maytansine and Neoplasm-Metastasis

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer, which accounts for 20 - 25% of cases of breast cancers, is highly aggressive. Due to cardiotoxicity and increasing resistance associated with trastuzumab, the first-line treatment, there is a need for effective second-line therapies in treating HER2-positive breast cancer. In this context, there has been increasing interest in the combination of lapatinib plus capecitabine. The aim of this systematic review was to assess the efficacy of lapatinib plus capecitabine for HER2-positive breast cancer after progression with trastuzumab therapy, in comparison with capecitabine monotherapy and other agents such as vinorelbine and trastuzumab emtansine.. We performed a keyword search in five electronic databases (OVID MEDLINE, the Cochrane Library, Web of Science, SCOPUS, and CINAHL; January 2010 to April 2017) for trials in patients with HER2-positive breast cancer that has progressed on trastuzumab. After screening, the relevant studies were assessed for their methodological quality (including selection bias, randomization, control for confounders, and blinding) by two reviewers independently.. A total of 50 studies were identified; only 6 of those met the inclusion criteria and were analyzed. Five received a weak rating on the quality assessment tool, and none could be considered as being of high scientific quality after taking the risk of bias and other confounding variables into account. The studies demonstrated that lapatinib plus capecitabine is effective in extending median overall (OS) and progression-free survival (PFS) outcomes, achieving OS of 37.6 - 108.7 weeks and PFS of 21.1 - 30 weeks across studies. However, median OS and PFS for trastuzumab emtansine therapy were found to be considerably better (133.9 weeks and 41.6 weeks, respectively) than for lapatinib plus capecitabine.. The results suggest that the combination of lapatinib plus capecitabine can improve PFS and OS in patients with HER2-positive breast cancer that has progressed on trastuzumab. However, it appears that trastuzumab emtansine provides better treatment outcomes in this context.
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Topics: Ado-Trastuzumab Emtansine; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Capecitabine; Disease Progression; Disease-Free Survival; Female; Humans; Lapatinib; Maytansine; Neoplasm Metastasis; Quinazolines; Receptor, ErbB-2; Survival Analysis; Time Factors; Trastuzumab; Treatment Outcome

Since the identification of the HER2 receptor amplification as an adverse prognostic factor that defined a special subtype of metastatic breast cancer, there has been a substantial improvement in survival of patients affected with this disease due to the development of anti-HER2 targeted therapies. The approval of trastuzumab and pertuzumab associated to a taxane in first line and subsequent treatment with the antibody-drug conjugate T-DM1 has certainly contributed to achieve these outcomes. The Tyrosine Kinase Inhibitor lapatinib was also approved in the basis of an improvement in progression free survival, becoming another commonly used treatment in combination with capecitabine. Inevitably, despite these therapeutic advances most patients progress on therapy due to primary or acquired resistance or because of an incorrect HER2 positivity assessment. Hence, it is crucial to correctly categorize HER2 amplified tumors and define mechanisms of resistance to design effective new treatment approaches. In addition, identifying biomarkers of response or resistance permits to tailor the therapeutic options for each patient sparing them from unnecessary toxicity as well as improving their outcomes. The aim of this review is to examine new strategies in development to treat HER2-positive metastatic breast cancer referring to the mechanisms of action of new drugs and new combinations including results reported so far.

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Capecitabine; Disease-Free Survival; Female; Humans; Lapatinib; Maytansine; Neoplasm Metastasis; Neoplasm Staging; Quinazolines; Receptor, ErbB-2; Trastuzumab

The aim of this review was to systematically evaluate the safety and efficacy of the addition of pertuzumab to trastuzumab emtansine (T-DM1) ± taxane in patients with human epidermal growth factor receptor 2 (HER2)-positive, locally advanced breast cancer (LABC) or metastatic breast cancer (MBC).. Several databases were searched for relevant clinical trials. The study characteristics, details of adverse events (AEs) and details of treatment efficacy were extracted for analysis.. Six studies with 996 patients were included. Common AEs of T-DM1 + pertuzumab ± taxane included fatigue, diarrhea, nausea, epistaxis, peripheral neuropathy, increased aspartate transaminase (AST), increased alanine transaminase (ALT) and thrombocytopenia. Major grade ≥3 AEs of T-DM1 + pertuzumab ± taxane included thrombocytopenia, neutropenia, fatigue, increased ALT, anemia and peripheral neuropathy. The addition of pertuzumab to T-DM1 ± taxane led to higher risks of diarrhea (especially grade ≥3 diarrhea), rash and vomiting, and decreased risks of thrombocytopenia and grade ≥3 increased AST. The relative risks of the addition of pertuzumab to T-DM1 ± taxane for objective response (1.068, 95% CI 0.945-1.207) and clinical benefit (1.038, 95% CI 0.974-1.106) were not statistically significant.. Common AEs should be carefully monitored in HER2-positive LABC or MBC patients treated with T-DM1 + pertuzumab ± taxane. The addition of pertuzumab to T-DM1 ± taxane showed noninferior, but not superior, objective response rate and clinical benefit rate. However, more studies are needed to further verify these findings.

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Maytansine; Neoplasm Metastasis; Receptor, ErbB-2; Taxoids; Trastuzumab

Anti-HER2 treatment for HER2-positive breast cancer has changed the natural biology of this disease. This Series article reviews the main achievements so far in the treatment of both metastatic and early HER2-positive breast cancer. The success of neoadjuvant therapy in HER2-positive early breast cancer is especially acknowledged, as pertuzumab has been approved on the basis of a higher proportion of patients achieving a pathological complete response with pertuzumab and trastuzumab than with trastuzumab alone in a neoadjuvant study. Event-free survival after the confirmatory adjuvant trial completed recruitment was numerically better with pertuzumab plus trastuzumab than with trastuzumab alone. With survival rates of almost 5 years in women with metastatic HER2-positive breast cancer and 75% of patients achieving a pathological complete response, new treatments in the past decade have clearly improved the prognosis of HER2-positive breast cancer. Despite these achievements, however, the persisting high toll of deaths resulting from HER2-positive breast cancer calls for continued, intensive clinical research of newer therapies and combinations.

Topics: Ado-Trastuzumab Emtansine; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; ErbB Receptors; Female; Humans; Maytansine; Molecular Targeted Therapy; Neoadjuvant Therapy; Neoplasm Metastasis; Receptor, ErbB-2; Trastuzumab

Trastuzumab emtansine (T-DM1), a new agent developed for the treatment of HER2-positive breast cancer, is an antibody-drug conjugate with a complex compound obtained by the conjugation of trastuzumab, a stable thioether linker, and the potent cytotoxic drug maytansine-derivate(DM1), which inhibits cell division and induces cell death.. PubMed database, ESMO, ASCO, San Antonio Breast Cancer Symposium Meeting abstracts and clinicaltrials.gov were searched using the terms "Anti-HER2 treatment breast cancer and trastuzumab emtansine (T-DM1) "; papers considered relevant for the aim of this review were selected.. The phase I trials have determined the safe dosing range of T-DM1, established at 3.6 mg/kg every 3 weeks. The phase III randomized EMILIA and TR3RESA trials have shown that T-DM1 provides objective tumor responses and significantly improves progression free survival and overall survival in HER2-positive metastatic breast cancer patients previously treated with anti-HER2-based regimens. The ongoing phase III trials KAITLIN and KATHERINE will give us further information about the place T-DM1 should occupy in the treatment of patients with early stage HER2-positive breast cancer. In this review we analyze the most relevant clinical trials conducted with T-DM1 and the role of this compound in the management of advanced breast cancer.. T-DM1 has shown clinically relevant activity in the treatment of HER2-positive breast cancer patients after progression on trastuzumab and taxane based therapy, both in the second line treatment setting and after early relapse on adjuvant trastuzumab therapy. This is accompanied by a favorable safety and tolerability profile.

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Clinical Trials, Phase III as Topic; Disease Progression; Female; Humans; Maytansine; Neoplasm Metastasis; Neoplasm Recurrence, Local; Receptor, ErbB-2; Trastuzumab

The National Institute for Health and Care Excellence (NICE) invited the manufacturer of trastuzumab emtansine (T-DM1) (Kadcyla(®); Roche) to submit evidence of its clinical and cost-effectiveness for treating human epidermal growth factor receptor 2 (HER2)-positive, unresectable, locally advanced or metastatic breast cancer after treatment with trastuzumab and a taxane. The School of Health and Related Research Technology Appraisal Group (ScHARR-TAG) at the University of Sheffield were the independent Evidence Review Group (ERG) who produced a critical review of the company's submission to NICE. The ERG also independently searched for relevant evidence and modified the submitted decision analytic model to produce a revised estimate of cost-effectiveness and examine the impact of altering some of the key assumptions. The clinical effectiveness data were taken from two randomised controlled trials that reported a significant advantage in progression-free survival (PFS) for T-DM1 over lapatinib in combination with capecitabine (EMILIA trial), and over the treatment of physician's choice (TH3RESA trial). A network meta-analysis suggested T-DM1 was the best treatment in terms of both overall survival and PFS compared with lapatinib in combination with capecitabine; trastuzumab in combination with capecitabine; and capecitabine monotherapy. Adverse event (AE) data were taken from a pooled analysis of additional trials of T-DM1 as a single agent. The most common grade 3 or greater AEs for T-DM1 were thrombocytopenia and hepatotoxicity. Following the clarification process, the manufacturer reported a deterministic incremental cost-effectiveness ratio (ICER) for T-DM1 compared with lapatinib in combination with capecitabine of £167,236, the latter of which was estimated to have an ICER of £49,798 compared with capecitabine monotherapy. The ERG produced similar values of £166,429 and £50,620 respectively. All other comparators were dominated. During the appraisal, the manufacturer offered an analysis of a patient access scheme (PAS), which suggested that T-DM1 had a 0 % probability of being cost-effective at an ICER of £30,000 per QALY gained. The NICE Appraisal Committee concluded that while the clinical effectiveness of T-DM1 had been proven, it was not likely to represent a cost-effective use of National Health Service resources and therefore its use could not be recommended.

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cost-Benefit Analysis; Decision Support Techniques; Disease-Free Survival; Female; Humans; Lapatinib; Maytansine; Neoplasm Metastasis; Quality-Adjusted Life Years; Quinazolines; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Survival Rate; Taxoids; Trastuzumab

Human epidermal growth factor receptor-2 (HER2)-positive breast cancer is an aggressive form of breast cancer associated with poorer prognosis and shortened survival. Primary and acquired resistance to existing HER2-targeted therapies presents a challenge for the management of patients with HER2-positive metastatic breast cancer. Ado-trastuzumab emtansine, a drug-antibody conjugate, has shown promising results for patients failing prior treatment with trastuzumab. Ado-trastuzumab emtansine consists of the monoclonal antibody trastuzumab linked to a potent microtubule inhibitor (emtansine), allowing a targeted delivery of chemotherapy to cells that overexpress HER2. Ado-trastuzumab emtansine has been approved for use in patients with metastatic breast cancer who have failed prior therapy with trastuzumab and a taxane. Although well-tolerated in clinical trials, thrombocytopenia has been reported and platelet values should be monitored closely. Increased liver enzymes and bilirubin, as well as cardiotoxicity, have also been documented, and recommendations for dose reduction or discontinuation due to these toxicities are available. Clinical trials are currently ongoing to further define the role of ado-trastuzumab emtansine in both the metastatic and early breast cancer settings.

Topics: Ado-Trastuzumab Emtansine; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Female; Humans; Immunoconjugates; Maytansine; Neoplasm Metastasis; Receptor, ErbB-2; Signal Transduction; Trastuzumab; Treatment Outcome; Tubulin Modulators

Adjuvant trastuzumab (AT) dramatically improved HER2-positive breast cancer prognosis. Relapsed disease after AT has different patterns and information is available from observational studies. In this Review Chemotherapy regimens combined to anti-HER2 blockade are discussed, focusing in particular the role of anthracyclines, taxanes and capecitabine. The use of trastuzumab beyond progression and the role of other anti-HER2 agents like lapatinib, pertuzumab and T-DM1 are explored, as also dual blockade and in trastuzumab resistant Patients. Metastatic "de novo" HER2 Luminal (co-expression of HER2 and hormone receptors) Patients are eligible for anastrozole and trastuzumab but if pretreated with trastuzumab they are also eligible for lapatinib and letrozole. In any case endocrine treatment plays a complementary role to chemotherapy which remains pivotal. The last topic explored is treatment options for patients with brain metastases where both trastuzumab given concurrent with radiotherapy or lapatinib and capecitabine appear as potentially active.

Topics: Ado-Trastuzumab Emtansine; Anthracyclines; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain; Brain Neoplasms; Breast; Breast Neoplasms; Capecitabine; Chemotherapy, Adjuvant; Female; Humans; Lapatinib; Maytansine; Neoplasm Metastasis; Neoplasm Recurrence, Local; Quinazolines; Receptor, ErbB-2; Taxoids; Trastuzumab

An update on completed and ongoing clinical trials of ado-trastuzumab emtansine for the treatment of metastatic breast cancer (MBC) is presented.. Ado-trastuzumab emtansine (Kadcyla, Genentech), the first U.S.-approved antibody-drug conjugate for MBC, is indicated for use as a single-agent therapy in patients with human epidermal growth factor receptor 2 (HER2)-positive MBC who have received prior treatment with unconjugated trastuzumab and a taxane-based regimen. The standard dosage of ado-trastuzumab is 3.6 mg/kg i.v. every three weeks. In completed Phase II or III clinical trials, ado-trastuzumab was found to confer significant survival and quality-of-life benefits. The largest of those trials (the EMILIA study, n = 991) showed that ado-trastuzumab was superior to a regimen of lapatinib plus capecitabine in terms of progression-free survival (9.6 months versus 6.4 months, p < 0.001) and overall survival (30.9 months versus 25.1 months, p < 0.001); it also had a more favorable tolerability profile, with lower rates of treatment-limiting adverse effects. The most common adverse effects of ado-trastuzumab are thrombocytopenia (reported in about 12% of clinical trial participants overall) and increased transaminase levels. Two ongoing Phase III trials-the TH3RESA study (slated for completion in June 2015) and the MARIANNE study (estimated completion in 2016)-may help determine the optimal role of ado-trastuzumab relative to other HER2-targeted agents and its potential use as a front-line therapy for both heavily pretreated and treatment-naive patients with MBC.. With a novel targeted mechanism of action, ado-trastuzumab is an effective treatment option for HER2-positive MBC in previously treated patient populations.

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Drug Costs; Drug Interactions; Female; Humans; Maytansine; Neoplasm Metastasis; Receptor, ErbB-2; Trastuzumab

Trastuzumab emtansine (Kadcyla™) is an antibody-drug conjugate consisting of the humanized anti-human epidermal growth factor receptor (HER) 2 antibody trastuzumab covalently linked to the highly potent microtubule inhibitory drug DM1 (a cytotoxic derivative of maytansine) via a stable thioether linker. Intravenous trastuzumab emtansine was recently approved for use in patients with HER2-positive, unresectable, locally advanced (in the EU) or metastatic (in the USA and EU) breast cancer who had previously received trastuzumab and a taxane (separately or in combination), making it the first antibody-drug conjugate approved in this indication. This article reviews the efficacy and tolerability of trastuzumab emtansine in these patients and summarizes its pharmacology. In the well-designed EMILIA study, trastuzumab emtansine significantly prolonged progression-free survival and overall survival, relative to treatment with lapatinib plus capecitabine, in patients with HER2-positive, unresectable, locally advanced or metastatic breast cancer who were previously treated with trastuzumab and a taxane. Trastuzumab emtansine was generally well tolerated in this study, with <6% of patients discontinuing treatment because of adverse events. Based on its efficacy and favourable tolerability, the US National Comprehensive Cancer Network guidelines recommend trastuzumab emtansine as the preferred option in patients with HER2-positive metastatic breast cancer who have received previous trastuzumab-based therapy.

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Disease-Free Survival; Female; Humans; Maytansine; Neoplasm Metastasis; Receptor, ErbB-2; Survival Rate; Trastuzumab

To review the pharmacology, pharmacokinetics, efficacy, adverse effects, drug-drug interactions, dosage and administration, and formulary considerations for ado-trastuzumab emtansine.. Sources of information were identified through a PubMed search (1966 to June 2014) using the key terms ado-trastuzumab emtansine, trastuzumab-DM1, trastuzumab-MCC-DM1, and T-DM1. Other information was obtained from clinicaltrials.gov, product labeling, and press releases.. All English-language clinical trials and abstracts evaluating ado-trastuzumab emtansine in humans were reviewed for inclusion.. Overexpression or amplification of human epidermal growth factor receptor 2 (HER2) occurs in approximately 20% of breast cancers and is associated with more aggressive tumors and poorer prognosis in the absence of treatment. Although effective therapies for the initial management of HER2-positive metastatic breast cancer (MBC) exist, many patients will experience disease progression. Most second-line therapies are associated with either significant toxicities or limited improvements in overall survival (OS). Ado-trastuzumab emtansine is a HER2-positive directed antibody drug conjugate (ADC) approved in February 2013. In phase III clinical trials comparing the efficacy and safety of ado-trastuzumab emtansine with lapatinib-capecitabine or physician's choice, ado-trastuzumab emtansine had a better tolerability profile and improved progression-free survival compared with lapatinib-capecitabine or physician's choice and increased OS compared with lapatinib-capecitabine.. Ado-trastuzumab emtansine is a novel ADC effective for HER2-positive MBC in patients previously treated with trastuzumab, lapatinib, and a taxane. Further studies will determine its use in the adjuvant and neoadjuvant setting and in combination with pertuzumab.

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Capecitabine; Clinical Trials as Topic; Deoxycytidine; Disease-Free Survival; Fluorouracil; Humans; Immunoconjugates; Lapatinib; Maytansine; Molecular Targeted Therapy; Neoplasm Metastasis; Quinazolines; Receptor, ErbB-2; Taxoids; Trastuzumab

Trastuzumab improves care of patients with HER2+ breast cancer and allows a major gain in terms of survival. T-DM1 and pertuzumab are two new treatments, which give very encouraging results in metastatic breast cancer. Their place in neo-adjuvant and adjuvant setting still remains to be defined. Bevacizumab have its place in metastatic breast cancer. In adjuvant setting, results are disappointing and in neo-adjuvant setting, we need more studies on subgroups, which can benefit more. Development of the PARP inhibitors was slowed down by recent negative results in metastatic breast cancer but studies continue with more targeted patient's. Finally, everolimus, inhibitor of mTOR, allows to by pass the hormono-resistance in metastatic phase. Its toxicity must be taken into account in particular in adjuvant setting.

