emtansine (3·6 mg/kg intravenously every 3 weeks) or control (capecitabine 1000 mg/m 2 self-administered orally twice daily on days 1–14 on each 21-day cycle, plus lapatinib 1250 mg orally once daily on days 1–21). Randomisation was stratified by world region (USA vs western Europe vs or other), number of previous chemotherapy regimens for unresectable, locally advanced, or metastatic disease (0 or 1 vs >1), and disease involvement (visceral vs non-visceral). The coprimary efficacy endpoints were progression-free survival (per independent review committee assessment) and overall survival. Efficacy was analysed in the intention-to-treat population; safety was analysed in all patients who received at least one dose of study treatment, with patients analysed according to the treatment actually received. On May 30, 2012, the study protocol was amended to allow crossover from control to Trastuzumab Emtansine after the second interim overall survival analysis crossed the prespecified overall survival efficacy boundary. This study is registered with ClinicalTrials.gov, number NCT00829166. Findings Between Feb 23, 2009, and Oct 13, 2011, 991 eligible patients were enrolled and randomly assigned to either Trastuzumab Emtansine (n=495) or capecitabine and lapatinib (control; n=496). In this final descriptive analysis, median overall survival was longer with Trastuzumab Emtansine than with control (29·9 months [95% CI 26·3–34·1] vs 25·9 months [95% CI 22·7–28·3]; hazard ratio 0·75 [95% CI 0·64–0·88]). 136 (27%) of 496 patients crossed over from control to Trastuzumab Emtansine after the second interim overall survival analysis (median follow-up duration 24·1 months [IQR 19·5–26·1]). Of those patients originally randomly assigned to Trastuzumab Emtansine, 254 (51%) of 495 received capecitabine and 241 [49%] of 495 received lapatinib (separately or in combination) after study drug discontinuation. In the safety population (488 patients treated with capecitabine plus lapatinib, 490 patients treated with Trastuzumab Emtansine), fewer grade 3 or worse adverse events occurred with Trastuzumab Emtansine (233 [48%] of 490) than with capecitabine plus lapatinib control treatment (291 [60%] of 488). In the control group, the most frequently reported grade 3 or worse adverse events were diarrhoea (103 [21%] of 488 patients) followed by palmar–plantar erythrodysaesthesia syndrome (87 [18%]), and vomiting (24 [5%]). The safety profile of Trastuzumab Emtansine was similar to that reported previously; the most frequently reported grade 3 or worse adverse events in the Trastuzumab Emtansine group were thrombocytopenia (70 [14%] of 490), increased aspartate aminotransferase levels (22 [5%]), and anaemia (19 [4%]). Nine patients died from adverse events; five of these deaths were judged to be related to treatment (two in the control group [coronary artery disease and multiorgan failure] and three in the Trastuzumab Emtansine group [metabolic encephalopathy, neutropenic sepsis, and acute myeloid leukaemia]). Interpretation This descriptive analysis of final overall survival in the EMILIA trial shows that Trastuzumab Emtansine improved overall survival in patients with previously treated HER2-positive metastatic breast cancer even in the presence of crossover treatment. The safety profile was similar to that reported in previous analyses, reaffirming Trastuzumab Emtansine as an efficacious and tolerable treatment in this patient population. Funding F Hoffmann-La Roche/Genentech.
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Trastuzumab Emtansine versus treatment of physician s choice in patients with previously treated her2 positive metastatic breast cancer th3resa final overall survival results from a randomised open label phase 3 trial
Lancet Oncology, 2017Co-Authors: Ian E Krop, Patricia Lorusso, Jeanmarc Ferrero, Melanie Smitt, Silke Hoersch, Antonio Gonzalez Martin, Tanja Badovinaccrnjevic, Hans WildiersAbstract:Summary Background In the randomised, parallel assignment, open-label, phase 3 TH3RESA study, progression-free survival was significantly longer with Trastuzumab Emtansine versus treatment of physician's choice in previously treated patients with HER2-positive advanced breast cancer. We report results from the final overall survival analysis of the TH3RESA trial. Methods Eligible patients for the TH3RESA trial were men and women (aged ≥18 years) with centrally confirmed HER2-positive advanced breast cancer previously treated with both Trastuzumab and lapatinib (advanced setting) and a taxane (any setting) and with progression on two or more HER2-directed regimens in the advanced setting. Patients had to have an Eastern Cooperative Oncology Group performance status of 0–2, left ventricular ejection fraction of at least 50%, and adequate organ function. Patients were randomly assigned (2:1) by an interactive voice and web response system with permuted block randomisation in blocks of six to receive Trastuzumab Emtansine (3·6 mg/kg intravenously every 21 days) or treatment of physician's choice administered per local practice. Randomisation was stratified by world region, number of previous regimens for advanced breast cancer, and presence of visceral disease. On Sept 12, 2012, the study protocol was amended to allow patients with disease progression to crossover from treatment of physician's choice to Trastuzumab Emtansine. The coprimary endpoints for TH3RESA were investigator-assessed progression-free survival and overall survival in the intention-to-treat population. We report results from a preplanned second interim analysis of overall survival, which was planned for when approximately 67% (n=330) of 492 expected deaths had occurred. This study is registered with ClinicalTrials.gov, number NCT01419197. Findings Between Sept 14, 2011, and Nov 19, 2012, 602 patients were enrolled from 146 centres in 22 countries and randomly assigned to Trastuzumab Emtansine (n=404) or treatment of physician's choice (n=198). At data cutoff (Feb 13, 2015), 93 (47%) of 198 patients in the physician's choice group had crossed over to Trastuzumab Emtansine. Overall survival was significantly longer with Trastuzumab Emtansine versus treatment of physician's choice (median 22·7 months [95% CI 19·4–27·5] vs 15·8 months [13·5–18·7]; hazard ratio 0·68 [95% CI 0·54–0·85]; p=0·0007). As the stopping boundary for overall survival was crossed, this overall survival analysis serves as the final and confirmatory analysis of overall survival and the study was terminated according to the protocol. The incidence of grade 3 or worse adverse events was 161 (40%) of 403 patients in the Trastuzumab Emtansine group and 87 (47%) of 184 patients in the treatment of physician's choice group. Of the most common grade 3 or worse adverse events (affecting ≥2% of patients in either group), those with a 3% or greater difference in incidence between groups that were more frequent with treatment of physician's choice than with Trastuzumab Emtansine were diarrhoea (three [1%] of 403 patients in the Trastuzumab Emtansine group vs eight [4%] of 184 patients in the treatment of physician's choice group), neutropenia (ten [3%] vs 29 [16%]), and febrile neutropenia (one [ vs seven [4%]); whereas those that were more frequent with Trastuzumab Emtansine were thrombocytopenia (24 [6%] of 403 patients vs five [3%] of 184 patients) and haemorrhage of any type (17 [4%] of 403 vs one [ Interpretation In patients who had progressed on two or more HER2-directed regimens, Trastuzumab Emtansine treatment resulted in a significant improvement in overall survival versus treatment of physician's choice. These data further solidify the role of Trastuzumab Emtansine in the management of patients with previously treated HER2-positive advanced breast cancer, and validate HER2 as a therapeutic target even after multiple lines of previous therapy. Funding F Hoffman-La Roche/Genentech.
