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2.
Am J Clin Oncol ; 44(7): 340-349, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34151896

RESUMO

OBJECTIVE: Ado-trastuzumab emtansine (T-DM1) was recently approved for patients with human epidermal growth factor receptor 2 positive (HER2+) early breast cancer (eBC) with residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment. Cost-effectiveness analysis was conducted to compare T-DM1 versus trastuzumab in the United States. MATERIALS AND METHODS: A Markov cohort-based model tracked clinical and economic outcomes over a lifetime horizon from a US payer perspective. The model included 6 health states: invasive disease-free, nonmetastatic (locoregional) recurrence, remission, first-line and second-line metastatic BC and death. Model state transitions were based on statistical extrapolation of the head-to-head KATHERINE study and published sources. Dosing and treatment duration reflected prescribing information and trials. Costs (2019 US dollars) associated with pharmaceutical treatment (wholesale acquisition costs), health state specific care, adverse events, and end-of-life care were included. Health state utilities were obtained from KATHERINE and published literature. RESULTS: T-DM1 dominated trastuzumab, yielding lower lifetime costs (-$40,271), and higher life-years (2.980) and quality-adjusted life-years (2.336). Results were driven by patients receiving T-DM1 spending less time in more costly downstream health states, as these patients are less likely to experience a recurrence overall, despite having a higher likelihood of metastatic disease (distant recurrence) in the subset of patients who experience recurrence. Probabilistic sensitivity analysis indicated robust results, with 96.7% of 5000 stochastic simulations producing dominance for T-DM1. The most influential variables were related to treatment costs, off treatment utilities, and health state costs. Additional scenario analyses tested a range of model inputs and assumptions, and produced consistent results. CONCLUSION: Relative to trastuzumab, T-DM1 treatment for patients with HER2+ eBC who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment is likely to reduce the overall financial burden of cancer, while simultaneously improving patient outcomes.


Assuntos
Ado-Trastuzumab Emtansina/economia , Ado-Trastuzumab Emtansina/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante/economia , Ado-Trastuzumab Emtansina/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/economia , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/economia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Análise Custo-Benefício , Custos de Medicamentos , Feminino , Humanos , Recidiva Local de Neoplasia , Qualidade de Vida , Trastuzumab/efeitos adversos , Trastuzumab/economia , Trastuzumab/uso terapêutico , Estados Unidos
3.
Breast Cancer Res Treat ; 189(1): 103-110, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34120223

RESUMO

PURPOSE: Chemotherapy-related amenorrhea (CRA) is a surrogate for ovarian toxicity and associated risk of infertility and premature menopause. Here, we compare CRA rate with paclitaxel (T)-trastuzumab (H) to that with ado-trastuzumab emtansine (T-DM1). METHODS: Patients with T1N0 HER2 + early-stage breast cancer (eBC) enrolled on the ATEMPT trial and were randomized 3:1 to T-DM1 3.6 mg/kg IV every (q) 3 weeks (w) × 17 vs. T 80 mg/m2 with H IV qw × 12 (4 mg/kg load → 2 mg/kg), followed by H (6 mg/kg IV q3w × 13). Enrollees who self-reported as premenopausal were asked to complete menstrual surveys at baseline and every 6-12 months for 60 months. 18-month CRA (no periods reported during prior 6 months on 18-month survey) was the primary endpoint of this analysis. RESULTS: Of 512 ATEMPT enrollees, 123 who began protocol therapy and answered baseline and at least one follow-up menstrual survey were premenopausal at enrollment. 76 had menstrual data available at 18 months without having received a gonadotropin-releasing hormone agonist or undergone hysterectomy and/or oophorectomy. Median age was 45 (range 23-53) among 18 who had received TH and 46 (range 34-54) among 58 who had received T-DM1. The 18-month rate of CRA was 50% after TH and 24% after T-DM1 (p = 0.045). CONCLUSION: Amenorrhea at 18 months was less likely in recipients of adjuvant T-DM1 than TH. Future studies are needed to understand how T-DM1 impacts risk of infertility and permanent menopause, and to assess amenorrhea rates when T-DM1 is administered after standard HER2-directed chemotherapy regimens.


Assuntos
Neoplasias da Mama , Maitansina , Ado-Trastuzumab Emtansina/efeitos adversos , Adulto , Amenorreia/induzido quimicamente , Amenorreia/epidemiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Maitansina/efeitos adversos , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Paclitaxel/uso terapêutico , Receptor ErbB-2/genética , Trastuzumab/efeitos adversos , Adulto Jovem
4.
Cancer Invest ; 39(6-7): 473-481, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34014777