Topics: Ado-Trastuzumab Emtansine; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Breast Neoplasms; Drug Delivery Systems; Female; Humans; Lapatinib; Maytansine; Neoadjuvant Therapy; Neoplasm Metastasis; Neovascularization, Pathologic; Poly(ADP-ribose) Polymerase Inhibitors; Quinazolines; Receptor, ErbB-2; TOR Serine-Threonine Kinases; Trastuzumab

Because metastatic breast cancer (MBC) is incurable in most cases, the goals of treatment are improvement in quality of life, management of symptoms, and prolonged survival. The human epidermal growth factor receptor 2 (HER2) is overexpressed in up to 30% of breast tumors, and before the development of HER-targeted therapy, HER2 positivity was predictive of poorer clinical outcomes. Trastuzumab and pertuzumab (anti-HER2 monoclonal antibodies), lapatinib (a small molecule inhibitor of HER2 and the epidermal growth factor receptor [EGFR]) are approved for treating HER2-positive MBC in the United States. Although trastuzumab plus chemotherapy is currently regarded as the first-line standard of care for HER2-positive MBC, it is not without shortcomings; these include its association with certain adverse events (e.g. cardiotoxic effect) and development of resistance. A number of investigational agents that target HER2 and other members of that receptor family are in clinical development for patients with HER2-positive MBC whose disease has progressed on trastuzumab. In addition, in an effort to overcome treatment resistance, clinical trials are evaluating combination therapy (investigational HER-targeted agents with trastuzumab or lapatinib). This review discusses recently completed and ongoing phase II and III clinical trials of investigational HER-targeted agents in the setting of trastuzumab-progressive, HER2-positive MBC.

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Lapatinib; Maytansine; Neoadjuvant Therapy; Neoplasm Metastasis; Protein Kinase Inhibitors; Quinazolines; Receptor, ErbB-2; Trastuzumab

Trastuzumab emtansine is an antibody-drug conjugate comprised of the receptor tyrosine-protein kinase erbB-2 (HER2) antibody trastuzumab, and a derivative of the cytostatic agent maytansinoid DM1, covalently linked by a thiol linker. The drug was developed in an attempt to overcome trastuzumab resistance in patients with HER2-positive breast carcinoma, but it is also of potential use in other HER2-positive cancers. The preclinical antitumor activity of trastuzumab emtansine was established in HER2-positive breast cancer cell lines and murine xenograft models. Preclinically, trastuzumab emtansine was efficacious in HER2-positive cells that were resistant to trastuzumab or lapatinib. Clinically, the drug is well tolerated in most patients, with a predictable pharmacokinetic profile and minimal systemic exposure to free cytotoxic DM1. Unlike with trastuzumab, cardiac toxicity has not been seen in patients receiving trastuzumab emtansine and less adverse events have been reported than with other chemotherapy regimens. Results from a number of phase II studies and early results from a phase III investigation (EMILIA) demonstrated response rates of 25-35% in patients with breast cancer who had previously received trastuzumab. Several phase II and III studies are under way investigating trastuzumab emtansine in combination with other regimens in patients with HER2-positive cancers.

Topics: Ado-Trastuzumab Emtansine; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Female; Humans; Maytansine; Neoplasm Metastasis; Receptor, ErbB-2; Trastuzumab; Xenograft Model Antitumor Assays

This phase I study, which to our knowledge is the first-in-human study of this kind, investigates the safety, tolerability, pharmacokinetics, and clinical activity of anetumab ravtansine, an antibody-drug conjugate of anti-mesothelin antibody linked to maytansinoid DM4, in patients with advanced, metastatic, or recurrent solid tumors known to express the tumor-differentiation antigen mesothelin.. This phase I, open-label, multicenter, dose-escalation and dose-expansion study of anetumab ravtansine enrolled 148 adult patients with multiple solid tumor types. Ten dose-escalation cohorts of patients with advanced or metastatic solid tumors (0.15-7.5 mg/kg) received anetumab ravtansine once every 3 weeks, and 6 expansion cohorts of patients with advanced, recurrent ovarian cancer or malignant mesothelioma received anetumab ravtansine at the maximum tolerated dose once every 3 weeks, 1.8 mg/kg once per week, and 2.2 mg/kg once per week.. Forty-five patients were enrolled across the 10 dose-escalation cohorts. The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg once every 3 weeks or 2.2 mg/kg once per week. Thirty-two patients were enrolled in the 6.5 mg/kg once-every-3-weeks, 35 in the 1.8 mg/kg once-per-week, and 36 in the 2.2 mg/kg once-per-week expansion cohorts. The most common drug-related adverse events were fatigue, nausea, diarrhea, anorexia, vomiting, peripheral sensory neuropathy, and keratitis/keratopathy. There were no drug-related deaths. Anetumab ravtansine pharmacokinetics were dose proportional; the average half-life was 5.5 days. Among 148 patients with mesothelioma or ovarian, pancreatic, non-small-cell lung, and breast cancers, 1 had a complete response, 11 had partial responses, and 66 had stable disease. High levels of tumor mesothelin expression were detected in patients with clinical activity.. Anetumab ravtansine exhibited a manageable safety and favorable pharmacokinetic profile with encouraging preliminary antitumor activity in heavily pretreated patients with mesothelin-expressing solid tumors. The results allowed for the determination of recommended doses, schedules, and patient populations for anetumab ravtansine in phase II studies.

Topics: Adult; Aged; Antineoplastic Agents, Immunological; Female; GPI-Linked Proteins; Humans; Immunoconjugates; Male; Maximum Tolerated Dose; Maytansine; Mesothelin; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms; Progression-Free Survival

In this prospective phase 2 trial, we assessed the efficacy of trastuzumab-emtansine (T-DM1) in HER2-negative metastatic breast cancer (MBC) patients with HER2-positive CTC.. Main inclusion criteria for screening were as follows: women with HER2-negative MBC treated with ≥ 2 prior lines of chemotherapy and measurable disease. CTC with a HER2/CEP17 ratio of ≥ 2.2 by fluorescent in situ hybridization (CellSearch) were considered to be HER2-amplified (HER2. CTC with HER2 amplification can be detected in a limited subset of HER2-negative MBC patients. Treatment with T-DM1 achieved a partial response in only one patient.. NCT01975142, Registered 03 November 2013.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; France; Gene Amplification; Humans; Maytansine; Middle Aged; Neoplasm Metastasis; Neoplastic Cells, Circulating; Progression-Free Survival; Prospective Studies; Receptor, ErbB-2; Trastuzumab

Patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)-targeted therapy have a worse prognosis than those who have no residual cancer. Trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy.. We conducted a phase 3, open-label trial involving patients with HER2-positive early breast cancer who were found to have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab. Patients were randomly assigned to receive adjuvant T-DM1 or trastuzumab for 14 cycles. The primary end point was invasive disease-free survival (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause).. At the interim analysis, among 1486 randomly assigned patients (743 in the T-DM1 group and 743 in the trastuzumab group), invasive disease or death had occurred in 91 patients in the T-DM1 group (12.2%) and 165 patients in the trastuzumab group (22.2%). The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group. Invasive disease-free survival was significantly higher in the T-DM1 group than in the trastuzumab group (hazard ratio for invasive disease or death, 0.50; 95% confidence interval, 0.39 to 0.64; P<0.001). Distant recurrence as the first invasive-disease event occurred in 10.5% of patients in the T-DM1 group and 15.9% of those in the trastuzumab group. The safety data were consistent with the known safety profile of T-DM1, with more adverse events associated with T-DM1 than with trastuzumab alone.. Among patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T-DM1 than with trastuzumab alone. (Funded by F. Hoffmann-La Roche/Genentech; KATHERINE ClinicalTrials.gov number, NCT01772472 .).

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Immunological; Breast Neoplasms; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Humans; Lymphatic Metastasis; Maytansine; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Staging; Neoplasm, Residual; Peripheral Nervous System Diseases; Radiotherapy; Receptor, ErbB-2; Trastuzumab; Treatment Outcome; Young Adult

In treating human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, the efficacy of capecitabine combined with HER2-directed agents such as trastuzumab and lapatinib is supported by some evidence. The combination of T-DM1 and S-1, another oral 5-FU, may be a safe alternative treatment for metastatic breast cancer.. The optimal dose of S-1 was evaluated in combination with T-DM1 for patients with HER2-positive advanced or metastatic breast cancer. The safety and clinical response of this combination treatment were also assessed.. This 3 + 3 dose-escalation study of S-1 given for the first 2 of 3 weeks, in combination with T-DM1 (3.6 mg/kg given every 3 weeks) to patients with trastuzumab-pretreated HER2-positive advanced or metastatic breast cancer was designed to evaluate the dose-limiting toxicity (DLT) occurrence in the first cycle. We also evaluated the safety and clinical activity of this combination treatment in multiple cycles. Two different dose levels of S-1 (65 and 80 mg/m2/day) were planned, although the capecitabine arm was abandoned because of slow recruitment.. Twelve out of the 13 patients enrolled were evaluable for DLT. One DLT (grade ≥3 non-hematological adverse events) occurred at dose level 0, leading to the expansion of this cohort to 6 patients, with an additional DLT (≥7 days discontinuation of medication), while no DLT occurred at dose level 1. As a result, the maximum tolerable dose of S-1 was determined to be 80 mg/m2/day for 14 days with T-DM1 3.6 mg/kg, repeated every 3 weeks. Two patients had grade 3 thrombocytopenia at dose level 0, and 1 patient at dose level 1.. S-1 can be safely combined with the clinically relevant dose of T-DM1 in patients with HER2-positive advanced or metastatic breast cancer. Further evaluation with a larger sample size is required for efficacy assessment.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Combinations; Female; Humans; Maytansine; Middle Aged; Neoplasm Metastasis; Oxonic Acid; Receptor, ErbB-2; Tegafur; Trastuzumab; Treatment Outcome

Treatment options for patients with disease progression after treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1) are limited. Tucatinib is an oral, potent, human epidermal growth factor receptor 2 (HER2)-specific tyrosine kinase inhibitor (TKI) being developed as a novel treatment for ERBB2/HER2-positive breast cancer.. To determine the maximum tolerated dosage of tucatinib in combination with T-DM1 in the treatment of patients with ERBB2/HER2-positive metastatic breast cancer with and without brain metastases.. In this phase 1b open-label, multicenter, clinical trial, 57 participants enrolled between January 22, 2014, and June 22, 2015, were 18 years of age or older with ERBB2/HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Data were analyzed between January and March 2018.. Tucatinib 300 mg or 350 mg administered orally twice per day for 21 days and T-DM1 3.6 mg/kg administered intravenously once every 21 days.. Safety assessments, pharmacokinetics, and response were assessed using RECIST 1.1 every 2 cycles for 6 cycles, followed by every 3 cycles.. Fifty-seven T-DM1-naive patients (median [IQR] 51 [44.0-63.0] years of age) who had undergone a median of 2 earlier HER2 therapies (range, 1-3) were treated. The tucatinib maximum tolerated dosage was determined to be 300 mg administered twice per day with dose-limiting toxic reactions seen at 350 mg twice per day. Pharmacokinetic analysis showed that there was no drug-drug interaction with T-DM1. Adverse events seen among the 50 patients treated at the maximum tolerated dosage regardless of causality included nausea (36 patients; 72%), diarrhea (30 patients; 60%), fatigue (28 patients; 56%), epistaxis (22 patients; 44%), headache (22 patients; 44%), vomiting (21 patients; 42%), constipation (21 patients; 42%), and decreased appetite (20 patients; 40%); the majority of adverse events were grade 1 or 2. Tucatinib-related toxic reactions that were grade 3 and above included thrombocytopenia (7 patients; 14%) and hepatic transaminitis (6 patients; 12%).. In this study, tucatinib in combination with T-DM1 appeared to have acceptable toxicity and to show preliminary antitumor activity among heavily pretreated patients with ERBB2/HER2-positive metastatic breast cancer with and without brain metastases.. ClinicalTrials.gov Identifier: NCT01983501.

Topics: Ado-Trastuzumab Emtansine; Adult; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Breast Neoplasms; Diarrhea; Drug Administration Schedule; Fatigue; Female; Humans; Kaplan-Meier Estimate; Maytansine; Middle Aged; Nausea; Neoplasm Metastasis; Protein Kinase Inhibitors; Receptor, ErbB-2; Response Evaluation Criteria in Solid Tumors; Trastuzumab

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.. 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.. 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 [<1%] 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 [<1%] of 184). Serious adverse events were reported in 102 (25%) of 403 patients in the trastuzumab emtansine group and 41 (22%) of 184 in the physician's choice group. Deaths from adverse events were reported in three patients (2%) in the physician's choice group (of which one was judged to be treatment related) and nine (2%) in the trastuzumab emtansine group (of which three were judged to be treatment related).. 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.. F Hoffman-La Roche/Genentech.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Breast Neoplasms, Male; Bridged-Ring Compounds; Chemotherapy-Induced Febrile Neutropenia; Diarrhea; Early Termination of Clinical Trials; Female; Hemorrhage; Humans; Lapatinib; Male; Maytansine; Middle Aged; Neoplasm Metastasis; Neutropenia; Practice Patterns, Physicians'; Quinazolines; Receptor, ErbB-2; Retreatment; Survival Rate; Taxoids; Thrombocytopenia; Trastuzumab

Trastuzumab emtansine significantly improved progression-free survival and overall survival when compared with lapatinib-capecitabine in pretreated human epidermal growth factor receptor 2-positive advanced breast cancer. However, data in Japanese populations are limited.. In the single-arm Phase II JO22997 study, Japanese patients with human epidermal growth factor receptor 2-positive inoperable locally advanced/recurrent or metastatic breast cancer previously treated with at least one prior chemotherapy regimen for locally advanced/recurrent or metastatic breast cancer and trastuzumab in any setting received 3.6 mg/kg trastuzumab emtansine every 3 weeks until progression, unacceptable toxicity or consent withdrawal. The primary endpoint was Independent Review Committee-assessed objective response rate. Secondary endpoints included progression-free survival, overall survival, safety and pharmacokinetics.. The objective response rate in 73 treated patients was 38.4% (90% confidence interval, 28.8-48.6%), exceeding the prespecified boundary for an objective response rate > 20%. After 6.5 months' median follow-up, median progression-free survival was 5.6 months (95% confidence interval, 4.6-8.2). After 28.9 months' median follow-up, median overall survival was 30.5 months (95% confidence interval 25.2-not reached). There were no treatment-related deaths. The most common Grade 3/4 adverse events were thrombocytopenia (22%) and aspartate aminotransferase elevations (14%). Thrombocytopenia did not require platelet transfusion and typically recovered before the next cycle. There were no substantial differences in trastuzumab emtansine or trastuzumab pharmacokinetic parameters between this study and previous data from non-Japanese patients.. JO22997 results suggest high activity of trastuzumab emtansine in Japanese patients, a safety profile consistent with previous studies in non-Japanese patients, no new safety signals and no evidence of pharmacokinetic differences between Japanese and non-Japanese populations. These results support trastuzumab emtansine therapy for Japanese patients with chemotherapy- and trastuzumab-pretreated human epidermal growth factor receptor 2-positive locally advanced/recurrent or metastatic breast cancer.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Asian People; Breast Neoplasms; Disease-Free Survival; Female; Half-Life; Humans; Japan; Maytansine; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Receptor, ErbB-2; Survival Rate; Thrombocytopenia; Trastuzumab; Treatment Outcome

HER2-positive breast cancer is heterogeneous. Some tumors express mutations, like activating PIK3CA mutations or reduced PTEN expression, that negatively correlate with response to HER2-targeted therapies. In this exploratory analysis, we investigated whether the efficacy of trastuzumab emtansine (T-DM1), an antibody-drug conjugate comprised of the cytotoxic agent DM1 linked to the HER2-targeted antibody trastuzumab, was correlated with the expression of specific biomarkers in the phase III EMILIA study.. Tumors were evaluated for HER2 (n = 866), EGFR (n = 832), and HER3 (n = 860) mRNA expression by quantitative reverse transcriptase PCR; for PTEN protein expression (n = 271) by IHC; and for PIK3CA mutations (n = 259) using a mutation detection kit. Survival outcomes were analyzed by biomarker subgroups. T-DM1 was also tested on cell lines and in breast cancer xenograft models containing PIK3CA mutations.. Longer progression-free survival (PFS) and overall survival (OS) were observed with T-DM1 compared with capecitabine plus lapatinib in all biomarker subgroups. PIK3CA mutations were associated with shorter median PFS (mutant vs. wild type: 4.3 vs. 6.4 months) and OS (17.3 vs. 27.8 months) in capecitabine plus lapatinib-treated patients, but not in T-DM1-treated patients (PFS, 10.9 vs. 9.8 months; OS, not reached in mutant or wild type). T-DM1 showed potent activity in cell lines and xenograft models with PIK3CA mutations.. Although other standard HER2-directed therapies are less effective in tumors with PI3KCA mutations, T-DM1 appears to be effective in both PI3KCA-mutated and wild-type tumors. Clin Cancer Res; 22(15); 3755-63. ©2016 AACR.

Topics: Ado-Trastuzumab Emtansine; Animals; Antineoplastic Agents, Immunological; Biomarkers, Tumor; Breast Neoplasms; Disease Models, Animal; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Maytansine; Mice; Neoplasm Metastasis; Neoplasm Staging; Phosphatidylinositol 3-Kinases; Proportional Hazards Models; Receptor, ErbB-2; Retreatment; Trastuzumab; Xenograft Model Antitumor Assays

Trastuzumab emtansine (T-DM1) exhibited enhanced antitumor activity when combined with docetaxel or pertuzumab in preclinical studies. This phase Ib/IIa study assessed the feasibility of T-DM1 + docetaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and T-DM1 + docetaxel ± pertuzumab in patients with HER2-positive locally advanced breast cancer (LABC).. Phase Ib (part 1) explored dose escalation, with T-DM1 + docetaxel administered for greater than or equal to six cycles in patients with MBC. Phase Ib (part 2) began with the maximum tolerated dose (MTD) identified in part 1. Patients with LABC were administered less than or equal to six cycles of T-DM1 + docetaxel or T-DM1 + docetaxel + pertuzumab. Phase IIa explored the MTDs identified in phase Ib.. Administered with T-DM1 (3.6 mg/kg), the docetaxel MTD was 60 mg/m(2) in MBC. In LABC, the MTD was 100 mg/m(2) docetaxel in combination with T-DM1 (3.6 mg/kg), given with granulocyte colony-stimulating factor (G-CSF). Administered with T-DM1 (3.6 mg/kg) + pertuzumab (840 mg, cycle 1; 420 mg, subsequent cycles), the docetaxel MTD in LABC was 75 mg/m(2) with G-CSF support. Neutropenia was the most common grade 3-4 adverse event (AE; MBC, 72% and LABC, 29%). In total, 48% (12/25) of MBC patients and 47% (34/73) of LABC patients experienced AEs requiring dose modification. In MBC (median prior systemic agents = 5), the objective response rate was 80.0% (20/25; 95% confidence interval [CI] 59.3-93.2) and the median progression-free survival was 13.8 months (range, 1.6-33.5). The pathologic complete response (ypT0/is, ypN0) rate in LABC was 60.3% (44/73; 95% CI 48.1-71.5). Pharmacokinetic analyses indicated a low risk of drug-drug interaction between T-DM1 and docetaxel.. T-DM1 combined with docetaxel ± pertuzumab appeared efficacious in MBC or LABC; however, nearly half of patients experienced AEs requiring dose reductions with these T-DM1 combinations.. NCT00934856.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Disease-Free Survival; Docetaxel; Female; Granulocyte Colony-Stimulating Factor; Humans; Maytansine; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Receptor, ErbB-2; Taxoids; Trastuzumab

Exposure-response (E-R) analyses for ado-trastuzumab emtansine (T-DM1, Kadcyla) were performed using data from a randomized, active control (lapatinib plus capecitabine) trial in patients with human epidermal growth factor 2-positive metastatic breast cancer. Kaplan-Meier survival analyses stratified by T-DM1 trough concentration on day 21 of cycle 1 (Cmin,C1D21) were performed for overall survival (OS) and progression-free survival (PFS). E-R analyses indicated that after adjusting for baseline risk factors, higher T-DM1 exposure is associated with improved efficacy. T-DM1-treated patients with Cmin,C1D21 lower than the median value had values of OS and PFS comparable to those of the active control arm. The percentage of patients who received T-DM1 dose adjustments was similar across the exposure range and was lower than that of the active control arm. Our findings suggest that there may be an opportunity to optimize Kadcyla dose in the patient subgroup with low T-DM1 exposure for improved efficacy with acceptable tolerability.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Deoxycytidine; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Lapatinib; Maytansine; Middle Aged; Neoplasm Metastasis; Quinazolines; Receptor, ErbB-2; Survival Rate; Trastuzumab; Treatment Outcome

Our phase IIa study characterized the safety and efficacy of two human epidermal growth factor receptor 2 (HER2) -targeted agents, trastuzumab emtansine (T-DM1) and pertuzumab, in patients with HER2-positive metastatic breast cancer (MBC).. Patients with HER2-positive locally advanced breast cancer or MBC were treated with 3.6 mg/kg T-DM1 plus pertuzumab (840-mg loading dose, then 420 mg subsequently) once every 3 weeks. The primary efficacy end point was investigator-assessed objective response rate (ORR).. Sixty-four patients (43 patients in the second-line or greater setting [advanced MBC]; 21 patients in the first-line setting [first-line MBC]) were enrolled. Patients with advanced MBC had received trastuzumab and a median of six prior nonhormonal treatments for MBC; 86% of first-line MBC patients had received trastuzumab in the (neo)adjuvant setting. The ORR was 41% overall, 33% in patients with advanced MBC, and 57% in first-line patients. Median progression-free survival was 6.6, 5.5, and 7.7 months, respectively. The most common adverse events were fatigue (61%), nausea (50%), and diarrhea (39%). The most frequent grade ≥ 3 adverse events were thrombocytopenia (13%), fatigue (11%), and liver enzyme elevations (increased ALT: 9%; increased AST: 9%). One patient had left ventricular ejection fraction of less than 40% after study drug discontinuation. Exploratory biomarker analyses demonstrated that patients with above-median tumor HER2 mRNA levels had a numerically higher ORR than patients with below-median levels (44% v 33%, respectively).. T-DM1 and pertuzumab can be combined at full doses with no unexpected toxicities. The preliminary efficacy in patients in the first-line and advanced MBC settings warrants further investigation.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Disease-Free Survival; Female; Genes, erbB-2; Humans; Kaplan-Meier Estimate; Maytansine; Middle Aged; Neoplasm Metastasis; Trastuzumab

Amplification of the human epidermal growth factor receptor 2 (HER2) gene occurs in approximately 20% of invasive breast cancer cases and is associated with a more aggressive disease course than HER2-negative breast cancer. HER2-targeted therapies have altered the natural history of HER2-positive breast cancer, a trend that will likely further improve with the recent approval of new agents. A prospective, observational cohort study was designed and initiated to provide real-world insights into current treatment patterns, long-term survival, and patients' experiences with initial and subsequent treatments for HER2-positive metastatic breast cancer (MBC).. The Systematic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs) is a US-based prospective observational cohort study enrolling patients ≥18 years of age with recently diagnosed HER2-positive MBC not previously treated with systemic therapy in the metastatic setting. The primary objective of the study is to identify treatment patterns and clinical outcomes in recently diagnosed patients in a variety of practice settings. Secondary objectives include comparative efficacy, safety, and patient-reported outcomes (PROs). Healthcare resource utilization is an exploratory end point. Tumor tissue and blood sample collection is optional.The SystHERs registry will enroll approximately 1000 patients over a 3-year period, after which the study will continue for ≥5 years, allowing for a maximum follow-up of 8 years. The treating physician will determine all care and the frequency of visits. PRO measures will be completed at study enrollment and every 90 days. Clinical data will be abstracted quarterly from patient records. The first patient was enrolled in June 2012, and preliminary descriptive data based on 25% to 30% of the final study population are expected at the end of 2013, and as of April 25, 2014, 386 patients are enrolled.. SystHERs is expected to provide in-depth data on demographic, clinicopathological, and treatment patterns and their associations with clinical outcomes, PROs, and healthcare resource utilization. Tumor tissue and DNA repositories will also be established for use in future translational research.. NCT01615068 (ClinicalTrials.gov identifier).

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Disease-Free Survival; Female; Humans; Maytansine; Neoplasm Metastasis; Receptor, ErbB-2; Trastuzumab; Treatment Outcome

Trastuzumab emtansine (T-DM1), an antibody-drug conjugate composed of the cytotoxic agent DM1 conjugated to trastuzumab via a stable thioether linker, has shown clinical activity in single-arm studies enrolling patients with human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (MBC) whose disease had progressed on HER2-targeted therapy in the metastatic setting.. Patients (N = 137) with HER2-positive MBC or recurrent locally advanced breast cancer were randomly assigned to trastuzumab plus docetaxel (HT; n = 70) or T-DM1 (n = 67) as first-line treatment until disease progression or unacceptable toxicity. Primary end points were investigator-assessed progression-free survival (PFS) and safety. Key secondary end points included overall survival (OS), objective response rate (ORR), duration of objective response, clinical benefit rate, and quality of life.. Median PFS was 9.2 months with HT and 14.2 months with T-DM1 (hazard ratio, 0.59; 95% CI, 0.36 to 0.97); median follow-up was approximately 14 months in both arms. ORR was 58.0% (95% CI, 45.5% to 69.2%) with HT and 64.2% (95% CI, 51.8% to 74.8%) with T-DM1. T-DM1 had a favorable safety profile versus HT, with fewer grade ≥ 3 adverse events (AEs; 46.4% v 90.9%), AEs leading to treatment discontinuations (7.2% v 34.8%), [corrected] and serious AEs (20.3% v 25.8%). Preliminary OS results were similar between treatment arms; median follow-up was approximately 23 months in both arms.. In this randomized phase II study, first-line treatment with T-DM1 for patients with HER2-positive MBC provided a significant improvement in PFS, with a favorable safety profile, versus HT.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Docetaxel; Female; Humans; Maytansine; Middle Aged; Neoplasm Metastasis; Receptor, ErbB-2; Taxoids; Trastuzumab; Treatment Outcome

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprised of trastuzumab and the cytotoxic agent DM1 (derivative of maytansine) linked by a stable linker N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC). T-DM1 targets an epitope located at subdomain IV of human epidermal growth factor receptor 2 (HER2). Pertuzumab is a monoclonal antibody that targets an epitope located at subdomain II of HER2, distinct from the epitope recognized by T-DM1. The pharmacokinetics (PK), safety, and efficacy of T-DM1 combined with pertuzumab were studied in a phase 1b/2 trial in 67 patients with HER2-positive, locally advanced or metastatic breast cancer (MBC). The therapeutic protein-drug interaction (TP-DI) potential of T-DM1 plus pertuzumab was evaluated. The PK of T-DM1-related analytes and pertuzumab were compared with historical PK data. The results show that the exposure of T-DM1 and DM1, as estimated by noncompartmental analyses, was comparable with that reported by historical single-agent studies in patients with HER2-positive MBC. T-DM1 clearance and volume of distribution in the central compartment, as estimated by population PK analysis, were also comparable between this study and historical single-agent studies in patients with HER2-positive MBC. Summary statistics of pertuzumab trough and maximal exposure (concentrations at predose and 15-30 minutes after the end of infusion at cycle 1 and at steady state) were similar with those observed in a representative historical single-agent study with the same dosing regimen. The visual predictive check plot by population simulation further confirmed that T-DM1 did not alter pertuzumab PK. Based on these data and the PK and pharmacodynamic properties of T-DM1 and pertuzumab, the risk of TP-DI appears to be low when T-DM1 and pertuzumab are given together.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Interactions; Female; Humans; Male; Maytansine; Middle Aged; Neoplasm Metastasis; Receptor, ErbB-2; Trastuzumab

To determine whether the antibody-drug conjugate trastuzumab emtansine (T-DM1), which combines human epidermal growth factor receptor 2 (HER2) -targeted delivery of the potent antimicrotubule agent DM1 with the antitumor activity of trastuzumab, is effective in patients with HER2-positive metastatic breast cancer (MBC) who have previously received all standard HER2-directed therapies.. In this single-arm phase II study, T-DM1 3.6 mg/kg was administered intravenously every 3 weeks to patients with HER2-positive MBC who had prior treatment with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. The primary objectives were overall response rate (ORR) by independent review and safety.. Among 110 pretreated patients (median, seven prior agents for MBC; median follow-up, 17.4 months), the ORR was 34.5% (95% CI, 26.1% to 43.9%), clinical benefit rate was 48.2% (95% CI, 38.8% to 57.9%), median progression-free survival (PFS) was 6.9 months (95% CI, 4.2 to 8.4 months), and median duration of response was 7.2 months (95% CI, 4.6 months to not estimable). In patients with confirmed HER2-positive tumors (n = 80 by retrospective central testing), the response rate was 41.3% (95% CI, 30.4% to 52.8%), and median PFS was 7.3 months (95% CI, 4.6 to 12.3 months). Most adverse events were grades 1 to 2; the most frequent grade ≥ 3 events were thrombocytopenia (9.1%), fatigue (4.5%), and cellulitis (3.6%).. T-DM1 is well tolerated and has single-agent activity in patients with HER2-positive MBC who have previously received both approved HER2-directed therapies and multiple chemotherapy agents. T-DM1 may be an effective new treatment for this patient population.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Anthracyclines; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Humans; Immunotoxins; Lapatinib; Male; Maytansine; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Quinazolines; Receptor, ErbB-2; Taxoids; Trastuzumab

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. The antibody and the cytotoxic agent are conjugated by means of a stable linker.. We randomly assigned patients with HER2-positive advanced breast cancer, who had previously been treated with trastuzumab and a taxane, to T-DM1 or lapatinib plus capecitabine. 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.. 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 lapatinib plus capecitabine (hazard ratio for progression or death from any cause, 0.65; 95% confidence interval [CI], 0.55 to 0.77; P<0.001), and median overall survival at the second interim analysis crossed the stopping boundary for efficacy (30.9 months vs. 25.1 months; hazard ratio for death from any cause, 0.68; 95% CI, 0.55 to 0.85; P<0.001). The objective response rate was higher with T-DM1 (43.6%, vs. 30.8% with lapatinib plus capecitabine; P<0.001); results for all additional secondary end points favored T-DM1. Rates of grade 3 or 4 adverse events were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia were higher with lapatinib plus capecitabine.. T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. (Funded by F. Hoffmann-La Roche/Genentech; EMILIA ClinicalTrials.gov number, NCT00829166.).

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Humans; Intention to Treat Analysis; Kaplan-Meier Estimate; Lapatinib; Maytansine; Middle Aged; Neoplasm Metastasis; Quinazolines; Receptor, ErbB-2; Survival Rate; Trastuzumab; Young Adult

Little data exist for comparing cardiac safety and survival outcomes of trastuzumab/pertuzumab or ado-T emtansine (TDM1) in metastatic breast cancer (MBC) patients enrolled in randomized clinical trial (RCT) vs the real-world.. This was a retrospective population-based cohort of all patients with MBC treated with trastuzumab/pertuzumab or TDM1 (2012-2017) in Ontario, Canada. Outcomes were incident heart failure (HF) and overall survival (OS). RCT data were obtained from digitizing survival curves and compared with cohort data using Kaplan-Meier analysis. Age-based comparison of outcomes was conducted for patients ≥ 65 years old vs younger than 65.. The two cohorts composed of 833 and 397 patients treated with trastuzumab/pertuzumab and TDM1, of whom 5.5% and 7.6% had baseline HF, respectively. Incident HF following trastuzumab/pertuzumab or TDM1 was low (trastuzumab/pertuzumab 1.8 events/100 person years; TDM1 0.02 events/100 person years). The median OS was 39.2 and 56.4 months in the trastuzumab/pertuzumab population-based cohort and CLEOPATRA, respectively. The median OS was 15.4 and 30.9 months in the TDM1 population-based cohort and EMILIA, respectively. Cohort OS was significantly worse than RCT OS (trastuzumab/pertuzumab HR 1.67, 95% CI 1.37-2.03, p < 0.0001; TDM1 HR 2.80, 95% CI 2.27-3.44, p < 0.0001). Older patients had worse OS than younger patients for trastuzumab/pertuzumab (HR 1.60, 95% CI 1.19-2.16, p = 0.0018), but not for TDM1 (HR 1.16, 95% CI 0.81-1.66, p = 0.43).. HF incidence during trastuzumab/pertuzumab or TDM1 therapy in this real-world cohort was low. Survival in this cohort was worse compared to RCT, suggesting that recruitment of patients similar to the real-world population is required.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Docetaxel; Female; Follow-Up Studies; Humans; Maytansine; Middle Aged; Neoplasm Metastasis; Prognosis; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Retrospective Studies; Survival Rate; Trastuzumab

Ado-trastuzumab emtansine (T-DM1/Kadcyla. We performed a cross-sectional, prospective study in all patients currently treated with T-DM1 or recently stopped in Ghent University Hospital, Belgium.. A total of 12 patients completed a full ophthalmic workup. Ten patients were currently using T-DM1, and two patients had recently (< 10 weeks) stopped treatment because of clinical non-response. Twenty eyes of 10 patients currently on T-DM1-treatment all exhibited coarse cystoid lesions to the deep corneal epithelial cells, primarily in the midperipheral area, both biomicroscopically and on confocal microscopy. The two patients who stopped treatment, displayed no corneal epithelial changes. Only three patients reported symptoms which were attributed to other ocular factors, likely not to be related to T-DM1 treatment.. This case series shows that asymptomatic, low-grade corneal epithelial changes are hallmark features in T-DM1-treatment and should not alarm clinicians. These findings are relatively stationary, reversible and thus do not require ocular treatment or cessation of systemic treatment.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Breast Neoplasms; Epithelium, Corneal; Female; Humans; Immunoconjugates; Maytansine; Middle Aged; Neoplasm Metastasis; Receptor, ErbB-2; Trastuzumab

Topics: Ado-Trastuzumab Emtansine; Antineoplastic Agents, Immunological; Breast Neoplasms; Female; Humans; Maytansine; Neoplasm Metastasis; Receptor, ErbB-2; Trastuzumab

Specific drug delivery to metastatic tumors remains a great challenge for antimetastasis therapy. We herein report a bioengineered macrophage-based delivery system (LD-MDS) that can be preferentially delivered to lung metastases and intelligently transformed into nanovesicles and secondary nanovesicles for antimetastasis therapy. LD-MDS was prepared by anchoring a legumain-specific propeptide of melittin (legM) and cytotoxic soravtansine (DM4) prodrug onto the membrane of living macrophages. LD-MDS is responsively activated by legumain protease and converted into DM4-loaded exosome-like nanovesicles (DENs), facilitating efficient internalization by metastatic 4T1 cancer cells and considerable cell death. Afterward, the damaged 4T1 cells can release secondary nanovesicles and free drug molecules to destroy neighboring cancer cells. In vivo, LD-MDS displays superior targeting efficiency for lung metastatic lesions with diameters less than 100 μm and remarkably inhibits lung metastasis. This study provides a new opportunity to explore endogenous macrophages as living drug delivery vehicles with controlled drug release to target metastatic lung tumors.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Cysteine Endopeptidases; Drug Carriers; Drug Liberation; Humans; Lung Neoplasms; Macrophages; Maytansine; Melitten; Mice, Nude; Nanoparticles; Neoplasm Metastasis; Prodrugs

This study was undertaken to target cell surface receptors other than the ones typically associated with breast cancer {estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)}. It was also launched to use small molecules other than those most widely used for active targeting in general ( e.g. folate and carbonic anhydrase IX ligands). Specifically, the focus of this study was on unique small molecules that bind the TrkC receptor, which is overexpressed in metastatic breast cancer. A conjugate (1) of a TrkC-targeting small molecule and the highly cytotoxic warhead, DM4 (a maytansinoid), was prepared. Cellular studies featuring TrkC

Topics: Animals; Breast Neoplasms; Dose-Response Relationship, Drug; Humans; Maytansine; Mice; Mice, Inbred BALB C; Neoplasm Metastasis

We evaluated the outcomes of patients treated with ado-trastuzumab emantasine (T-DM1) after first-line pertuzumab/trastuzumab, compared with those receiving a trastuzumab-only-based regimen.. Patients who received second-line T-DM1 after pertuzumab/trastuzumab (n = 34) were compared with those who received only trastuzumab (n = 73).. Overall response rate was 33.3% in patients with prior pertuzumab and 57.1% in the remaining subjects. Disease control rate was 47 and 43%, respectively, and the clinical benefit rate was 43.3 and 71.1%, respectively. Median progression-free survival was 5.0 and 11.0 months, respectively (hazard ratio: 2.02; 95% CI: 1.14-3.58; p = 0.01).. Patients treated with T-DM1 who previously received pertuzumab present poorer clinical outcomes compared with those receiving a trastuzumab-only-based regimen in the first-line setting.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Maytansine; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Receptor, ErbB-2; Retreatment; Survival Analysis; Trastuzumab; Treatment Outcome

The management of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has changed dramatically with the introduction and widespread use of HER2-targeted therapies. However, there is relatively limited real-world information on patterns of use, effectiveness and safety in whole of population cohorts. The research programme detailed in this protocol will generate evidence on the prescribing patterns, safety monitoring and outcomes of patients with BC treated with HER2-targeted therapies in Australia.. Our ongoing research programme will involve a series of retrospective cohort studies that include every patient accessing Commonwealth-funded HER2-targeted therapies for the treatment of early BC and advanced BC in Australia. At the time of writing, our cohorts consist of 11 406 patients with early BC and 5631 with advanced BC who accessed trastuzumab and lapatinib between 2001 and 2014. Pertuzumab and trastuzumab emtansine were publicly funded for metastatic BC in 2015, and future data updates will include patients accessing these medicines. We will use dispensing claims for cancer and other medicines, medical service claims and demographics data for each patient accessing HER2-targeted therapies to undertake this research.. Ethics approval has been granted by the Population Health Service Research Ethics Committee and data access approval has been granted by the Australian Department of Human Services (DHS) External Review Evaluation Committee. Our findings will be reported in peer-reviewed publications, conference presentations and policy forums. By providing detailed information on the use and outcomes associated with HER2-targeted therapies in a national cohort treated in routine clinical care, our research programme will better inform clinicians and patients about the real-world use of these treatments and will assist third-party payers to better understand the use and economic costs of these treatments.

Topics: Ado-Trastuzumab Emtansine; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Australia; Breast Neoplasms; Cohort Studies; Humans; Immunohistochemistry; In Situ Hybridization; Maytansine; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Neoplasm Staging; Receptor, ErbB-2; Trastuzumab

The antibody-drug conjugate T-DM1 spurs immune cells to infiltrate HER2-positive breast tumors in patients. Treating mice that carry breast tumors with T-DM1 improves survival, but the tumors suppress the infiltrating lymphocytes. Combining T-DM1 with checkpoint inhibitors that block CTLA-4 and PD-1 overcomes this effect, eliminating breast tumors from 95% of the mice.

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Cycle Checkpoints; Cell Cycle Proteins; Female; Humans; Maytansine; Mutation; Neoplasm Metastasis; Receptor, ErbB-2; Survival Analysis; Trastuzumab; Treatment Outcome

Purpose Ado-trastuzumab emtansine (T-DM1) is currently approved for treatment in patients with human epidermal growth factor receptor 2 (HER2)-positive, metastatic breast cancer (MBC) who previously received trastuzumab and a taxane. However, there are no data on the activity of T-DM1 in patients who received prior pertuzumab, which is now included as standard first-line therapy. The goal of this study was to assess the efficacy of T-DM1 in routine clinical practice in a contemporary patient population that received both prior trastuzumab and pertuzumab. Patients and Methods We identified all patients with HER2-positive MBC who received T-DM1 after trastuzumab and pertuzumab between March 1, 2013, and July 15, 2015, via electronic pharmacy records and departmental databases at three institutions: MD Anderson Cancer Center, Smilow Cancer Hospital at Yale, and The James Cancer Hospital at the Ohio State University. We reviewed medical records of each case to confirm treatment sequencing and outcome. Results Of patients, 82 were identified and 78 were available for outcome analysis; 32% received T-DM1 as first- and second-line line therapy, and 48% received it as fourth-line treatment or later. Rate of prolonged duration on therapy, defined as duration on therapy ≥ 6 months, was 30.8% (95% CI, 20.6% to 41.1%), and tumor response rate was 17.9% (95% CI, 9.4% to 26.4%). Median duration on therapy was 4.0 months (95% CI, 2.7 to 5.1; range, 0 to 22.5 months). T-DM1 was discontinued for disease progression in 84% of patients and for toxicity in 10%. Conclusion Tumor response rates were lower than in prior reports of trastuzumab-resistant, HER2-positive MBC, but one third of patients received therapy with T-DM1 for ≥ 6 months, which suggests a clinically relevant benefit in patients who received prior pertuzumab.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Disease Progression; Humans; Maytansine; Middle Aged; Neoplasm Metastasis; Receptor, ErbB-2; Response Evaluation Criteria in Solid Tumors; Retreatment; Retrospective Studies; Trastuzumab

Trastuzumab emtansine (T-DM1) is indicated for previously treated HER2-positive metastatic breast cancer. Ethnic sensitivity assessment of T-DM1 was conducted using data from eight clinical studies to ensure that the clinically recommended dose is appropriate across ethnicities.. Four approaches were used: (1) non-compartmental analysis (NCA) comparing pharmacokinetic parameters of T-DM1 and relevant analytes across ethnic groups, (2) population pharmacokinetic (popPK) analysis assessing the impact of ethnicity on pharmacokinetics, (3) comparison of T-DM1 pharmacokinetics in Japanese patients versus the global population, and (4) exposure-response analyses assessing the impact of ethnicity on safety and efficacy.. NCA pharmacokinetic parameters (T-DM1, total trastuzumab, DM1) were comparable across ethnic groups; mean cycle 1 T-DM1 AUCinf was 475, 442, and 518 day µg/mL for white (n = 461), Asian (n = 68), and others (n = 57), respectively. PopPK analysis showed that ethnicity (white, Asian, and others) was not a significant covariate for T-DM1 pharmacokinetics (n = 671). Additionally, visual predictive check plots indicated that observed pharmacokinetic profiles in Japanese patients (n = 42) were within the prediction interval generated from the final PopPK model. Exposure-response analyses showed that ethnicity was not a significant covariate impacting efficacy or hepatotoxicity risk, but there was a trend of greater thrombocytopenia risk among Asians versus non-Asians, which could not be explained by similar exposure between the ethnic groups. Most Asians with thrombocytopenia were able to continue T-DM1 using dose-adjustment rules recommended for the global population.. These results suggest that T-DM1 pharmacokinetics are comparable across ethnic groups and that use of the current dosing regimen is appropriate across ethnicities.

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Area Under Curve; Asian People; Breast Neoplasms; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Ethnicity; Female; Humans; Maytansine; Models, Biological; Neoplasm Metastasis; Receptor, ErbB-2; Trastuzumab; Treatment Outcome

Human epidermal growth factor receptor (HER2)-positive breast cancer is associated with a more aggressive disease and poor prognosis. The development of trastuzumab, a HER2-targeted agent, has changed the paradigm of HER2-positive breast cancer treatment and improved survival rates dramatically. However, metastatic HER2-positive breast cancer patients eventually develop resistance to this treatment regimen eventually. A new anti-HER2 antibody-drug conjugate, Trastuzumab emtansine (T-DM1), has been shown to improve treatment efficacy. However, side effects that differ from trastuzumab, including thrombocytopenia, liver dysfunction, fatigue, cardiotoxicity, pneumonitis, and peripheral neuropathy, may occur. Clinical nurses must understand the mechanism of this new agent and be aware of the symptoms and signs related to its side effects. Furthermore, clinical nurses should understand the varying degrees of these side effects, their probable causes, and the potential approaches to their management. Finally, clinical nurses must understand how to administer this agent in order to ensure patient safety. Understanding the side effects of T-DM1 and their management will help elevate nursing quality and caring efficacy.. HER2陽性轉移性乳癌治療新希望—從護理的觀點談賀癌寧（trastuzumab emtansine）及其照護.. 第二型人類上皮細胞生長因子接受器（human epidermal growth factor receptor, HER2）陽性的乳癌病患，具較嚴重的疾病及較差的預後。對抗HER2的標靶藥物－賀癌平（trastuzumab）的發展，使得HER2陽性乳癌的病患存活率顯著提升。然而，轉移性HER2陽性的乳癌最終都將會發展出抗藥性。近年來，新的抗體與化學治療複合（anti body-drug conjugate）的藥物－賀癌寧（trastuzumab emtansine, T-DM1），可以改善抗藥性乳癌的治療成效。賀癌寧可能會出現的副作用有：血小板減少、肝功能指數升高、疲憊、心臟功能的影響、肺炎及周邊神經病變等。護理師必須瞭解此藥物的作用機制及副作用、給藥注意事項、評估副作用及處理方法，以確保病患安全，提升照護能力及護理品質。.

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Female; Humans; Maytansine; Neoplasm Metastasis; Receptor, ErbB-2; Trastuzumab

Trastuzumab emtansine (T-DM1, KADCYLA(®)) is an antibody-drug conjugate comprised of the cytotoxic agent DM1 and trastuzumab (HERCEPTIN(®)). The safety profile of T-DM1 in human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane was investigated in the phase III EMILIA trial. The trial demonstrated clinically and statistically meaningful differences in the safety profile between T-DM1 and capecitabine plus lapatinib (CAP + LAP). The objective of this study was to estimate the costs of managing treatment-related grade ≥ 3 adverse events (AEs) that occurred in ≥ 2% of patients and grade 2 AEs that occurred in ≥ 5% of patients taking T-DM1 compared with patients taking CAP + LAP based on the EMILIA trial, from the perspective of Canadian public payers.. An Excel-based model was utilized to estimate the relevant costs. Clinical data were obtained from the EMILIA trial. Cost information was obtained from the literature, clinical experts, and standard cost sources. The analysis was conducted from the Canadian public-payer perspective and reported in 2014 Canadian dollars (CAD).. The management of included treatment-related AEs resulted in higher estimated per-patient costs of CAD6901 for CAP + LAP versus CAD3380 for T-DM1, resulting in savings of CAD3521.. From a Canadian perspective, this analysis demonstrated that utilizing T-DM1 for the management of HER2-positive metastatic breast cancer results in substantial savings to the public health-care system when considering the costs of treatment-related AEs, due to fewer amount of toxicities compared with CAP + LAP. Results of various sensitivity analyses investigating changes in number and costs of AEs confirmed the findings; however, the magnitude of cost savings varied. Further analyses are necessary to determine whether these cost savings would occur in other countries and health-care systems.

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Canada; Capecitabine; Delivery of Health Care; Female; Health Care Costs; Humans; Lapatinib; Maytansine; Middle Aged; Neoplasm Metastasis; Quinazolines; Receptor, ErbB-2; Trastuzumab

To compare results of trastuzumab-emtansine (T-DM1) treatment in our clinical practice with data from phase III clinical trials.. A retrospective chart review of all 23 patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer who were started on T-DM1 until April 2014 was performed.. Four patients (17.4%) received T-DM1 as first-line, three (13.0%) as second-line, six (26.0%) as third-line, and 10 (43.5%) as fifth- or further-line therapy. Overall, the response rate (ORR) was 26.0%, disease control rate 78.3% and median progression-free survival (PFS) 8.4 months. The only toxicities of grade 3 or more were fatigue (21.7%), thrombocytopenia (4.3%) and elevation of liver enzymes (8.7%). ORR and PFS were similar to the TH3RESA and EMILIA trials. Compared to the EMILIA study, we recorded higher rates of newly-diagnosed cerebral metastasis and cerebral progression in patients with stable peripheral metastases.. T-DM1 is effective and well-tolerated even in intensively pre-treated patients.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Cohort Studies; Disease Progression; Female; Humans; Kaplan-Meier Estimate; Maytansine; Middle Aged; Neoplasm Metastasis; Practice Patterns, Physicians'; Receptor, ErbB-2; Trastuzumab; Treatment Outcome

A 51-year-old woman had previously received treatment for breast cancer at another hospital but had refused early and aggressive treatment. Therefore, she was treated with symptomatic therapy. As her disease progressed, the patient wished to receive palliative care, and was transferred to a palliative care hospital. However, based on her general condition, it was determined that aggressive treatment should not be abandoned, and she was referred to our hospital for treatment. During her initial visit, the patient was found to have left breast cancer with chest wall invasion, right breast metastasis, multiple liver and lung metastases, left pleural effusion accompanied by pleural dissemination, and left upper limb edema. There was no evidence of bone metastases. The patient's pain was managed with oral oxycodone sustained-release tablets (320 mg daily), using high-dose (80 mg) oral oxycodone hydrochloride hydrate as rescue medication. The results of immunohistochemical testing, confirmed by her previous hospital, were ER (-), PgR (-) and HER2/neu positive. First-line treatment was initiated with paclitaxel (PTX) plus trastuzumab (Tmab), and the response was rated as stable disease (SD). During the course of treatment, she developed drug-induced interstitial pneumonia, which was probably caused by the taxane. Therefore, the first-line treatment was discontinued and T-DM1 was initiated as second-line treatment. However, beginning with cycle 3 of the T-DM1 treatment, the patient began complaining of joint pain, mainly in the upper limbs. Therefore, the dose of oxycodone sustained-release tablets was increased to 600 mg per day. However, the patient's joint pain showed no improvement and it was considered unlikely that the pain was due to bone metastases. It was suspected that the pain was an adverse reaction to T-DM1, and the dose of T-DM1 was reduced by one step in cycle 7 of treatment. This resulted in a dramatic improvement of the patient's symptoms. Since oxycodone sustained-release tablets was being used at a high dose, sleepiness caused by the drug interfered with her activities of daily living. Consequently, as part of an opioid rotation scheme, topical fentanyl citrate was used concomitantly, and the initial daily oxycodone sustained-release tablets dose of 600 mg was reduced to 40 mg and administered in combination with fentanyl citrate (12mg). These findings suggest that uncontrollable joint pain can occur as an adverse reaction to T-DM1.

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Arthralgia; Breast Neoplasms; Female; Humans; Maytansine; Middle Aged; Neoplasm Metastasis; Oxycodone; Trastuzumab

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) therapeutic for treatment of human epidermal growth factor receptor 2 (HER2)-positive cancers. The T-DM1 dose product contains a mixture of drug-to-antibody ratio (DAR) moieties whereby the small molecule DM1 is chemically conjugated to trastuzumab antibody. The pharmacokinetics (PK) underlying this system and other ADCs are complex and have not been elucidated. Accordingly, we have developed two PK modeling approaches from preclinical data to conceptualize and understand T-DM1 PK, to quantify rates of DM1 deconjugation, and to elucidate the link between trastuzumab, T-DM1, and DAR measurements. Preclinical data included PK studies in rats (n = 34) and cynomolgus monkeys (n = 18) at doses ranging from 0.3 to 30 mg/kg and in vitro plasma stability. T-DM1 and total trastuzumab (TT) plasma concentrations were measured by enzyme-linked immunosorbent assay. Individual DAR moieties were measured by affinity capture liquid chromatography-mass spectrophotometry. Two PK modeling approaches were developed for T-DM1 using NONMEM 7.2 software: a mechanistic model fit simultaneously to TT and DAR concentrations and a reduced model fit simultaneously to TT and T-DM1 concentrations. DAR moieties were well described with a three-compartmental model and DM1 deconjugation in the central compartment. DM1 deconjugated fastest from the more highly loaded trastuzumab molecules (i.e., DAR moieties that are ≥3 DM1 per trastuzumab). T-DM1 clearance (CL) was 2-fold faster than TT CL due to deconjugation. The two modeling approaches provide flexibility based on available analytical measurements for T-DM1 and a framework for designing ADC studies and PK-pharmacodynamic modeling of ADC efficacy- and toxicity-related endpoints.

Topics: Ado-Trastuzumab Emtansine; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Biotransformation; Breast Neoplasms; Chromatography, Liquid; Drug Stability; Female; Humans; Injections, Intravenous; Macaca fascicularis; Male; Mass Spectrometry; Maytansine; Models, Biological; Neoplasm Metastasis; Rats; Rats, Sprague-Dawley; Receptor, ErbB-2; Reproducibility of Results; Trastuzumab

Treatment of HER2-positive metastatic breast cancer with ado-trastuzumab emtansine (T-DM1), a novel antibody-drug conjugate, has resulted in both improved progression-free and overall survival. Recognition and treatment of diverse adverse events related to T-DM1 is critical for safety and tolerability. The most frequent adverse events with T-DM1 include fatigue, diarrhea, anemia, elevated transaminases, and mild-to-moderate hemorrhagic events, which are thought to be related to induced thrombocytopenia. Here, we present five case series of cutaneous and mucosal telangiectasias, definitely related to T-DM1. The development of telangiectasias represents a newly recognized adverse effect of T-DM1. We provide description and timing of the telangiectasias and review the mechanisms that may explain the formation of these vascular lesions in association with T-DM1. Further, we describe associated bleeding events and propose that induced telangiectasias could represent an additional cause of T-DM1-associated hemorrhage.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Female; Humans; Maytansine; Middle Aged; Neoplasm Metastasis; Skin; Telangiectasis; Trastuzumab

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.. 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.. Among 884 T-DM1-exposed patients, the most commonly reported all-grade AEs were fatigue (46.4%), nausea (43.0%), thrombocytopenia (32.2%), headache (29.4%), and constipation (26.5%). The most common grade 3 to 4 AEs were the laboratory abnormalities of thrombocytopenia (11.9%) and increased AST serum concentration (4.3%). These were manageable and not generally associated with clinical symptoms. There were 12 AE-related deaths. AEs resulted in dose reductions in 17.2% of patients and drug discontinuations in 7.0%.. In this analysis of 884 T-DM1-exposed patients, grade 3 or greater AEs were infrequent and typically asymptomatic and manageable. This favorable safety profile makes T-DM1 treatment suitable for exploration in other breast cancer settings.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Female; Humans; Maytansine; Middle Aged; Neoplasm Metastasis; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Trastuzumab; Treatment Outcome

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Breast Neoplasms; Drug Administration Schedule; Drug Interactions; Female; Humans; Infusions, Intravenous; Maytansine; Neoplasm Metastasis; Receptor, ErbB-2; Trastuzumab; United States

Increased understanding of the molecular composition of breast cancer tumors has led to the development of targeted anticancer agents. Novel therapies directed against human epidermal growth factor receptor 2 (HER2) in breast cancer have been developed. One such agent, trastuzumab emtansine (T-DM1), is an antibody drug conjugate that has been shown to be effective in the treatment of women with HER2-positive breast cancer. Phase I and II studies have determined a maximum tolerated dose, and several phase Ib/II, II, and III studies have shown improved tolerability and efficacy compared with the combination of trastuzumab and chemotherapy. The most concerning grade 3 or higher adverse events associated with T-DM1 include thrombocytopenia and transaminitis. To ensure that these adverse events do not delay or interrupt treatment, oncology nurses need to familiarize themselves with these risks and their management. This article reviews the clinical development of T-DM1 and its usage, with a focus on the nurse's role in preventing and managing adverse events associated with T-DM1 therapy.

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Female; Humans; Maytansine; Neoplasm Metastasis; Trastuzumab

Topics: Adolescent; Adult; Aged; Drug Evaluation; Female; Humans; Male; Maytansine; Middle Aged; Neoplasm Metastasis; Oxazines; Sarcoma

Topics: Adenocarcinoma; Adult; Aged; Carcinoma; Drug Evaluation; Female; Humans; Lung Neoplasms; Male; Maytansine; Middle Aged; Neoplasm Metastasis; Oxazines