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Trastuzumab Emtansine in human epidermal growth factor receptor 2 positive metastatic breast cancer an integrated safety analysis
Journal of Clinical Oncology, 2014Co-Authors: Véronique Diéras, Melanie Smitt, Natalia Chernyukhin, Meghna Samant, N Harbeck, Thomas G Budd, Joel K Greenson, Alice Elizabeth Guardino, Ian E KropAbstract:Purpose The antibody–drug conjugate Trastuzumab Emtansine (T-DM1) combines the cytotoxic activity of DM1 with the human epidermal growth factor receptor 2 (HER2) –targeted, antitumor properties of Trastuzumab. T-DM1 has shown activity in phase I and II single-arm studies in patients with pretreated HER2-positive metastatic breast cancer (MBC) and has demonstrated superior efficacy and improved tolerability versus standard MBC treatments in randomized phase II and III studies. This analysis, combining available data from all single-agent T-DM1 studies to date, was conducted to better define the T-DM1 safety profile. Patients and Methods Six studies in patients with HER2-positive MBC who received T-DM1 3.6 mg/kg every 3 weeks and follow-up data from patients in an extension study were analyzed. Analyses included adverse events (AEs) by grade; AEs leading to death, drug discontinuation, or dose reduction; and select AEs. Results Among 884 T-DM1–exposed patients, the most commonly reported all-grade AEs were ...
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Trastuzumab Emtansine versus treatment of physician s choice for pretreated her2 positive advanced breast cancer th3resa a randomised open label phase 3 trial
Lancet Oncology, 2014Co-Authors: Ian E Krop, Antonio Gonzalezmartin, Patricia Lorusso, Jeanmarc Ferrero, Melanie Smitt, Ron Yu, Abraham C F Leung, Hans WildiersAbstract:Summary Background Patients with progressive disease after two or more HER2-directed regimens for recurrent or metastatic breast cancer have few effective therapeutic options. We aimed to compare Trastuzumab Emtansine, an antibody–drug conjugate comprising the cytotoxic agent DM1 linked to Trastuzumab, with treatment of physician's choice in this population of patients. Methods This randomised, open-label, phase 3 trial took place in medical centres in 22 countries across Europe, North America, South America, and Asia-Pacific. Eligible patients (≥18 years, left ventricular ejection fraction ≥50%, Eastern Cooperative Oncology Group performance status 0–2) with progressive HER2-positive advanced breast cancer who had received two or more HER2-directed regimens in the advanced setting, including Trastuzumab and lapatinib, and previous taxane therapy in any setting, were randomly assigned (in a 2:1 ratio) to Trastuzumab Emtansine (3·6 mg/kg intravenously every 21 days) or physician's choice using a permuted block randomisation scheme by an interactive voice and web response system. Patients were stratified according to world region (USA vs western Europe vs other), number of previous regimens (excluding single-agent hormonal therapy) for the treatment of advanced disease (two to three vs more than three), and presence of visceral disease (any vs none). Coprimary endpoints were investigator-assessed progression-free survival (PFS) and overall survival in the intention-to-treat population. We report the final PFS analysis and the first interim overall survival analysis. This study is registered with ClinicalTrials.gov, number NCT01419197. Findings From Sept 14, 2011, to Nov 19, 2012, 602 patients were randomly assigned (404 to Trastuzumab Emtansine and 198 to physician's choice). At data cutoff (Feb 11, 2013), 44 patients assigned to physician's choice had crossed over to Trastuzumab Emtansine. After a median follow-up of 7·2 months (IQR 5·0–10·1 months) in the Trastuzumab Emtansine group and 6·5 months (IQR 4·1–9·7) in the physician's choice group, 219 (54%) patients in the Trastuzumab Emtansine group and 129 (65%) of patients in the physician's choice group had PFS events. PFS was significantly improved with Trastuzumab Emtansine compared with physician's choice (median 6·2 months [95% CI 5·59–6·87] vs 3·3 months [2·89–4·14]; stratified hazard ratio [HR] 0·528 [0·422–0·661]; p vs 80 events [43%] in 184 patients). Neutropenia (ten [2%] vs 29 [16%]), diarrhoea (three [ vs eight [4%]), and febrile neutropenia (one [ vs seven [4%]) were grade 3 or worse adverse events that were more common in the physician's choice group than in the Trastuzumab Emtansine group. Thrombocytopenia (19 [5%] vs three [2%]) was the grade 3 or worse adverse event that was more common in the Trastuzumab Emtansine group. 74 (18%) patients in the Trastuzumab Emtansine group and 38 (21%) in the physician's choice group reported a serious adverse event. Interpretation Trastuzumab Emtansine should be considered as a new standard for patients with HER2-positive advanced breast cancer who have previously received Trastuzumab and lapatinib. Funding Genentech.
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Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer
The New England Journal of Medicine, 2012Co-Authors: Sunil Verma, Véronique Diéras, Ian E Krop, David Miles, Mark D Pegram, Manfred Welslau, Jose Baselga, Luca Gianni, Youn Oh, Ellie GuardinoAbstract:Background Trastuzumab Emtansine (T-DM1) is an antibody–drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)–targeted antitumor properties of tras tuz u mab with the cytotoxic activity of the microtubule-inhibitory agent DM1. The antibody and the cytotoxic agent are conjugated by means of a stable linker. Methods We randomly assigned patients with HER2-positive advanced breast cancer, who had previously been treated with tras tuz u mab and a taxane, to T-DM1 or la pa ti nib plus cap e ci ta bine. The primary end points were progression-free survival (as assessed by independent review), overall survival, and safety. Secondary end points included progression-free survival (investigator-assessed), the objective response rate, and the time to symptom progression. Two interim analyses of overall survival were conducted. Results Among 991 randomly assigned patients, median progression-free survival as assessed by independent review was 9.6 months with T-DM1 versus 6.4 months with la pa ti nib plus cap e ci ta bine (hazard ratio for progression or death from any cause, 0.65; 95% confidence interval [CI], 0.55 to 0.77; P
Sara A Hurvitz - One of the best experts on this subject based on the ideXlab platform.
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neoadjuvant Trastuzumab Emtansine and pertuzumab in human epidermal growth factor receptor 2 positive breast cancer three year outcomes from the phase iii kristine study
Journal of Clinical Oncology, 2019Co-Authors: Sara A Hurvitz, Miguel Martin, Kyung Hae Jung, Chiunsheng Huang, Nadia Harbeck, Vicente Valero, Daniil Stroyakovskiy, Hans Wildiers, Mario Campone, Jeanfrancois BoileauAbstract:PURPOSEThe KRISTINE study compared neoadjuvant Trastuzumab Emtansine plus pertuzumab (T-DM1+P) with docetaxel, carboplatin, Trastuzumab plus P (TCH+P) for the treatment human epidermal growth facto...
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neoadjuvant Trastuzumab pertuzumab and chemotherapy versus Trastuzumab Emtansine plus pertuzumab in patients with her2 positive breast cancer kristine a randomised open label multicentre phase 3 trial
Lancet Oncology, 2018Co-Authors: Sara A Hurvitz, Miguel Martin, Kyung Hae Jung, Chiunsheng Huang, Nadia Harbeck, Vicente Valero, Daniil Stroyakovskiy, Fraser W Symmans, Alastair M Thompson, Hans WildiersAbstract:Summary Background HER2-targeted treatments have improved outcomes in patients with HER2-positive breast cancer in the neoadjuvant, adjuvant, and metastatic settings; however, some patients remain at risk of relapse or death for many years after treatment of early-stage disease. Therefore, new strategies are needed. We did a phase 3 trial to assess a neoadjuvant regimen for HER2-positive breast cancer that replaces traditional systemic chemotherapy with targeted treatment. Methods We did a randomised, open-label phase 3 KRISTINE trial in 68 Translational Research In Oncology centres (hospitals and specialty cancer centres in Asia, Europe, USA, and Canada). Eligible participants were aged 18 years or older with centrally confirmed HER2-positive stage II–III operable breast cancer (>2 cm tumour size), an Eastern Cooperative Oncology Group performance status of 0–1, and a baseline left ventricular ejection fraction of at least 55% (by echocardiogram or multiple-gated acquisition scan). We randomly assigned participants (1:1) to receive either Trastuzumab Emtansine plus pertuzumab or docetaxel, carboplatin, and Trastuzumab plus pertuzumab. We did the randomisation via an interactive response system under a permuted block randomisation scheme (block size of four), stratified by hormone receptor status, stage at diagnosis, and geographical location. Patients received six cycles (every 3 weeks) of neoadjuvant Trastuzumab Emtansine plus pertuzumab (Trastuzumab Emtansine 3·6 mg/kg; pertuzumab 840 mg loading dose, 420 mg maintenance doses) or docetaxel, carboplatin, and Trastuzumab plus pertuzumab (docetaxel 75 mg/m 2 ; carboplatin area under the concentration–time curve 6 mg/mL × min; Trastuzumab 8 mg/kg loading dose, 6 mg/kg maintenance doses) plus pertuzumab [same dosing as in the other group]). All treatments were administered intravenously. The primary objective was to compare the number of patients who achieved a pathological complete response (ypT0/is, ypN0), between groups in the intention-to-treat population (two-sided assessment), based on local evaluation of tumour samples taken at breast cancer surgery done between 14 days and 6 weeks after completion of neoadjuvant therapy. Safety was analysed in patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02131064, and follow-up of the adjuvant phase is ongoing. Findings Between June 25, 2014, and June 15, 2015, we randomly assigned 444 patients to neoadjuvant treatment with Trastuzumab Emtansine plus pertuzumab (n=223) or docetaxel, carboplatin, and Trastuzumab plus pertuzumab (n=221). A pathological complete response was achieved by 99 (44·4%) of 223 patients in the Trastuzumab Emtansine plus pertuzumab group and 123 (55·7%) of 221 patients in the docetaxel, carboplatin, and Trastuzumab plus pertuzumab group (absolute difference −11·3 percentage points, 95% CI −20·5 to −2·0; p=0·016). During neoadjuvant treatment, compared with patients receiving docetaxel, carboplatin, and Trastuzumab plus pertuzumab, fewer patients receiving Trastuzumab Emtansine plus pertuzumab had a grade 3–4 adverse event (29 [13%] of 223 vs 141 [64%] of 219) or a serious adverse event (11 [5%] of 223 vs 63 [29%] of 219). The most common grade 3–4 adverse events in the Trastuzumab Emtansine plus pertuzumab group were decreased platelet count (three [1%] of 223 patients vs 11 [5%] of 219 with docetaxel, carboplatin, and Trastuzumab plus pertuzumab), fatigue (three [1%] vs seven [3%]), alanine aminotransferase increase (three [1%] vs four [2%]), and hypokalaemia (three [1%] vs five [2%]). The most common grade 3–4 adverse events in the docetaxel, carboplatin, and Trastuzumab plus pertuzumab group were neutropenia (55 [25%] of 219 vs one [ vs 2 [ vs 0). No deaths were reported during neoadjuvant treatment. Interpretation Traditional neoadjuvant systemic chemotherapy plus dual HER2-targeted blockade (docetaxel, carboplatin, and Trastuzumab plus pertuzumab) resulted in significantly more patients achieving a pathological complete response than HER2-targeted chemotherapy plus HER2-targeted blockade (Trastuzumab Emtansine plus pertuzumab); however, numerically more grade 3–4 and serious adverse events occurred in the chemotherapy plus Trastuzumab and pertuzumab group. Further efforts to improve the efficacy of chemotherapy without imparting more toxicity are warranted. Funding F Hoffmann-La Roche and Genentech.
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profiling and targeting her2 positive breast cancer using Trastuzumab Emtansine
Pharmacogenomics and Personalized Medicine, 2014Co-Authors: Saeed Sadeghi, Olga Olevsky, Sara A HurvitzAbstract:Purpose: This article reviews the mechanism of action of Trastuzumab Emtansine (T-DM1), existing clinical data relating to its use for human growth factor receptor 2 (HER2)-positive breast cancer, potential pathways of resistance, and ongoing studies evaluating this novel agent. Background: The development of HER2-targeted therapies has dramatically improved clinical outcomes for patients with any stage of HER2-positive breast cancer. Although the positive effect of these treatments cannot be overstated, treatment resistance develops in the vast majority of those diagnosed with stage IV HER2-positive breast cancer. Moreover, HER2-directed therapies are most effective when combined with cytotoxic chemotherapy. The need for chemotherapy leads to significant adverse effects and a clear decrease in quality of life for those dealing with a chronic incurable disease. T-DM1 is a recently developed, novel antibody–drug conjugate in which highly potent maytanisinoid chemotherapy is stably linked to the HER2-targeted monoclonal antibody, Trastuzumab. Results: Preclinical and phase 1–3 clinical data support the significant antitumor activity of T-DM1. Importantly, several randomized studies also now demonstrate its clear superiority in terms of tolerability compared with standard chemotherapy-containing regimens. Its role in the treatment of Trastuzumab-resistant metastatic breast cancer has now been established on the basis of the results of two phase 3 randomized studies, EMILIA (An Open-label Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine + Lapatinib in Patients With HER2-positive Locally Advanced or Metastatic Breast Cancer) and TH3RESA (A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician’s Choice in Patients With HER2-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy). The most common toxicities seen with T-DM1 are thrombocytopenia and an elevation in liver transaminases. Significant cardiac toxicity has not been demonstrated. Both in vitro cell line– based studies as well as exploratory analyses of archived tumor samples from the clinical trials are seeking to understand potential mechanisms of resistance to T-DM1. Ongoing studies are also evaluating the use of T-DM1 in the first-line metastatic, neoadjuvant, and adjuvant settings, as well as in combination with other targeted therapies. Conclusion: T-DM1 represents the first successfully developed antibody drug conjugate for the treatment of HER2-positive advanced breast cancer.
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ado Trastuzumab Emtansine t dm1 in human epidermal growth factor receptor 2 her2 positive metastatic breast cancer latest evidence and clinical potential
Therapeutic Advances in Medical Oncology, 2014Co-Authors: Parvin F Peddi, Sara A HurvitzAbstract:In February 2013, ado-Trastuzumab Emtansine (T-DM1, Kadcyla®) received regulatory approval in the United States for treatment-refractory human epidermal growth factor receptor 2 (HER2) positive metastatic or locally advanced breast cancer based on results from EMILIA, a large phase III trial that compared standard of care lapatinib plus capecitabine to T-DM1. Several other studies have been reported in the metastatic setting and multiple trials are ongoing or planned in the neoadjuvant, adjuvant and advanced disease settings. Here we provide an updated and comprehensive review of clinical trials evaluating T-DM1, discuss management of toxicity associated with this drug, propose potential mechanisms of resistance and offer practical considerations for the treating oncologist.
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Trastuzumab Emtansine the first targeted chemotherapy for treatment of breast cancer
Future Oncology, 2013Co-Authors: Parvin F Peddi, Sara A HurvitzAbstract:Trastuzumab Emtansine (T-DM1) is a novel antibody–drug conjugate, comprised of a potent cytotoxic drug connected via a stable linker to the anti-HER2 antibody, Trastuzumab, thereby primarily targeting chemotherapy delivery to cells overexpressing the HER2 receptor. A Phase II randomized trial of T-DM1 in the front-line metastatic breast cancer setting revealed promising activity and improved safety compared with standard chemotherapy plus Trastuzumab. Subsequently, a Phase III trial in patients with Trastuzumab-pretreated metastatic breast cancer showed T-DM1 to be associated with prolonged progression-free and overall survival compared with lapatinib plus capecitabine. T-DM1 represents a major shift in the treatment of patients with breast cancer as it replaces traditional nontargeted chemotherapy with a ‘smart’ medication that directs the cytotoxic therapy to cancer cells by using a known biomarker.
Hans Wildiers - One of the best experts on this subject based on the ideXlab platform.
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neoadjuvant Trastuzumab Emtansine and pertuzumab in human epidermal growth factor receptor 2 positive breast cancer three year outcomes from the phase iii kristine study
Journal of Clinical Oncology, 2019Co-Authors: Sara A Hurvitz, Miguel Martin, Kyung Hae Jung, Chiunsheng Huang, Nadia Harbeck, Vicente Valero, Daniil Stroyakovskiy, Hans Wildiers, Mario Campone, Jeanfrancois BoileauAbstract:PURPOSEThe KRISTINE study compared neoadjuvant Trastuzumab Emtansine plus pertuzumab (T-DM1+P) with docetaxel, carboplatin, Trastuzumab plus P (TCH+P) for the treatment human epidermal growth facto...
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neoadjuvant Trastuzumab pertuzumab and chemotherapy versus Trastuzumab Emtansine plus pertuzumab in patients with her2 positive breast cancer kristine a randomised open label multicentre phase 3 trial
Lancet Oncology, 2018Co-Authors: Sara A Hurvitz, Miguel Martin, Kyung Hae Jung, Chiunsheng Huang, Nadia Harbeck, Vicente Valero, Daniil Stroyakovskiy, Fraser W Symmans, Alastair M Thompson, Hans WildiersAbstract:Summary Background HER2-targeted treatments have improved outcomes in patients with HER2-positive breast cancer in the neoadjuvant, adjuvant, and metastatic settings; however, some patients remain at risk of relapse or death for many years after treatment of early-stage disease. Therefore, new strategies are needed. We did a phase 3 trial to assess a neoadjuvant regimen for HER2-positive breast cancer that replaces traditional systemic chemotherapy with targeted treatment. Methods We did a randomised, open-label phase 3 KRISTINE trial in 68 Translational Research In Oncology centres (hospitals and specialty cancer centres in Asia, Europe, USA, and Canada). Eligible participants were aged 18 years or older with centrally confirmed HER2-positive stage II–III operable breast cancer (>2 cm tumour size), an Eastern Cooperative Oncology Group performance status of 0–1, and a baseline left ventricular ejection fraction of at least 55% (by echocardiogram or multiple-gated acquisition scan). We randomly assigned participants (1:1) to receive either Trastuzumab Emtansine plus pertuzumab or docetaxel, carboplatin, and Trastuzumab plus pertuzumab. We did the randomisation via an interactive response system under a permuted block randomisation scheme (block size of four), stratified by hormone receptor status, stage at diagnosis, and geographical location. Patients received six cycles (every 3 weeks) of neoadjuvant Trastuzumab Emtansine plus pertuzumab (Trastuzumab Emtansine 3·6 mg/kg; pertuzumab 840 mg loading dose, 420 mg maintenance doses) or docetaxel, carboplatin, and Trastuzumab plus pertuzumab (docetaxel 75 mg/m 2 ; carboplatin area under the concentration–time curve 6 mg/mL × min; Trastuzumab 8 mg/kg loading dose, 6 mg/kg maintenance doses) plus pertuzumab [same dosing as in the other group]). All treatments were administered intravenously. The primary objective was to compare the number of patients who achieved a pathological complete response (ypT0/is, ypN0), between groups in the intention-to-treat population (two-sided assessment), based on local evaluation of tumour samples taken at breast cancer surgery done between 14 days and 6 weeks after completion of neoadjuvant therapy. Safety was analysed in patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02131064, and follow-up of the adjuvant phase is ongoing. Findings Between June 25, 2014, and June 15, 2015, we randomly assigned 444 patients to neoadjuvant treatment with Trastuzumab Emtansine plus pertuzumab (n=223) or docetaxel, carboplatin, and Trastuzumab plus pertuzumab (n=221). A pathological complete response was achieved by 99 (44·4%) of 223 patients in the Trastuzumab Emtansine plus pertuzumab group and 123 (55·7%) of 221 patients in the docetaxel, carboplatin, and Trastuzumab plus pertuzumab group (absolute difference −11·3 percentage points, 95% CI −20·5 to −2·0; p=0·016). During neoadjuvant treatment, compared with patients receiving docetaxel, carboplatin, and Trastuzumab plus pertuzumab, fewer patients receiving Trastuzumab Emtansine plus pertuzumab had a grade 3–4 adverse event (29 [13%] of 223 vs 141 [64%] of 219) or a serious adverse event (11 [5%] of 223 vs 63 [29%] of 219). The most common grade 3–4 adverse events in the Trastuzumab Emtansine plus pertuzumab group were decreased platelet count (three [1%] of 223 patients vs 11 [5%] of 219 with docetaxel, carboplatin, and Trastuzumab plus pertuzumab), fatigue (three [1%] vs seven [3%]), alanine aminotransferase increase (three [1%] vs four [2%]), and hypokalaemia (three [1%] vs five [2%]). The most common grade 3–4 adverse events in the docetaxel, carboplatin, and Trastuzumab plus pertuzumab group were neutropenia (55 [25%] of 219 vs one [ vs 2 [ vs 0). No deaths were reported during neoadjuvant treatment. Interpretation Traditional neoadjuvant systemic chemotherapy plus dual HER2-targeted blockade (docetaxel, carboplatin, and Trastuzumab plus pertuzumab) resulted in significantly more patients achieving a pathological complete response than HER2-targeted chemotherapy plus HER2-targeted blockade (Trastuzumab Emtansine plus pertuzumab); however, numerically more grade 3–4 and serious adverse events occurred in the chemotherapy plus Trastuzumab and pertuzumab group. Further efforts to improve the efficacy of chemotherapy without imparting more toxicity are warranted. Funding F Hoffmann-La Roche and Genentech.
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Trastuzumab Emtansine versus treatment of physician s choice in patients with previously treated her2 positive metastatic breast cancer th3resa final overall survival results from a randomised open label phase 3 trial
Lancet Oncology, 2017Co-Authors: Ian E Krop, Patricia Lorusso, Jeanmarc Ferrero, Melanie Smitt, Silke Hoersch, Antonio Gonzalez Martin, Tanja Badovinaccrnjevic, Hans WildiersAbstract:Summary Background In the randomised, parallel assignment, open-label, phase 3 TH3RESA study, progression-free survival was significantly longer with Trastuzumab Emtansine versus treatment of physician's choice in previously treated patients with HER2-positive advanced breast cancer. We report results from the final overall survival analysis of the TH3RESA trial. Methods Eligible patients for the TH3RESA trial were men and women (aged ≥18 years) with centrally confirmed HER2-positive advanced breast cancer previously treated with both Trastuzumab and lapatinib (advanced setting) and a taxane (any setting) and with progression on two or more HER2-directed regimens in the advanced setting. Patients had to have an Eastern Cooperative Oncology Group performance status of 0–2, left ventricular ejection fraction of at least 50%, and adequate organ function. Patients were randomly assigned (2:1) by an interactive voice and web response system with permuted block randomisation in blocks of six to receive Trastuzumab Emtansine (3·6 mg/kg intravenously every 21 days) or treatment of physician's choice administered per local practice. Randomisation was stratified by world region, number of previous regimens for advanced breast cancer, and presence of visceral disease. On Sept 12, 2012, the study protocol was amended to allow patients with disease progression to crossover from treatment of physician's choice to Trastuzumab Emtansine. The coprimary endpoints for TH3RESA were investigator-assessed progression-free survival and overall survival in the intention-to-treat population. We report results from a preplanned second interim analysis of overall survival, which was planned for when approximately 67% (n=330) of 492 expected deaths had occurred. This study is registered with ClinicalTrials.gov, number NCT01419197. Findings Between Sept 14, 2011, and Nov 19, 2012, 602 patients were enrolled from 146 centres in 22 countries and randomly assigned to Trastuzumab Emtansine (n=404) or treatment of physician's choice (n=198). At data cutoff (Feb 13, 2015), 93 (47%) of 198 patients in the physician's choice group had crossed over to Trastuzumab Emtansine. Overall survival was significantly longer with Trastuzumab Emtansine versus treatment of physician's choice (median 22·7 months [95% CI 19·4–27·5] vs 15·8 months [13·5–18·7]; hazard ratio 0·68 [95% CI 0·54–0·85]; p=0·0007). As the stopping boundary for overall survival was crossed, this overall survival analysis serves as the final and confirmatory analysis of overall survival and the study was terminated according to the protocol. The incidence of grade 3 or worse adverse events was 161 (40%) of 403 patients in the Trastuzumab Emtansine group and 87 (47%) of 184 patients in the treatment of physician's choice group. Of the most common grade 3 or worse adverse events (affecting ≥2% of patients in either group), those with a 3% or greater difference in incidence between groups that were more frequent with treatment of physician's choice than with Trastuzumab Emtansine were diarrhoea (three [1%] of 403 patients in the Trastuzumab Emtansine group vs eight [4%] of 184 patients in the treatment of physician's choice group), neutropenia (ten [3%] vs 29 [16%]), and febrile neutropenia (one [ vs seven [4%]); whereas those that were more frequent with Trastuzumab Emtansine were thrombocytopenia (24 [6%] of 403 patients vs five [3%] of 184 patients) and haemorrhage of any type (17 [4%] of 403 vs one [ Interpretation In patients who had progressed on two or more HER2-directed regimens, Trastuzumab Emtansine treatment resulted in a significant improvement in overall survival versus treatment of physician's choice. These data further solidify the role of Trastuzumab Emtansine in the management of patients with previously treated HER2-positive advanced breast cancer, and validate HER2 as a therapeutic target even after multiple lines of previous therapy. Funding F Hoffman-La Roche/Genentech.
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Trastuzumab Emtansine versus treatment of physician s choice for pretreated her2 positive advanced breast cancer th3resa a randomised open label phase 3 trial
Lancet Oncology, 2014Co-Authors: Ian E Krop, Antonio Gonzalezmartin, Patricia Lorusso, Jeanmarc Ferrero, Melanie Smitt, Ron Yu, Abraham C F Leung, Hans WildiersAbstract:Summary Background Patients with progressive disease after two or more HER2-directed regimens for recurrent or metastatic breast cancer have few effective therapeutic options. We aimed to compare Trastuzumab Emtansine, an antibody–drug conjugate comprising the cytotoxic agent DM1 linked to Trastuzumab, with treatment of physician's choice in this population of patients. Methods This randomised, open-label, phase 3 trial took place in medical centres in 22 countries across Europe, North America, South America, and Asia-Pacific. Eligible patients (≥18 years, left ventricular ejection fraction ≥50%, Eastern Cooperative Oncology Group performance status 0–2) with progressive HER2-positive advanced breast cancer who had received two or more HER2-directed regimens in the advanced setting, including Trastuzumab and lapatinib, and previous taxane therapy in any setting, were randomly assigned (in a 2:1 ratio) to Trastuzumab Emtansine (3·6 mg/kg intravenously every 21 days) or physician's choice using a permuted block randomisation scheme by an interactive voice and web response system. Patients were stratified according to world region (USA vs western Europe vs other), number of previous regimens (excluding single-agent hormonal therapy) for the treatment of advanced disease (two to three vs more than three), and presence of visceral disease (any vs none). Coprimary endpoints were investigator-assessed progression-free survival (PFS) and overall survival in the intention-to-treat population. We report the final PFS analysis and the first interim overall survival analysis. This study is registered with ClinicalTrials.gov, number NCT01419197. Findings From Sept 14, 2011, to Nov 19, 2012, 602 patients were randomly assigned (404 to Trastuzumab Emtansine and 198 to physician's choice). At data cutoff (Feb 11, 2013), 44 patients assigned to physician's choice had crossed over to Trastuzumab Emtansine. After a median follow-up of 7·2 months (IQR 5·0–10·1 months) in the Trastuzumab Emtansine group and 6·5 months (IQR 4·1–9·7) in the physician's choice group, 219 (54%) patients in the Trastuzumab Emtansine group and 129 (65%) of patients in the physician's choice group had PFS events. PFS was significantly improved with Trastuzumab Emtansine compared with physician's choice (median 6·2 months [95% CI 5·59–6·87] vs 3·3 months [2·89–4·14]; stratified hazard ratio [HR] 0·528 [0·422–0·661]; p vs 80 events [43%] in 184 patients). Neutropenia (ten [2%] vs 29 [16%]), diarrhoea (three [ vs eight [4%]), and febrile neutropenia (one [ vs seven [4%]) were grade 3 or worse adverse events that were more common in the physician's choice group than in the Trastuzumab Emtansine group. Thrombocytopenia (19 [5%] vs three [2%]) was the grade 3 or worse adverse event that was more common in the Trastuzumab Emtansine group. 74 (18%) patients in the Trastuzumab Emtansine group and 38 (21%) in the physician's choice group reported a serious adverse event. Interpretation Trastuzumab Emtansine should be considered as a new standard for patients with HER2-positive advanced breast cancer who have previously received Trastuzumab and lapatinib. Funding Genentech.
Véronique Diéras - One of the best experts on this subject based on the ideXlab platform.
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Trastuzumab Emtansine versus capecitabine plus lapatinib in patients with previously treated her2 positive advanced breast cancer emilia a descriptive analysis of final overall survival results from a randomised open label phase 3 trial
Lancet Oncology, 2017Co-Authors: Véronique Diéras, Ian E Krop, David Miles, Sunil Verma, Mark D Pegram, Manfred Welslau, Jose Baselga, K L Blackwell, Silke Hoersch, Jin XuAbstract:Summary Background The antibody–drug conjugate Trastuzumab Emtansine is indicated for the treatment of patients with HER2-positive metastatic breast cancer previously treated with Trastuzumab and a taxane. Approval of this drug was based on progression-free survival and interim overall survival data from the phase 3 EMILIA study. In this report, we present a descriptive analysis of the final overall survival data from that trial. Methods EMILIA was a randomised, international, open-label, phase 3 study of men and women aged 18 years or older with HER2-positive unresectable, locally advanced or metastatic breast cancer previously treated with Trastuzumab and a taxane. Enrolled patients were randomly assigned (1:1) via a hierarchical, dynamic randomisation scheme and an interactive voice response system to Trastuzumab Emtansine (3·6 mg/kg intravenously every 3 weeks) or control (capecitabine 1000 mg/m 2 self-administered orally twice daily on days 1–14 on each 21-day cycle, plus lapatinib 1250 mg orally once daily on days 1–21). Randomisation was stratified by world region (USA vs western Europe vs or other), number of previous chemotherapy regimens for unresectable, locally advanced, or metastatic disease (0 or 1 vs >1), and disease involvement (visceral vs non-visceral). The coprimary efficacy endpoints were progression-free survival (per independent review committee assessment) and overall survival. Efficacy was analysed in the intention-to-treat population; safety was analysed in all patients who received at least one dose of study treatment, with patients analysed according to the treatment actually received. On May 30, 2012, the study protocol was amended to allow crossover from control to Trastuzumab Emtansine after the second interim overall survival analysis crossed the prespecified overall survival efficacy boundary. This study is registered with ClinicalTrials.gov, number NCT00829166. Findings Between Feb 23, 2009, and Oct 13, 2011, 991 eligible patients were enrolled and randomly assigned to either Trastuzumab Emtansine (n=495) or capecitabine and lapatinib (control; n=496). In this final descriptive analysis, median overall survival was longer with Trastuzumab Emtansine than with control (29·9 months [95% CI 26·3–34·1] vs 25·9 months [95% CI 22·7–28·3]; hazard ratio 0·75 [95% CI 0·64–0·88]). 136 (27%) of 496 patients crossed over from control to Trastuzumab Emtansine after the second interim overall survival analysis (median follow-up duration 24·1 months [IQR 19·5–26·1]). Of those patients originally randomly assigned to Trastuzumab Emtansine, 254 (51%) of 495 received capecitabine and 241 [49%] of 495 received lapatinib (separately or in combination) after study drug discontinuation. In the safety population (488 patients treated with capecitabine plus lapatinib, 490 patients treated with Trastuzumab Emtansine), fewer grade 3 or worse adverse events occurred with Trastuzumab Emtansine (233 [48%] of 490) than with capecitabine plus lapatinib control treatment (291 [60%] of 488). In the control group, the most frequently reported grade 3 or worse adverse events were diarrhoea (103 [21%] of 488 patients) followed by palmar–plantar erythrodysaesthesia syndrome (87 [18%]), and vomiting (24 [5%]). The safety profile of Trastuzumab Emtansine was similar to that reported previously; the most frequently reported grade 3 or worse adverse events in the Trastuzumab Emtansine group were thrombocytopenia (70 [14%] of 490), increased aspartate aminotransferase levels (22 [5%]), and anaemia (19 [4%]). Nine patients died from adverse events; five of these deaths were judged to be related to treatment (two in the control group [coronary artery disease and multiorgan failure] and three in the Trastuzumab Emtansine group [metabolic encephalopathy, neutropenic sepsis, and acute myeloid leukaemia]). Interpretation This descriptive analysis of final overall survival in the EMILIA trial shows that Trastuzumab Emtansine improved overall survival in patients with previously treated HER2-positive metastatic breast cancer even in the presence of crossover treatment. The safety profile was similar to that reported in previous analyses, reaffirming Trastuzumab Emtansine as an efficacious and tolerable treatment in this patient population. Funding F Hoffmann-La Roche/Genentech.
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Trastuzumab Emtansine in human epidermal growth factor receptor 2 positive metastatic breast cancer an integrated safety analysis
Journal of Clinical Oncology, 2014Co-Authors: Véronique Diéras, Melanie Smitt, Natalia Chernyukhin, Meghna Samant, N Harbeck, Thomas G Budd, Joel K Greenson, Alice Elizabeth Guardino, Ian E KropAbstract:Purpose The antibody–drug conjugate Trastuzumab Emtansine (T-DM1) combines the cytotoxic activity of DM1 with the human epidermal growth factor receptor 2 (HER2) –targeted, antitumor properties of Trastuzumab. T-DM1 has shown activity in phase I and II single-arm studies in patients with pretreated HER2-positive metastatic breast cancer (MBC) and has demonstrated superior efficacy and improved tolerability versus standard MBC treatments in randomized phase II and III studies. This analysis, combining available data from all single-agent T-DM1 studies to date, was conducted to better define the T-DM1 safety profile. Patients and Methods Six studies in patients with HER2-positive MBC who received T-DM1 3.6 mg/kg every 3 weeks and follow-up data from patients in an extension study were analyzed. Analyses included adverse events (AEs) by grade; AEs leading to death, drug discontinuation, or dose reduction; and select AEs. Results Among 884 T-DM1–exposed patients, the most commonly reported all-grade AEs were ...
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The success story of Trastuzumab Emtansine, a targeted therapy in HER2-positive breast cancer
Targeted Oncology, 2014Co-Authors: Véronique Diéras, Thomas BachelotAbstract:Trastuzumab Emtansine is a unique antibody–drug conjugate targeting selectively human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells, thus conferring high efficacy with minimal systemic toxicities. Trastuzumab Emtansine consists of a monoclonal antibody Trastuzumab and potent cytotoxic agent DM1, combined together through a stable thioether bond. First-in-man phase I study set the maximum tolerated dose at 3.6 mg/kg given intravenously on a 3-weekly regimen. In phase II studies, Trastuzumab Emtansine at 3.6 mg/kg provided objective tumour responses and clinical benefit with an encouraging safety profile. Over these studies, Trastuzumab Emtansine had favourable pharmacokinetics. No accumulation of Trastuzumab Emtansine or catabolites was observed even after repeated dosing and free DM1 was very low in circulation. The stability of Trastuzumab Emtansine in circulation justifies the minimal systemic toxicity observed. Recently, a randomised international open-label phase III study confirmed the efficacy and safety of Trastuzumab Emtansine versus lapatinib plus capecitabine in patients with HER2-positive locally advanced or metastatic breast cancer. Overall survival was significantly improved in the Trastuzumab Emtansine arm. Safety outcomes were also favourable. The adverse events traditionally related to chemotherapy were markedly lower or absent with Trastuzumab Emtansine. Cardiotoxicity, frequently observed in HER2-directed therapy, was not reported. Although thrombocytopenia and elevations in hepatic enzymes were reported with Trastuzumab Emtansine, these events were reversible and manageable. Ongoing trials investigating Trastuzumab Emtansine as a single-agent or in combination with other agents, will determine the place of Trastuzumab Emtansine in the current therapeutic strategies deployed for HER2-metastatic breast cancer.
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Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer
The New England Journal of Medicine, 2012Co-Authors: Sunil Verma, Véronique Diéras, Ian E Krop, David Miles, Mark D Pegram, Manfred Welslau, Jose Baselga, Luca Gianni, Youn Oh, Ellie GuardinoAbstract:Background Trastuzumab Emtansine (T-DM1) is an antibody–drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)–targeted antitumor properties of tras tuz u mab with the cytotoxic activity of the microtubule-inhibitory agent DM1. The antibody and the cytotoxic agent are conjugated by means of a stable linker. Methods We randomly assigned patients with HER2-positive advanced breast cancer, who had previously been treated with tras tuz u mab and a taxane, to T-DM1 or la pa ti nib plus cap e ci ta bine. The primary end points were progression-free survival (as assessed by independent review), overall survival, and safety. Secondary end points included progression-free survival (investigator-assessed), the objective response rate, and the time to symptom progression. Two interim analyses of overall survival were conducted. Results Among 991 randomly assigned patients, median progression-free survival as assessed by independent review was 9.6 months with T-DM1 versus 6.4 months with la pa ti nib plus cap e ci ta bine (hazard ratio for progression or death from any cause, 0.65; 95% confidence interval [CI], 0.55 to 0.77; P
Melanie Smitt - One of the best experts on this subject based on the ideXlab platform.
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Trastuzumab Emtansine versus treatment of physician s choice in patients with previously treated her2 positive metastatic breast cancer th3resa final overall survival results from a randomised open label phase 3 trial
Lancet Oncology, 2017Co-Authors: Ian E Krop, Patricia Lorusso, Jeanmarc Ferrero, Melanie Smitt, Silke Hoersch, Antonio Gonzalez Martin, Tanja Badovinaccrnjevic, Hans WildiersAbstract:Summary Background In the randomised, parallel assignment, open-label, phase 3 TH3RESA study, progression-free survival was significantly longer with Trastuzumab Emtansine versus treatment of physician's choice in previously treated patients with HER2-positive advanced breast cancer. We report results from the final overall survival analysis of the TH3RESA trial. Methods Eligible patients for the TH3RESA trial were men and women (aged ≥18 years) with centrally confirmed HER2-positive advanced breast cancer previously treated with both Trastuzumab and lapatinib (advanced setting) and a taxane (any setting) and with progression on two or more HER2-directed regimens in the advanced setting. Patients had to have an Eastern Cooperative Oncology Group performance status of 0–2, left ventricular ejection fraction of at least 50%, and adequate organ function. Patients were randomly assigned (2:1) by an interactive voice and web response system with permuted block randomisation in blocks of six to receive Trastuzumab Emtansine (3·6 mg/kg intravenously every 21 days) or treatment of physician's choice administered per local practice. Randomisation was stratified by world region, number of previous regimens for advanced breast cancer, and presence of visceral disease. On Sept 12, 2012, the study protocol was amended to allow patients with disease progression to crossover from treatment of physician's choice to Trastuzumab Emtansine. The coprimary endpoints for TH3RESA were investigator-assessed progression-free survival and overall survival in the intention-to-treat population. We report results from a preplanned second interim analysis of overall survival, which was planned for when approximately 67% (n=330) of 492 expected deaths had occurred. This study is registered with ClinicalTrials.gov, number NCT01419197. Findings Between Sept 14, 2011, and Nov 19, 2012, 602 patients were enrolled from 146 centres in 22 countries and randomly assigned to Trastuzumab Emtansine (n=404) or treatment of physician's choice (n=198). At data cutoff (Feb 13, 2015), 93 (47%) of 198 patients in the physician's choice group had crossed over to Trastuzumab Emtansine. Overall survival was significantly longer with Trastuzumab Emtansine versus treatment of physician's choice (median 22·7 months [95% CI 19·4–27·5] vs 15·8 months [13·5–18·7]; hazard ratio 0·68 [95% CI 0·54–0·85]; p=0·0007). As the stopping boundary for overall survival was crossed, this overall survival analysis serves as the final and confirmatory analysis of overall survival and the study was terminated according to the protocol. The incidence of grade 3 or worse adverse events was 161 (40%) of 403 patients in the Trastuzumab Emtansine group and 87 (47%) of 184 patients in the treatment of physician's choice group. Of the most common grade 3 or worse adverse events (affecting ≥2% of patients in either group), those with a 3% or greater difference in incidence between groups that were more frequent with treatment of physician's choice than with Trastuzumab Emtansine were diarrhoea (three [1%] of 403 patients in the Trastuzumab Emtansine group vs eight [4%] of 184 patients in the treatment of physician's choice group), neutropenia (ten [3%] vs 29 [16%]), and febrile neutropenia (one [ vs seven [4%]); whereas those that were more frequent with Trastuzumab Emtansine were thrombocytopenia (24 [6%] of 403 patients vs five [3%] of 184 patients) and haemorrhage of any type (17 [4%] of 403 vs one [ Interpretation In patients who had progressed on two or more HER2-directed regimens, Trastuzumab Emtansine treatment resulted in a significant improvement in overall survival versus treatment of physician's choice. These data further solidify the role of Trastuzumab Emtansine in the management of patients with previously treated HER2-positive advanced breast cancer, and validate HER2 as a therapeutic target even after multiple lines of previous therapy. Funding F Hoffman-La Roche/Genentech.
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An integrated pharmacokinetic-pharmacodynamic (PKPD) modeling analysis of Trastuzumab Emtansine (T-DM1)-induced thrombocytopenia (TCP) and hepatotoxicity in patients with HER2–positive metastatic breast cancer
2016Co-Authors: Brendan Bender, Melanie Smitt, Angelica L Quartino, Chunze Li, Shang-chiung Chen, Alexander Strasak, Natalia Chernyukhin, Bei Wang, Sandhya GirishAbstract:An integrated pharmacokinetic-pharmacodynamic (PKPD) modeling analysis of Trastuzumab Emtansine (T-DM1)-induced thrombocytopenia (TCP) and hepatotoxicity in patients with HER2–positive metastatic breast cancer
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Trastuzumab Emtansine in human epidermal growth factor receptor 2 positive metastatic breast cancer an integrated safety analysis
Journal of Clinical Oncology, 2014Co-Authors: Véronique Diéras, Melanie Smitt, Natalia Chernyukhin, Meghna Samant, N Harbeck, Thomas G Budd, Joel K Greenson, Alice Elizabeth Guardino, Ian E KropAbstract:Purpose The antibody–drug conjugate Trastuzumab Emtansine (T-DM1) combines the cytotoxic activity of DM1 with the human epidermal growth factor receptor 2 (HER2) –targeted, antitumor properties of Trastuzumab. T-DM1 has shown activity in phase I and II single-arm studies in patients with pretreated HER2-positive metastatic breast cancer (MBC) and has demonstrated superior efficacy and improved tolerability versus standard MBC treatments in randomized phase II and III studies. This analysis, combining available data from all single-agent T-DM1 studies to date, was conducted to better define the T-DM1 safety profile. Patients and Methods Six studies in patients with HER2-positive MBC who received T-DM1 3.6 mg/kg every 3 weeks and follow-up data from patients in an extension study were analyzed. Analyses included adverse events (AEs) by grade; AEs leading to death, drug discontinuation, or dose reduction; and select AEs. Results Among 884 T-DM1–exposed patients, the most commonly reported all-grade AEs were ...
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Trastuzumab Emtansine versus treatment of physician s choice for pretreated her2 positive advanced breast cancer th3resa a randomised open label phase 3 trial
Lancet Oncology, 2014Co-Authors: Ian E Krop, Antonio Gonzalezmartin, Patricia Lorusso, Jeanmarc Ferrero, Melanie Smitt, Ron Yu, Abraham C F Leung, Hans WildiersAbstract:Summary Background Patients with progressive disease after two or more HER2-directed regimens for recurrent or metastatic breast cancer have few effective therapeutic options. We aimed to compare Trastuzumab Emtansine, an antibody–drug conjugate comprising the cytotoxic agent DM1 linked to Trastuzumab, with treatment of physician's choice in this population of patients. Methods This randomised, open-label, phase 3 trial took place in medical centres in 22 countries across Europe, North America, South America, and Asia-Pacific. Eligible patients (≥18 years, left ventricular ejection fraction ≥50%, Eastern Cooperative Oncology Group performance status 0–2) with progressive HER2-positive advanced breast cancer who had received two or more HER2-directed regimens in the advanced setting, including Trastuzumab and lapatinib, and previous taxane therapy in any setting, were randomly assigned (in a 2:1 ratio) to Trastuzumab Emtansine (3·6 mg/kg intravenously every 21 days) or physician's choice using a permuted block randomisation scheme by an interactive voice and web response system. Patients were stratified according to world region (USA vs western Europe vs other), number of previous regimens (excluding single-agent hormonal therapy) for the treatment of advanced disease (two to three vs more than three), and presence of visceral disease (any vs none). Coprimary endpoints were investigator-assessed progression-free survival (PFS) and overall survival in the intention-to-treat population. We report the final PFS analysis and the first interim overall survival analysis. This study is registered with ClinicalTrials.gov, number NCT01419197. Findings From Sept 14, 2011, to Nov 19, 2012, 602 patients were randomly assigned (404 to Trastuzumab Emtansine and 198 to physician's choice). At data cutoff (Feb 11, 2013), 44 patients assigned to physician's choice had crossed over to Trastuzumab Emtansine. After a median follow-up of 7·2 months (IQR 5·0–10·1 months) in the Trastuzumab Emtansine group and 6·5 months (IQR 4·1–9·7) in the physician's choice group, 219 (54%) patients in the Trastuzumab Emtansine group and 129 (65%) of patients in the physician's choice group had PFS events. PFS was significantly improved with Trastuzumab Emtansine compared with physician's choice (median 6·2 months [95% CI 5·59–6·87] vs 3·3 months [2·89–4·14]; stratified hazard ratio [HR] 0·528 [0·422–0·661]; p vs 80 events [43%] in 184 patients). Neutropenia (ten [2%] vs 29 [16%]), diarrhoea (three [ vs eight [4%]), and febrile neutropenia (one [ vs seven [4%]) were grade 3 or worse adverse events that were more common in the physician's choice group than in the Trastuzumab Emtansine group. Thrombocytopenia (19 [5%] vs three [2%]) was the grade 3 or worse adverse event that was more common in the Trastuzumab Emtansine group. 74 (18%) patients in the Trastuzumab Emtansine group and 38 (21%) in the physician's choice group reported a serious adverse event. Interpretation Trastuzumab Emtansine should be considered as a new standard for patients with HER2-positive advanced breast cancer who have previously received Trastuzumab and lapatinib. Funding Genentech.