RESUMO

AIM: The aim of this study is to evaluate the efficacy and toxicity of trastuzumab emtansine (T-DM1) in cases with metastatic breast cancer (mBC) in different lines of treatment. METHOD: Retrospective analysis of T-DM1 results of human epidermal growth factor receptor 2 (Her2) positive 414 cases with mBC from 31 centers in Turkey. FINDINGS: Except 2, all of the cases were female with a median age of 47. T-DM1 had been used as second-line therapy in 37.7% of the cases and the median number of T-DM1 cycles was 9. Progression-free survival (PFS) and overall survival (OS) times were different according to the line of treatment. The median OS was found as 43, 41, 46, 23 and 17 months for 1st, 2nd, 3rd, 4th and 5th line, respectively (p = 0.032) while the median PFS was found as 37, 12, 8, 8 and 8 months, respectively (p = 0.0001). Treatment was well tolerated by the patients. The most common grade 3-4 adverse effects were thrombocytopenia (2.7%) and increased serum gamma-glutamyl transferase (2%). DISCUSSION: The best of our knowledge this is the largest real-life experience about the safety and efficacy of T-DM1 use in cases with mBC after progression of Her2 targeted treatment. This study suggests and supports that T-DM1 is more effective in earlier lines of treatment and is a reliable option for mBC.


Assuntos
Ado-Trastuzumab Emtansina/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Ado-Trastuzumab Emtansina/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Receptor ErbB-2/genética , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Turquia
5.
BMC Cancer ; 21(1): 223, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33663447

RESUMO

BACKGROUND: Due to recent concerns about the toxicity of trastuzumab emtansine (T-DM1) with stereotactic radiation, we assessed our institutional outcomes treating HER2-positive breast cancer brain metastases (BCBM) with T-DM1 and stereotactic radiation. METHODS: This is a single institution series of 16 patients with HER2-positive breast cancer who underwent 18 stereotactic sessions to 40 BCBM from 2013 to 2019 with T-DM1 delivered within 6 months. The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), distant intracranial control (DIC), and systemic progression-free survival (sPFS) from the date of SRS. A neuro-radiologist independently reviewed follow-up imaging. RESULTS: One patient had invasive lobular carcinoma, and 15 patients had invasive ductal carcinoma. All cases were HER2-positive, while 10 were hormone receptor (HR) positive. Twenty-four lesions were treated with stereotactic radiosurgery (SRS) to a median dose of 21 Gy (14-24 Gy). Sixteen lesions were treated with fractionated stereotactic radiation (FSRT) with a median dose of 25 Gy (20-30Gy) delivered in 3 to 5 fractions. Stereotactic radiation was delivered concurrently with T-DM1 in 19 lesions (48%). Median follow up time was 13.2 months from stereotactic radiation. The 1-year LC, DIC, sPFS, and OS were 75, 50, 30, and 67%, respectively. There was 1 case of leptomeningeal progression and 1 case (3%) of symptomatic radionecrosis. CONCLUSIONS: We demonstrate that stereotactic radiation and T-DM1 is well-tolerated and effective for patients with HER2-positive BCBM. An increased risk for symptomatic radiation necrosis was not noted in our series.


Assuntos
Ado-Trastuzumab Emtansina/uso terapêutico , Neoplasias Encefálicas/secundário , Neoplasias da Mama/terapia , Radiocirurgia , Receptor ErbB-2/análise , Ado-Trastuzumab Emtansina/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/patologia , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Terapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Necrose , Radiocirurgia/efeitos adversos , Dosagem Radioterapêutica
6.
J Oncol Pharm Pract ; 27(3): 547-554, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32423326

RESUMO

BACKGROUND: Ado-trastuzumab emtansine is an antibody-drug conjugate that combines the cytotoxic activity of emtansine with human epidermal growth factor receptor 2-targeted antitumor features of trastuzumab. OBJECTIVE: We conducted a study of metastatic breast cancer patients treated with trastuzumab emtansine. By evaluating progression-free survival, overall survival, and response rates, we aimed to find prognostic factors of trastuzumab emtansine treatment. METHODS: Our study is a single-center, retrospective, observational study. We have clinical data from 78 patients treated with trastuzumab emtansine for metastatic breast cancer, from May 2016 through May 2019, at Kartal Dr Lutfi Kirdar Education and Research Hospital, Medical Oncology Department. Our objective is to assess the survival and response rates in trastuzumab emtansine-treated individuals and the factors associated with survival. The factors we analyzed were cancer antigen 15-3 sensitivity, Eastern Cooperative Oncology Group-Performance Status, presence or absence of visceral metastases, presence or absence of cranial metastases, and treatment-associated thrombocytopenia. RESULTS: Among 78 patients, median progression-free survival was 7.8 months, and overall survival was 21.1 months. Twenty of the patients had an objective tumor response. The results showed that trastuzumab emtansine was tolerable with a manageable safety profile and consistent with the results of the previous literature. Mostly seen adverse events were anemia, thrombocytopenia, fatigue, and increased levels of alkaline phosphatase. Patients with Eastern Cooperative Oncology Group-Performance Status = 2 had worse progression-free survival and overall survival compared to ones with Eastern Cooperative Oncology Group-Performance Status < 2; progression-free survival and overall survival are worse in cancer antigen 15-3-sensitive breast cancer patients. According to our findings, treatment-associated thrombocytopenia was a significant prognostic factor for survival. Patients with thrombocytopenia had 12 months progression-free survival, whereas patients without thrombocytopenia had only 4.1 months progression-free survival. In like manner, overall survival was much better in the thrombocytopenia-experienced patients as 29.5 versus 11.8 months. CONCLUSIONS: Trastuzumab emtansine prolongs progression-free survival and overall survival with a manageable safety profile. Thrombocytopenia, Eastern Cooperative Oncology Group-Performance Status, and cancer antigen 15-3 are correlated with progression-free survival and/or overall survival.


Assuntos
Ado-Trastuzumab Emtansina/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/genética , Ado-Trastuzumab Emtansina/efeitos adversos , Idoso , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias da Mama/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mucina-1/genética , Metástase Neoplásica , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Análise de Sobrevida , Trombocitopenia/induzido quimicamente , Resultado do Tratamento
7.
Strahlenther Onkol ; 197(1): 1-7, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32737515

RESUMO

PURPOSE: Following neoadjuvant chemotherapy for breast cancer, postoperative systemic therapy, also called post-neoadjuvant treatment, has been established in defined risk settings. We reviewed the evidence for sequencing of postoperative radiation and chemotherapy, with a focus on a capecitabine and trastuzumab emtansine (T-DM1)-based regimen. METHODS: A systematic literature search using the PubMed/MEDLINE/Web of Science database was performed. We included prospective and retrospective reports published since 2015 and provided clinical data on toxicity and effectiveness. RESULTS: Six studies were included, five of which investigated capecitabine-containing regimens. Of these, four were prospective investigations and one a retrospective matched comparative analysis. One randomized prospective trial was found for T­DM1 and radiotherapy. In the majority of these reports, radiation-associated toxicities were not specifically addressed. CONCLUSION: Regarding oncologic outcome, the influence of sequencing radiation therapy with maintenance capecitabine chemotherapy in the post-neoadjuvant setting is unclear. Synchronous administration of capecitabine is feasible, but reports on possible excess toxicities are partially conflicting. Dose reduction of capecitabine should be considered, especially if normofractionated radiotherapy is used. In terms of tolerance, hypofractionated schedules seem to be superior in terms of toxicity in concurrent settings. T­DM1 can safely be administered concurrently with radiotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Ado-Trastuzumab Emtansina/administração & dosagem , Ado-Trastuzumab Emtansina/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/radioterapia , Capecitabina/administração & dosagem , Capecitabina/efeitos adversos , Cardiomiopatias/induzido quimicamente , Ensaios Clínicos como Assunto , Terapia Combinada , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Humanos , Estudos Multicêntricos como Assunto , Terapia Neoadjuvante , Estudos Prospectivos , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
8.
Am J Clin Oncol ; 43(12): 895-901, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33027084

RESUMO

OBJECTIVES: The treatment of nonmetastatic HER2-positive breast cancer with residual invasive disease using concurrent Trastuzumab emtansine (T-DM1) and radiotherapy appears to be an effective option. Our aim was to evaluate the acute side effects of this treatment regime. METHODS: Fourteen patients were treated between March 2019 and April 2020 concurrent T-DM1 and radiotherapy. Left ventricular ejection fraction was assessed at baseline, before and after radiotherapy. All toxicities were evaluated using Common Terminology Criteria of Adverse Events (CTCAE) version 3.0. RESULTS: The median age was 55 years (range 36 to 72). All patients received total dose of 50 Gy for the breast/ chest wall, 10 patients got lymph node irradiation, 4 patients received an additional tumor bed boost. The most common side effect was grade 1 radiodermatitis. A reversible grade 2 left ventricular ejection fraction decrease occurred in 2 patients. During our examination 3 patients showed alanine aminotransferases increase after the cycle 4 of T-DM1, 1 patient had grade 1, 1 patient grade 2, and 1 patient grade 3 alanine aminotransferase increases. CONCLUSIONS: The acute toxicity rate especially focusing on skin and cardiac toxicity were assumed acceptable in our cohort. To safely administer this concomitant treatment, further examination and prospective data are needed.


Assuntos
Ado-Trastuzumab Emtansina/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/radioterapia , Quimiorradioterapia/efeitos adversos , Ado-Trastuzumab Emtansina/administração & dosagem , Ado-Trastuzumab Emtansina/efeitos adversos , Adulto , Idoso , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Quimiorradioterapia/métodos , Fracionamento da Dose de Radiação , Feminino , Humanos , Pessoa de Meia-Idade , Radiodermatite/etiologia , Receptor ErbB-2/metabolismo , Resultado do Tratamento , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/efeitos da radiação
9.
Mol Cancer Ther ; 19(9): 1866-1874, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32651200

RESUMO

Trastuzumab and the related ADC, ado-trastuzumab emtansine (T-DM1), both target HER2-overexpressing cells. Together, these drugs have treatment indications in both early-stage and metastatic settings for HER2+ breast cancer. T-DM1 retains the antibody functionalities of trastuzumab and adds the potency of a cytotoxic maytansine payload. Interestingly, in the clinic, T-DM1 cannot always replace the use of trastuzumab plus chemotherapy administered together as single agents. We hypothesize that this failure may be due, in part, to the limited systemic exposure achieved by T-DM1 relative to trastuzumab because of toxicity-related dosing constraints on the ADC. We have developed a trastuzumab-based ADC site specifically conjugated to maytansine through a noncleavable linker. This construct, termed CAT-01-106, has a drug-to-antibody ratio (DAR) of 1.8, approximately half the average DAR of T-DM1, which comprises a mixture of antibodies variously conjugated with DARs ranging from 0 to 8. The high DAR species present in T-DM1 contribute to its toxicity and limit its clinical dose. CAT-01-106 showed superior in vivo efficacy compared with T-DM1 at equal payload dosing and was equally or better tolerated compared with T-DM1 at equal payload dosing up to 120 mg/kg in Sprague-Dawley rats and 60 mg/kg in cynomolgus monkeys. CAT-01-106 also showed improved pharmacokinetics in rats relative to T-DM1, with 40% higher ADC exposure levels. Together, the data suggest that CAT-01-106 may be sufficiently tolerable to enable clinical dosing at trastuzumab-equivalent exposure levels, combining the functions of both the antibody and the payload in one drug and potentially improving patient outcomes.


Assuntos
Ado-Trastuzumab Emtansina/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Imunoconjugados/administração & dosagem , Maitansina/química , Trastuzumab/química , Ado-Trastuzumab Emtansina/efeitos adversos , Ado-Trastuzumab Emtansina/farmacocinética , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/química , Imunoconjugados/farmacocinética , Macaca fascicularis , Dose Máxima Tolerável , Ratos , Ratos Sprague-Dawley , Receptor ErbB-2/metabolismo , Trastuzumab/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Curr Opin Oncol ; 32(5): 494-502, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32657795

RESUMO

PURPOSE OF REVIEW: Antibody-drug conjugates (ADCs) represent an interesting new class of anticancer agents, capable of exploiting the specificity of monoclonal antibodies toward cellular-antigens for a targeted release of potent cytotoxic drugs, with a potential increased activity and reduced toxicity compared with traditional chemotherapies. The aim of this article is to review the efficacy and safety of ADCs in breast cancer. RECENT FINDINGS: Following the approval of T-DM1 both in early and advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer, novel anti-HER2 ADCs have been investigated. Some of these compounds, such as the recently FDA-approved trastuzumab deruxtecan, have shown relevant activity in T-DM1-pretreated patients, possibly thanks to the so-called bystander effect, namely the ability to exert cytotoxic activity also against antigen-negative cells. Such feature allows to overcome the HER2 intratumoral heterogeneity in breast cancer and could explain in the preliminary activity demonstrated also in HER2-low breast cancers. However, several ADCs targeting other cancer-associated antigens than HER2 are under development, representing a promising strategy for the treatment of triple-negative tumors, exemplified by the encouraging results of sacituzumab govitecan. SUMMARY: ADCs are innovative and effective therapeutic drugs in breast cancer. Research efforts are ongoing to identify novel targets and combination with other treatment modalities, particularly with immunotherapy, to further improve patients' outcomes.


Assuntos
Neoplasias da Mama/imunologia , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Ado-Trastuzumab Emtansina/efeitos adversos , Ado-Trastuzumab Emtansina/imunologia , Ado-Trastuzumab Emtansina/farmacologia , Ado-Trastuzumab Emtansina/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Ensaios Clínicos como Assunto , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/metabolismo
11.
Cancer Treat Res Commun ; 24: 100188, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32619830

RESUMO

BACKGROUND: Ado-trastuzumab emtansine (T-DM1) is standard of care for patients with advanced HER2+ breast cancer who relapse within 6 months of adjuvant trastuzumab or progress on first-line anti-HER2 therapy. We evaluated its safety and efficacy in our real-world population. METHODS: We identified patients on T-DM1 from 01/01/2014 to 12/03/2018 from our electronic records. Patients', tumour characteristics, safety and efficacy outcomes were recorded. Chi-squared/Fishers exact test and Kaplan-Meier methods were utilised. RESULTS: 128 patients receiving T-DM1 were included in the analysis with a median age of 55 years (26-85). 89.8% of patients had ECOG PS 0-1 and 21.1% had presented with de novo metastatic disease. 57.8% had ER-positive disease and 38.3% central nervous system involvement. 88.3% of patients had received trastuzumab for advanced disease (with pertuzumab in 28.9%) and 11.7% had only received trastuzumab in the adjuvant setting. Grade ≥3 adverse events occurred in 35.9% of patients. These were liver toxicity (19.5%), anaemia (6.2%) and thrombocytopenia (4.7%). Peripheral neuropathy of any grade was reported in 21.9% of cases, bleeding in 9.4% and ejection fraction decline in 5 patients. Median progression-free survival was 8.7 months and overall survival 20.4 months. Prior pertuzumab did not influence survival outcomes. CONCLUSIONS: The safety of T-DM1 in our population is similar to available literature, although we observed higher rates of peripheral neuropathy and deranged liver function. These findings are relevant for the potential role of TDM-1 in the curative setting.


Assuntos
Ado-Trastuzumab Emtansina/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/terapia , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Recidiva Local de Neoplasia/epidemiologia , Doenças do Sistema Nervoso Periférico/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Mama/patologia , Mama/cirurgia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Feminino , Humanos , Mastectomia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controle , Estadiamento de Neoplasias , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Intervalo Livre de Progressão , Receptor ErbB-2/análise , Receptor ErbB-2/metabolismo , Estudos Retrospectivos , Reino Unido/epidemiologia
12.
Breast Cancer Res Treat ; 183(1): 23-39, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32591987

RESUMO

PURPOSE: Anti-human epidermal growth factor receptor 2 (HER2) therapies are associated with interstitial lung disease (ILD), also referred to as pneumonitis. In this literature review, we describe the incidence of ILD among patients with HER2-positive metastatic breast cancer (MBC) receiving anti-HER2 therapies, and we describe existing recommendations for monitoring and managing drug-induced ILD among these patients. METHODS: We searched PubMed and Embase to identify clinical trials and postmarket observational studies that investigated anti-HER2 therapies for HER2-positive MBC, reported on ILD, and were published during January 1, 2009 to July 15, 2019. Articles were screened by two researchers; data were extracted from the full-text articles. RESULTS: The 18 articles selected for this review assessed 9,886 patients who received trastuzumab (8 articles), lapatinib (4 articles), trastuzumab emtansine (3 articles), trastuzumab deruxtecan (2 articles), or trastuzumab duocarmazine (1 article). The overall incidence of all-grade ILD was 2.4% (n = 234), with 66.7% (n = 156) occurring as grade 1-2 events, 0.5% grade 3-4 (n = 54; incidence), and 0.2% grade 5 (n = 16; incidence). The highest ILD incidence (21.4%) was among patients receiving trastuzumab combined with everolimus and paclitaxel. Ten studies indicated that ILD events were managed via dose interruption, dose reduction, or treatment discontinuation; two studies included detailed guidelines on managing drug-induced ILD. CONCLUSIONS: ILD is a well-described adverse drug reaction associated with several anti-HER2 drugs. Published ILD management guidelines are available for few anti-HER2 treatment regimens; however, guidance for monitoring for anti-HER2 drug-induced ILD is lacking.


Assuntos
Ado-Trastuzumab Emtansina/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Camptotecina/análogos & derivados , Imunoconjugados/efeitos adversos , Doenças Pulmonares Intersticiais/induzido quimicamente , Pneumonia/induzido quimicamente , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/efeitos adversos , Ado-Trastuzumab Emtansina/administração & dosagem , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Gerenciamento Clínico , Monitoramento de Medicamentos , Everolimo/administração & dosagem , Feminino , Humanos , Imunoconjugados/administração & dosagem , Incidência , Lapatinib/efeitos adversos , Doenças Pulmonares Intersticiais/epidemiologia , Metástase Neoplásica , Paclitaxel/administração & dosagem , Pneumonia/epidemiologia , Receptor ErbB-2/análise , Trastuzumab/administração & dosagem
13.
Biomed Pharmacother ; 129: 110407, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32570117

RESUMO

PURPOSE: Human epidermal growth factor receptor 2 (HER2) is overexpressed in 15-20% of patients with breast cancer. HER2 overexpression is the result of a genetic alteration and this marker is associated with poor clinical outcomes. HER2-targeted therapy can significantly improve the prognosis of patients with either early or advanced HER2-positive breast cancer. One such therapy is the antibody drug conjugate (ADC) trastuzumab emtansine (T-DM1), a combination of trastuzumab and the cytotoxic antimicrotubule agent DM1. After T-DM1 binds HER2, DM1 is subsequently released into the cell. T-DM1 is generally well tolerated and has a relatively low incidence of adverse events. However, there are clinical concerns regarding T-DM1-induced high-grade thrombocytopenia. METHODS: Here, we summarize the incidence of thrombocytopenia from several clinical trials and review experimental studies to explore the causes for T-DM1-induced thrombocytopenia. Progress in several other ADCs targeting HER2-positive breast cancer was also reviewed. CONCLUSIONS: We conclude that T-DM1 uptake by megakaryocytes occurs through either Fcγ receptor binding or through pinocytosis, and we suggest several methods through which these processes could be interrupted to potentially improve the clinical safety of T-DM1. More generally, we recommend that toxicity should be carefully addressed during the development of ADCs.


Assuntos
Ado-Trastuzumab Emtansina/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Imunoconjugados/efeitos adversos , Megacariócitos/efeitos dos fármacos , Trombocitopenia/induzido quimicamente , Ado-Trastuzumab Emtansina/sangue , Animais , Antineoplásicos Imunológicos/sangue , Feminino , Humanos , Imunoconjugados/sangue , Incidência , Megacariócitos/metabolismo , Pinocitose , Receptores de IgG/sangue , Trombocitopenia/sangue , Trombocitopenia/diagnóstico , Trombocitopenia/epidemiologia , Resultado do Tratamento
14.
JAMA Oncol ; 6(8): 1203-1209, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32584367

RESUMO

Importance: ERBB2 (HER2)-targeted therapy provides benefits in metastatic breast cancer (mBC) and gastric cancer, but additional treatments are needed to maximize efficacy and quality of life. Objective: To determine maximum tolerated doses (MTDs) of trastuzumab emtansine (T-DM1) plus capecitabine in patients with previously treated ERBB2-positive mBC and locally advanced/metastatic gastric cancer (LA/mGC) (phase 1) and the efficacy and safety of this combination vs T-DM1 alone in patients with mBC (phase 2). Design, Setting, and Participants: The MTD in phase 1 was assessed using a 3 + 3 design with capecitabine dose modification. Phase 2 was an open-label, randomized, international multicenter study of patients with mBC treated with T-DM1 plus capecitabine or T-DM1 alone. Eligible patients had previously treated ERBB2-positive mBC or LA/mGC with no prior chemotherapy treatment for advanced disease. Interventions: Patients in the phase 1 mBC cohort received capecitabine (750 mg/m2, 700 mg/m2, or 650 mg/m2 twice daily, days 1-14 of a 3-week cycle) plus T-DM1 3.6 mg/kg every 3 weeks. Patients with LA/mGC received capecitabine at the mBC phase 1 MTD, de-escalating as needed, plus T-DM1 2.4 mg/kg weekly. In phase 2, patients with mBC were randomized (1:1) to receive capecitabine (at the phase 1 MTD) plus T-DM1 or T-DM1 alone. Main Outcomes and Measures: The phase 1 primary objective was to identify the MTD of capecitabine plus T-DM1. The phase 2 primary outcome was investigator-assessed overall response rate (ORR). Results: In phase 1, the median (range) age was 54.0 (37-71) and 57.5 (53-70) years for patients with mBC and patients with LA/mGC, respectively. The capecitabine MTD was identified as 700 mg/m2 in 11 patients with mBC and 6 patients with LA/mGC evaluable for dose-limiting toxic effects. In phase 2, between October 2014 and April 2016, patients with mBC (median [range] age, 52.0 [28-80] years) were randomized to receive combination therapy (n = 81) or T-DM1 (n = 80). The ORR was 44% (36 of 81 patients) and 36% (29 of 80 patients) in the combination and T-DM1 groups, respectively (difference, 8.2%; 90% CI, -4.5 to 20.9; P = .34; clinical cutoff, May 31, 2017). Adverse events (AEs) were reported in 78 of 82 patients (95%) in the combination group, with 36 (44%) experiencing grade 3-4 AEs, and 69 of 78 patients (88%) in the T-DM1 group, with 32 (41%) experiencing grade 3-4 AEs. No grade 5 AEs were reported. Conclusions and Relevance: Adding capecitabine to T-DM1 did not statistically increase ORR associated with T-DM1 in patients with previously treated ERBB2-positive mBC. The combination group reported more AEs, but with no unexpected toxic effects. Trial Registration: ClinicalTrials.gov Identifier: NCT01702558.


Assuntos
Ado-Trastuzumab Emtansina/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Capecitabina/administração & dosagem , Ado-Trastuzumab Emtansina/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptor ErbB-2 , Resultado do Tratamento
15.
J Clin Pharm Ther ; 45(4): 832-835, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32412114

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Trastuzumab-emtansine is an antibody-drug conjugate developed to decrease off-target toxicity. According to the product label, reactions secondary to extravasation are mild or moderate. CASE SUMMARY: We report on a 51-year-old woman who developed epidermal necrosis after extravasation of trastuzumab-emtansine, which required surgical intervention. Six weeks later, the lesions were healed with residual hyperpigmentation. WHAT IS NEW AND CONCLUSION: We describe the course of a case of severe toxicity following trastuzumab-emtansine extravasation. We provide treatment recommendations and recommend amending the information on the product label on extravasation.


Assuntos
Ado-Trastuzumab Emtansina/efeitos adversos , Antineoplásicos/efeitos adversos , Epiderme/patologia , Extravasamento de Materiais Terapêuticos e Diagnósticos/complicações , Imunoconjugados/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Necrose
16.
Cancer ; 126(13): 3132-3139, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32286687

RESUMO

BACKGROUND: The phase 3 KATHERINE trial demonstrated significantly improved invasive disease-free survival with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab in patients with HER2-positive early breast cancer and residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy. METHODS: Patients who received taxane- and trastuzumab-containing neoadjuvant therapy (with/without anthracyclines) and had residual invasive disease (breast and/or axillary nodes) at surgery were randomly assigned to 14 cycles of adjuvant T-DM1 (3.6 mg/kg intravenously every 3 weeks) or trastuzumab (6 mg/kg intravenously every 3 weeks). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) and breast cancer module (QLQ-BR23) were completed at screening, at day 1 of cycles 5 and 11, within 30 days after study drug completion, and at 6- and 12-month follow-up visits. RESULTS: Of patients who were randomly assigned to T-DM1 (n = 743) and trastuzumab (n = 743), 612 (82%) and 640 (86%), respectively, had valid baseline and ≥1 postbaseline assessments. No clinically meaningful changes (≥10 points) from baseline in mean QLQ-C30 and QLQ-BR23 scores occurred in either arm. More patients receiving T-DM1 reported clinically meaningful deterioration at any assessment point in role functioning (49% vs 41%), appetite loss (38% vs 28%), constipation (47% vs 38%), fatigue (66% vs 60%), nausea/vomiting (39% vs 30%), and systemic therapy side effects (49% vs 36%). These differences were no longer apparent at the 6-month follow-up assessment, except for role functioning (23% vs 16%). CONCLUSION: These data suggest that health-related quality of life was generally maintained in both study arms over the course of treatment.


Assuntos
Ado-Trastuzumab Emtansina/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasia Residual/tratamento farmacológico , Receptor ErbB-2/genética , Trastuzumab/administração & dosagem , Ado-Trastuzumab Emtansina/efeitos adversos , Adulto , Idoso , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Neoplasia Residual/epidemiologia , Neoplasia Residual/patologia , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Trastuzumab/efeitos adversos
17.
J Oncol Pharm Pract ; 26(7): 1780-1784, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32192389

RESUMO

INTRODUCTION: Trastuzumab emtansine is an antibody-drug conjugate targeting the human epidermal growth factor receptor 2 use in recurrent metastatic breast cancer. Cases of trastuzumab emtansine-induced nodular regenerative hyperplasia are often reported as overt noncirrhotic portal hypertension with ascites and variceal bleeding. CASE REPORT: We report the case of a 61-year-old woman who present multiple stellate angiomas with gradual increased liver transaminases and reduced platelet count during a 27-months course on trastuzumab emtansine therapy for recurrent metastatic breast cancer. After the nodular regenerative hyperplasia was histologically confirmed, the trastuzumab emtansine was stopped. After two months, trastuzumab was restarted together with exemestane. During trastuzumab therapy, the patient had a normalization of liver transaminases, platelet count and a gradual improvement of her stellate angiomas. Trastuzumab was continued for 15 months without any reoccurrence of nodular regenerative hyperplasia. MANAGEMENT AND OUTCOME: Nodular regenerative hyperplasia should be suspected after one year of trastuzumab emtansine treatment in patients with signs of portal hypertension without cirrhosis. Definitive cessation of trastuzumab emtansine is required after a diagnosis of nodular regenerative hyperplasia and complete resolution of symptoms generally takes several months. DISCUSSION: Based on fundamental studies, nodular regenerative hyperplasia is probably caused by the emtansine (DM1) part of the trastuzumab emtansine. It is still unclear if trastuzumab therapy can be reintroduced after nodular regenerative hyperplasia induced by trastuzumab emtansine, depriving the patient of a HER2-targeted therapy. Only one case reported having given trastuzumab in this situation over one month. In our case, trastuzumab was reintroduced without any complications for a long extent following TDM1-associated nodular regenerative hyperplasia.


Assuntos
Ado-Trastuzumab Emtansina/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Hiperplasia/induzido quimicamente , Ado-Trastuzumab Emtansina/administração & dosagem , Antineoplásicos/efeitos adversos , Varizes Esofágicas e Gástricas/induzido quimicamente , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Receptor ErbB-2/metabolismo
18.
Eur J Cancer ; 126: 65-73, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31923729

RESUMO

INTRODUCTION: T-DM1 has been approved for the treatment of HER2+ breast cancer. Cardiac dysfunction is a side effect of trastuzumab, a component of T-DM1. However, little is known about T-DM1-associated cardiotoxicity. METHODS: We have conducted a pooled analysis of T-DM1 trials in advanced HER2+ breast cancer cases to understand the incidence, clinical presentation as well as to establish possible risk factors for T-DM1-associated cardiotoxicity. The primary endpoint was the incidence of cardiac events (CEs). CEs were categorized as follows: (1) congestive heart failure (CHF) or grade 3/4 LVEF drop; (2) cardiac ischemia, (3) cardiac arrhythmia, (4) grade 1/2 LVEF drop. Secondary endpoints included CE recovery rate and impact of CEs on treatment discontinuation. Logistic regression was used to assess possible risk factors for CEs. RESULTS: Individual patient-level data from 1961 patients exposed to T-DM1 in seven trials were pooled. Of these, 1544 received T-DM1 and 417 T-DM1 + pertuzumab. CHF/LVEF drop grade 3/4 was reported in 0.71%, cardiac ischemia in 0.1%, cardiac arrhythmia in 0.71% and grade 1/2 LVEF drop in 2.04%. The total CE rate was 3.37% (95% confidence interval (CI), 2.6%-4.3%). Multivariate analysis showed patient's age ≥65 (OR 3.0; 95% CI, 1.77-5.14; P-value <0.001) and baseline LVEF<55% (OR 2.62; 95% CI, 1.29-5.32; P-value 0.008) as risk factors. CEs resolved in most (79%) patients after treatment discontinuation. CONCLUSION: The incidence of CEs in patients receiving T-DM1 was low. Older patients receiving T-DM1 should be carefully followed for cardiac safety during treatment.


Assuntos
Ado-Trastuzumab Emtansina/efeitos adversos , Arritmias Cardíacas/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Insuficiência Cardíaca/diagnóstico , Isquemia Miocárdica/diagnóstico , Ado-Trastuzumab Emtansina/uso terapêutico , Idoso , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Arritmias Cardíacas/induzido quimicamente , Neoplasias da Mama/metabolismo , Cardiotoxicidade/diagnóstico , Cardiotoxicidade/etiologia , Cardiotoxicidade/fisiopatologia , Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Fase II como Assunto/estatística & dados numéricos , Ensaios Clínicos Fase III como Assunto/métodos , Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Feminino , Insuficiência Cardíaca/induzido quimicamente , Humanos , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto/métodos , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Isquemia Miocárdica/induzido quimicamente , Receptor ErbB-2/metabolismo
19.
Clin Breast Cancer ; 20(2): e220-e228, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31892489

RESUMO

INTRODUCTION: Thrombocytopenia is a common and potentially serious adverse event of ado-trastuzumab emtansine (T-DM1) use in patients with advanced breast cancer. However, the risk factors have been minimally explored. Our aim was to develop a clinical prediction model from the clinicopathologic data that would allow for quantification of the personalized risks of thrombocytopenia from T-DM1 usage. MATERIALS AND METHODS: Data from 3 clinical trials, EMILIA (a study of trastuzumab emtansine versus capecitabine + lapatinib in participants with HER2 [human epidermal growth factor receptor 2]-positive locally advanced or metastatic breast cancer), TH3RESA (a study of trastuzumab emtansine in comparison with treatment of physician's choice in participants with HER2-positive breast cancer who have received at least two prior regimens of HER2-directed therapy), and MARIANNE [a study of trastuzumab emtansine (T-DM1) plus pertuzumab/pertuzumab placebo versus trastuzumab (Herceptin) plus a taxane in participants with metastatic breast cancer], were pooled. Cox proportional hazard analysis was used to assess the association between the pretreatment clinicopathologic data and grade ≥ 3 thrombocytopenia occurring within the first 365 days of T-DM1 use. A multivariable clinical prediction model was developed using a backward elimination process. RESULTS: Of the 1620 participants, 141 (9%) had experienced grade ≥ 3 thrombocytopenia. On univariable analysis, the body mass index, race, presence of brain metastasis, platelet count, white blood cell count, and concomitant corticosteroid use were significantly associated with the occurrence of grade ≥ 3 thrombocytopenia (P < .05). The multivariable prediction model was optimally defined by race (Asian vs. non-Asian) and platelet count (100-220 vs. 220-300 vs. >300 × 109/L). A large discrimination between the prognostic subgroups was observed. The highest risk subgroup (Asian and platelet count of 100-220 cells ×109/L) had a 40% probability of grade ≥ 3 thrombocytopenia within the first 365 days of T-DM1 therapy compared with 2% for the lowest risk subgroup (non-Asian and platelet count > 300 × 109/L). CONCLUSION: A clinical prediction model, defined by race and pretreatment platelet count, was able to discriminate subgroups with a significantly different risk of grade ≥ 3 thrombocytopenia after T-DM1 initiation. The model allows for improved interpretation of the personalized risks and risk/benefit ratio of T-DM1.


Assuntos
Ado-Trastuzumab Emtansina/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Trombocitopenia/epidemiologia , Adulto , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Ensaios Clínicos como Assunto , Conjuntos de Dados como Assunto , Feminino , Humanos , Pessoa de Meia-Idade , Contagem de Plaquetas , Prognóstico , Modelos de Riscos Proporcionais , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Estudos Retrospectivos , Medição de Risco/métodos , Fatores de Risco , Índice de Gravidade de Doença , Trombocitopenia/induzido quimicamente , Trombocitopenia/diagnóstico
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