Dataset Information

Long-term trastuzumab (Herceptin®) treatment in a continuation study of patients with HER2-positive breast cancer or HER2-positive gastric cancer.

ABSTRACT: Trastuzumab (Herceptin® [H]) is the standard of care for HER2-positive locally advanced/metastatic breast cancer and gastric/gastroesophageal junction (GEJ) cancer. However, there is a paucity of data available on long-term H treatment of patients. The Rollover Protocol (ROP) Study was conducted to report safety data for patients with HER2-positive locally advanced/metastatic breast and gastric/GEJ cancer who have received long-term H therapy (? 5 years and ? 3 years for breast and gastric/GEJ cancer, respectively).The ROP Study was a single-arm, multicenter, international continuation trial of H in patients who had previously completed a global Roche-sponsored trial with H therapy, had stable disease, and were receiving H at the end of the lead-in trial. Patients with chronic heart failure during the lead-in trial could be included following a risk-benefit analysis. The primary objectives were to provide H therapy to patients with HER2-overexpressing locally advanced/metastatic breast or gastric/GEJ cancer at the end of the lead-in study, and to follow the long-term outcomes and long-term overall safety in these patients.Twenty-five of 69 patients enrolled in the ROP Study received long-term H therapy (19 breast cancer and 6 gastric/GEJ cancer). The median duration of H treatment for patients with breast cancer was 8 years 7 months, and 5 years 2 months for patients with gastric/GEJ cancer. The cardiac status of the patients remained stable over time, with no serious cardiac adverse events or marked changes in left ventricular ejection fraction (LVEF). The median overall worst LVEF measurement was 57.0%, and no patients experienced an LVEF of

SUBMITTER: Muller V

PROVIDER: S-EPMC5856394 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Long-term trastuzumab (Herceptin®) treatment in a continuation study of patients with HER2-positive breast cancer or HER2-positive gastric cancer.

Müller Volkmar V Clemens Michael M Jassem Jacek J Al-Sakaff Nedal N Auclair Petra P Nüesch Eveline E Holloway Debbie D Shing Mona M Bang Yung-Jue YJ

BMC cancer 20180315 1

<h4>Background</h4>Trastuzumab (Herceptin® [H]) is the standard of care for HER2-positive locally advanced/metastatic breast cancer and gastric/gastroesophageal junction (GEJ) cancer. However, there is a paucity of data available on long-term H treatment of patients. The Rollover Protocol (ROP) Study was conducted to report safety data for patients with HER2-positive locally advanced/metastatic breast and gastric/GEJ cancer who have received long-term H therapy (≥ 5 years and ≥ 3 years for breas ...[more]

PMID: 29544445

Similar Datasets

Project description:PURPOSE:PF-05280014 is a biosimilar to trastuzumab (Herceptin®). Following demonstration of pharmacokinetic (PK) similarity in healthy volunteers, a comparative clinical study in patients with HER2-positive metastatic breast cancer (mBC) compared the efficacy, safety and immunogenicity of PF-05280014 and trastuzumab sourced from the EU (trastuzumab-EU), both with paclitaxel. METHODS:Population PK of PF-05280014 and trastuzumab-EU was evaluated. RESULTS:Overall, 702 patients were treated: PF-05280014 (n?=?349) and trastuzumab-EU (n?=?353). Peak-and-trough serum drug concentration samples were collected (selected doses) following repeated intravenous administration of PF-05280014 or trastuzumab-EU. Population PK analysis was performed with drug concentration-time data to cycle 17 for each compound, using nonlinear mixed effect modeling. Potential baseline covariates (circulating HER2 concentrations, body weight, Japanese race, Eastern Cooperative Oncology Group status, number of metastatic sites and antidrug antibody status) were evaluated. Concentration-time data of PF-05280014 and trastuzumab-EU were adequately described by a two-compartment model with first-order elimination, with inter-individual variability (IIV) on clearance (CL), volumes of distribution in central compartment (V1) and peripheral compartments, and intercompartment clearance. Similar estimated PK parameters and IIV were obtained for both treatments. For PF-05280014 and trastuzumab-EU, baseline body weight was an influential covariate on CL and V1; the magnitude was comparable between treatments. PK was consistent between the limited number of Japanese and non-Japanese patients for both compounds. CONCLUSIONS:PF-05280014 and trastuzumab-EU had similar PK parameters and influential PK covariates in patients with HER2-positive mBC. These results provided further evidence in patients for PK similarity between PF-05280014 and trastuzumab-EU. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov, NCT01989676.

Project description:BackgroundDespite the wide spread use of trastuzumab in human epidermal growth factor receptor 2 (HER2) overexpressing metastatic gastric cancer patients, its optimal duration of administration beyond first-line disease progression is unknown. In HER2 overexpressing metastatic breast cancer, trastuzumab continuation beyond first-line disease progression has shown improvement in time to progression (TTP) without an increased risk of treatment related toxicity.MethodsHER2-overexpressing metastatic gastric cancer patients were identified from our database between January 2010 and December 2014. We retrospectively reviewed the medical records of 43 patients who received trastuzumab in combination with chemotherapy as first-line and continued trastuzumab beyond disease progression.ResultsForty-three cases were identified, 27 males (62.8%), median age of the patients was 58 years. Thirty-five (81.4%) presented with stage 4 as their initial presentation. Eighty one percent had 3+ HER2 overexpression by immunohistochemistry (IHC) and 18% had 2+ HER2 overexpression confirmed by fluorescence in situ hybridization (FISH). Thirteen (52%) were moderately differentiated, 16 (37.1%) were poorly differentiated. The most common sites of metastasis were liver 35 (81.4%) and lung 14 (32.5%). The most commonly used first-line regimen was oxaliplatin, 5-fluorouracil (5-FU), and trastuzumab in 22 (51.1%) patients. Twenty-five (58.1%) patients received irinotecan, 5-FU and trastuzumab in the second-line. Progression-free survival (PFS) was 5 months (95% CI: 4.01-5.99 months). Five patients are still alive and excluded from calculating the median overall survival (OS) which was 11 months (range, 5-53 months) for the remaining 20 subjects of this second-line group. Trastuzumab was not discontinued due to side effects in any of the study population.ConclusionsIn conclusion, this retrospective analysis suggests that continuation of trastuzumab beyond disease progression in patients with HER2-overexpressing metastatic gastric cancer is feasible and safe. Randomized studies are warranted.

Project description:BackgroundHuman epidermal growth factor receptor 2-positive (HER2+) breast cancer is an aggressive disease that makes up about 20% of all invasive breast cancers. HER2+ breast cancer is associated with poor prognosis and high mortality rates, but the development of HER2-targeted therapies, such as originator trastuzumab (Herceptin®), has substantially improved patient survival. Numerous clinical trials and reviews have investigated the efficacy of HER2-targeted therapies over the past few decades; however, no study has specifically investigated the vast body of evidence on trastuzumab in comparison to chemotherapy regimens, endocrine therapies, and other targeted therapies. This systematic review and cumulative network meta-analysis (NMA) will synthesize available evidence to evaluate the survival benefit conferred by the addition of originator trastuzumab to standard chemotherapy and to compare the most widely used trastuzumab regimens in patients with HER2+ early breast cancer, based on results from randomized controlled trials (RCTs) and comparative observational studies.Methods/designA systematic search of Embase, MEDLINE®, and the Cochrane Library has been designed by an experienced medical information specialist and peer reviewed by another senior information specialist. RCTs and comparative observational studies of patients with HER2+ early breast cancer indexed from 1990 onwards will be eligible for inclusion. Two investigators will independently assess studies for inclusion and use standardized data extraction templates to collect data on study and patient characteristics. The primary outcome of interest is overall survival. Bayesian cumulative NMA methods will be used to quantify the evolution of publicly available evidence using both fixed and random effects models.DiscussionThis study will evaluate survival trends associated with originator trastuzumab in patients with HER2+ early breast cancer. As originator trastuzumab has been researched in both clinical and real-world settings for close to 20 years, a cumulative NMA is likely to show improved precision around the parameter estimates for trastuzumab now compared with when the drug was initially launched in the USA in 1998. A better understanding of the evolution of publicly available comparative evidence for originator trastuzumab will further inform treatment for patients with HER2+ early breast cancer, providing benefit to patients, health professionals, and researchers.Systematic review registrationPROSPERO CRD42017055763 https://www.crd.york.ac.uk/PROSPERO.

Project description:BACKGROUND:HER2-positive gastric cancer (GC) affects 7%-34% of patients with GC. Trastuzumab-based first-line treatment has become the standard of care for HER2-positive advanced gastric cancer (AGC). However, there are no clinically validated biomarkers for resistance to HER2-targeted therapies. Upregulation of PI3K pathway and tyrosine kinase receptor (TKR) alterations have been noted as molecular mechanisms of resistance in breast cancer. Our study aimed to perform a molecular characterization of HER2-positive AGC and investigate the role of PI3K/Akt/mTOR signaling pathway activation and TKR gene copy number (GCN) gains as predictive biomarkers in HER2-positive AGC treated with trastuzumab. PATIENTS AND METHODS:Forty-two HER2-positive GC samples from patients treated with trastuzumab-based first-line chemotherapy were selected. DNA samples were sequenced. PTEN and MET immunohistochemistry were also performed. RESULTS:Concurrent genetic alterations were detected in 97.1% of HER2-positive AGC. We found activation of PI3K/Akt/mTOR pathway in 52.4% of patients and TKR GCN gains in 38.1%. TKR GCN gains did not correlate with overall survival (OS) or progression-free survival (PFS). Multivariate Cox models showed that PI3K/Akt/mTOR activation negatively affects the effectiveness of trastuzumab-based chemotherapy in terms of OS and PFS. CONCLUSION:Our results provide for the first time a detailed molecular profile of concurrent genetic alterations in HER2-positive AGC. PI3K pathway activation could be used as a predictive marker of worse outcome in this patient population. In addition, gains in copy number of other TKR genes in this subgroup may also influence the survival benefit obtained with trastuzumab. IMPLICATIONS FOR PRACTICE:This article reports, for the first time, a detailed molecular profile of genomic alterations in patients with HER2-positive advanced gastric cancer (AGC). PI3K/Akt/mTOR signaling pathway activation seems to have a differentially negative effect on overall survival and progression-free survival in AGC treated with trastuzumab-based chemotherapy. Combining different targeted agents could be a successful therapeutic strategy to improve the prognosis of HER2-positive AGC.

Dataset Information

Long-term trastuzumab (Herceptin®) treatment in a continuation study of patients with HER2-positive breast cancer or HER2-positive gastric cancer.

Publications

Long-term trastuzumab (Herceptin®) treatment in a continuation study of patients with HER2-positive breast cancer or HER2-positive gastric cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets