Trastuzumab: in HER2-positive metastatic gastric cancer

Trastuzumab is a recombinant humanized IgG? monoclonal antibody directed against the extracellular domain of the human epidermal growth factor receptor type 2 (HER2) that inhibits HER2-dependent tumour cell proliferation and survival. Proliferation of gastric cancer cells overexpressing HER2 is inhibited by trastuzumab in vitro and in vivo. HER2-positive expression (defined as immunohistochemistry 3+ or fluorescence in situ hybridization-positive) was observed in 22.1% of almost 4000 metastatic gastric cancers in patients who were screened for randomization in the open-label, multicentre, phase III ToGA trial. In patients with HER2-positive metastatic gastric cancer (n?=?584), median overall survival (primary endpoint) was significantly longer for recipients of intravenous trastuzumab plus chemotherapy (comprising cisplatin and either fluorouracil or capecitabine) than in those receiving chemotherapy alone in the ToGA trial. Furthermore, the overall response rate was significantly higher and the median time to disease progression and median time of progression-free survival were also significantly longer with trastuzumab plus chemotherapy than with chemotherapy alone. In general, combination therapy with trastuzumab and chemotherapy was relatively well tolerated in patients with metastatic gastric cancer with no reports of new or unexpected adverse events.     

Tumor hormone/HER2 receptor status and pharmacologic treatment of metastatic breast cancer in Western Europe

Abstract

Introduction:

Tumor hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) expression are important factors influencing treatment response and selection in patients with metastatic breast cancer (mBC). Using the LifeLink Oncology Analyzer Database, we classified mBC patients by combined HR and HER2 status, and evaluated the use of pharmacological treatment modalities both overall and within these subtypes in Western Europe.     

Trastuzumab and chemotherapy after the treatment failure of lapatinib for HER2-positive metastatic breast cancer

We describe a patient with human epidermal growth factor receptor type 2 (HER2/c-erbB-2)-positive metastatic breast cancer who survived for approximately 6 years after the initiation of combination therapy with trastuzumab and varying types of chemotherapeutic agents. The patient was a 48-year-old postmenopausal female who underwent partial mastectomy with axillary node dissection for cancer of the right breast in March 1994. She developed lung metastases 2 years thereafter, but survived free of relapse for 8 years following chemotherapy and pulmonary lobectomy. The patient failed to respond to lapatinib, a HER1 (EGFR)/HER2 tyrosine kinase inhibitor, received during the course of her treatment but then again responded to subsequently administered trastuzumab. Primary treatment with trastuzumab and paclitaxel was initiated in April 2004 when the patient developed hepatic metastases 8 years after undergoing surgery for lung metastases. Long-term combination therapy with continued trastuzumab and a variety of chemotherapeutic agents was administered for 6 years without any significant adverse events. We discuss the treatment strategies for HER2-positive breast cancer and the role of lapatinib, a recently approved anticancer drug.     

Trastuzumab: a review of its use in the treatment of metastatic breast cancer overexpressing HER2.

Trastuzumab is a humanised monoclonal antibody developed to target the HER2 receptor which is overexpressed by some cancer cells, including 25 to 30% of breast cancers. Binding with high affinity to the extracellular domain of HER2, trastuzumab inhibits the proliferation of tumour cells that overexpress HER2. A large well designed multicentre study found that the addition of trastuzumab to either an anthracycline plus cyclophosphamide or to paclitaxel, as first-line therapy for metastatic breast cancer overexpressing the HER2 receptor, significantly increased time to disease progression, rate of objective response, duration of response and survival compared with chemotherapy alone. Single-agent trastuzumab was associated with an objective response in 15% of extensively pretreated patients with metastatic breast cancer overexpressing HER2, and 26% of previously untreated patients. Patients with a HER2 overexpression level of 3+ using immunohistochemical (IHC) assay or a positive HER2 result using fluorescence in situ hybridisation (FISH), benefit more from trastuzumab therapy than those with tumours overexpressing at a level of 2+. Trastuzumab has demonstrated synergistic action with several chemotherapy agents preclinically but the optimal combination clinically is yet to be determined. Trastuzumab is generally well tolerated by most patients; the most significant adverse effects being acute fever and/or chills and the potential to cause cardiac dysfunction. Serious adverse events, including anaphylaxis and death, have occurred in 0.25% of patients. Symptomatic or asymptomatic cardiac dysfunction occurred in 27% of patients receiving an anthracycline and cyclophosphamide combined with trastuzumab. Thus, combination therapy with anthracyclines is not recommended. Symptomatic or asymptomatic cardiac dysfunction occurred in 13% of patients receiving trastuzumab plus paclitaxel and in 4.7% of patients receiving trastuzumab alone. CONCLUSION: Intravenous trastuzumab is effective as a single-agent, and in combination with chemotherapy it significantly improves the median time to disease progression and survival time in patients with metastatic breast cancer overexpressing the HER2 receptor compared with chemotherapy alone. Cardiotoxicity is the main concern with therapy; particularly in patients with pre-existing cardiac dysfunction, the elderly and in combination with, or following, anthracyclines. Trastuzumab is indicated for use with paclitaxel as first-line therapy or as a single agent in second- or third-line treatment regimens for patients with metastatic breast cancer overexpressing HER2. Investigation is ongoing to ascertain the optimal combination regimen containing trastuzumab and antineoplastic agents. In addition, current research is focusing on the optimal timing, sequencing and duration of therapy as well as administration in the neoadjuvant and adjuvant setting.     

Trastuzumab: a review of its use in the management of HER2-positive metastatic and early-stage breast cancer

Trastuzumab (Herceptin) is a humanised monoclonal antibody used in the treatment of breast cancer that overexpresses human epidermal growth factor receptor 2 (HER2), which is associated with clinically aggressive disease and a poor prognosis. The addition of intravenous trastuzumab to first-line chemotherapy improved the time to disease progression, objective response rate, duration of response, and overall survival in randomised, multicentre trials in women with HER2-positive metastatic breast cancer. As such, trastuzumab has become the standard of care in this setting, despite its high acquisition cost and potential for cardiac events, and is licensed for use in combination with paclitaxel (Europe and the US) or docetaxel (Europe). In addition, trastuzumab monotherapy is approved for use in patients with HER2-positive metastatic breast cancer who have previously received chemotherapy for their metastatic disease. Recent data from large phase III trials with trastuzumab in the adjuvant setting revealed significant improvements in disease-free and overall survival. Thus, trastuzumab is also rapidly becoming a standard component of adjuvant therapy for patients with HER2-positive early-stage breast cancer.     

Trastuzumab induces gastrointestinal side effects in HER2-overexpressing breast cancer patients

Summary   Purpose: To characterise the gastrointestinal toxicities associated with Trastuzumab administration in HER2-overexpressing breast cancer patients. Methods: All patients (n = 46) who received Trastuzumab as a single agent or in conjunction with conventional anti-cancer treatment within the Royal Adelaide Hospital Cancer Centre from 2002–2007 were included in this study. A retrospective analysis of case-notes was conducted to investigate the toxicities associated with Trastuzumab. Results: Trastuzumab as a single agent induced toxicities following 22% of administrations. Gastrointestinal toxicities were observed following 12% of administrations and included nausea and vomiting, diarrhoea, abdominal pain and bloating. However, other prominent toxicities that were not related to the gastrointestinal tract were also observed including fatigue and lung symptoms (10.4%). Elderly patients (≥60 years) and those with metastatic disease experienced the highest frequency of toxicity. Conclusion: Trastuzumab induces a range of gastrointestinal toxicities in HER2-overexpressing breast cancer patients. These toxicities are separate to those caused by concurrent chemotherapy and/or radiotherapy.     

Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II and pharmacokinetic study in Japan

Tolerability and response rate to weekly combination chemotherapy with trastuzumab and vinorelbine in Japanese women with HER2-overexpressing breast cancer not previously receiving either therapy were assessed. Tumor response was evaluated every 4 weeks and adverse events were graded. A total of 23 patients from six participating centers in Japan were enrolled. Median dose intensity of vinorelbine was 16.9 mg/m2/week and response rate was 73% (complete response+partial response); complete response=9%, partial response=64%, and progressive disease=5%. Time to progression was 361 days, with 75.0% of liver metastases and 60% of lung metastases responding to this treatment. The most common adverse events were leukocytopenia and neutropenia (96%); however, hematologic toxicity associated with vinorelbine was manageable by adjusting the dose. No pharmacokinetic differences for vinorelbine were found between single administration and combination with trastuzumab. This combination therapy produced high response rates and good tolerability, indicating a promising role in first-line chemotherapy for HER2-overexpressing metastatic breast cancer in Japan.     

Trastuzumab emtansine (T-DM1) for HER2-positive breast cancer

Abstract

Background:

Trastuzumab emtansine (T-DM1), a novel drug developed for the treatment of HER2-positive breast cancer, is a human epidermal growth factor receptor (HER2) targeted antibody drug conjugate, composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1 (derivative of maytansine). It has been shown that, in preclinical studies, it has anti-tumor activity in trastuzumab refractory cancer cells. In this review, we aim to show the clinical data about trastuzumab-DM1 (T-DM1) therapy and to discuss the therapy advantages for the management of patients with HER2-positive breast cancer.     

Pertuzumab: in the first-line treatment of HER2-positive metastatic breast cancer

The humanized monoclonal antibody pertuzumab is the first in a new class of drugs, the human epidermal growth factor receptor (HER) dimerization inhibitors. Given that pertuzumab binds to a different epitope of the HER2 extracellular domain than trastuzumab, combination therapy with pertuzumab plus trastuzumab may result in more comprehensive blockade of HER2 signalling than can be achieved with trastuzumab alone. The efficacy of adding pertuzumab to trastuzumab plus docetaxel for the first-line treatment of HER2-positive metastatic breast cancer was demonstrated in the randomized, double-blind, multinational, phase III CLEOPATRA trial. Both independently assessed progression-free survival (primary endpoint) and investigator-assessed progression-free survival were significantly improved in patients receiving pertuzumab plus trastuzumab and docetaxel compared with those receiving placebo plus trastuzumab and docetaxel. The prespecified interim analysis of survival revealed a strong trend towards a survival benefit associated with pertuzumab, although this was not considered statistically significant. The objective response rate was higher with pertuzumab than with placebo. Intravenous pertuzumab had an acceptable tolerability profile when added to trastuzumab and docetaxel in the CLEOPATRA trial.     

Variation in hormone receptor and HER-2 status between primary and metastatic breast cancer: review of the literature

Importance of the field: Hormone and human epidermal growth factor receptor 2 (HER-2) receptors are two important pharmaceutical targets that affect the survival of patients with metastatic breast cancer. Discordance of hormone and HER-2 receptors were reported in a series of studies. Receptor status was reported to change in both directions, yet alteration occurs mostly in the loss of positivity for both receptors. We do not know both the exact mechanism of this process or the contribution rate of technical mistakes; a number of mechanisms might be responsible. Factors suggested include: tumor heterogeneity, clonal selection of tumor cell subpopulations, genetic instability of tumor cells, local or systemic treatments, the time interval between primary tumor and metastasis, receptor status determination techniques, and the site of metastasis.

Areas covered in this review: Studies of estrogen, progesterone and HER-2 receptor discordance between primary and metastasis of breast cancer are summarized. Laboratory evaluation of estrogen, progesterone and HER-2 receptors, and possible causes of receptor discordance, are summarized. Literature data are reviewed; the major shortcoming of these studies is that they are mostly retrospective.

What the reader will gain: The reader will read a concise literature review about the studies on estrogen, progesterone and HER-2 receptor discordances between primary and metastasis of breast cancer.

Take home message: We do not know whether the changes in receptor expression account for a true biological phenomenon or may result from inconsistent measurement. However, in light of current data, for the treatment plans that target the receptors, biopsy specimen from the metastatis of breast cancer must also be evaulated for alterations in the receptor status.     

Epidermal growth factor receptor gene copy number may predict lapatinib sensitivity in HER2-positive metastatic breast cancer

Objective: Lapatinib, a dual HER2/EGFR tyrosine kinase inhibitor (TKI), associated to capecitabine represents the treatment of choice in HER2-positive metastatic breast cancer (BC) patients in progression after trastuzumab-based therapy. Though lapatinib-based therapy prolongs the time to progression, its efficacy is often limited by the development of drug resistance. It is aimed to evaluate novel biomarkers predictive of lapatinib response, we analyzed EGFR protein and gene status in a series of 50 metastatic HER2-positive BC patients.

Methods: Lapatinib was given at 1250 mg/day continuously and capecitabine at 2000 mg/m²/day every 3 weeks. EGFR protein expression and gene copy number (GCN) were assessed by immunohistochemistry and FISH, respectively. Receiver operating curve (ROC) analysis identified the value of > 3.36 EGFR copies/nucleus as the cut-off point able to discriminate responders versus non-responders.

Results: A statistical significant correlation between EGFR GCN value > 3.36 and response to lapatinib (p = 0.01) was found. Cox regression analysis further supported these findings evidencing that HER2 score 3+ and EGFR GCN increase are positive predictor factors of lapatinib response.

Conclusions: Though further investigations are needed to confirm these findings, EGFR GCN could be a suitable screening to identify the subset of BC patients particularly responsive to the dual TKI lapatinib.     

曲妥珠单抗联合化疗治疗HER2阳性乳腺癌经济性的系统综述

目的：对曲妥珠单抗联合化疗治疗HER2阳性乳腺癌的药物经济学进行系统分析。方法： 计算机检索PubMed、ScienceDirect、SpringerLink等数据库2003—2013年间已发表的药物经济学文献,按照一定标准进行筛选,根据药物经济学方法,进行系统综述。结果：曲妥珠单抗治疗的增量成本效果比（ICER）值美国在34307~126933美元每QALY之间,瑞典为35975~52753欧元每QALY,挪威每一个LYS需要多付出8148~162417欧元,日本为17000欧元每LYG。结论：曲妥珠单抗联合化疗治疗HER2阳性乳腺癌是否具有经济性的研究结论不一致。在15篇研究中,有4篇研究认为曲妥珠单抗联合化疗方案不具有成本效果。     

Pertuzumab in HER2-positive breast cancer

Abstract

Background:

Lack of response in some patients and relapse during the course of therapy in the treatment of HER2-positive early breast cancer and metastatic breast cancer continue to challenge researchers and clinicians towards a better understanding of the fundamental mechanisms of trastuzumab action and new therapies for HER2. The aim of this review is to discuss current and future treatment options with pertuzumab in the light of new insights into HER2-positive breast cancer.     

Pharmacodynamics,pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations

Introduction: Despite the availability of several potent HER2-directed targeted agents, primary and acquired resistance continues to influence patient outcomes in HER2-positive breast cancer. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor in late-phase clinical development.

Areas covered: This review article focuses on neratinib in the treatment of HER2-positive breast cancer – early and metastatic stage – and HER2-mutant breast cancer, with particular emphasis on the pharmacokinetics and pharmacodynamics of the drug.

Expert opinion: The phase III ExteNET trial shows that neratinib improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in early-stage HER2-positive breast cancer, and in particular HER2+/HR+ tumors. Survival data are awaited. The investigational role of neratinib in high-risk patients or conversely in de-escalation dual regimens with other anti-HER2 therapies and without chemotherapy are of interest. Phase II trials show that neratinib has efficacy, either as monotherapy or in combination with other chemotherapeutic or endocrine agents, in patients with HER2-positive metastatic breast cancer and in tumors harboring HER2 mutations. The role of neratinib in therapeutic algorithms of HER2-positive patients, as well as delaying CNS events, awaits the results of ongoing trials such as NALA. Diarrhea, the main toxicity of neratinib, can be effectively managed with early loperamide prophylaxis.     

Efficacy and safety of a combination of HER2-targeted agents as first-line treatment for metastatic HER2-positive breast cancer: a network meta-analysis

Background: Using network meta-analysis, we assessed the efficacy and safety of a combination regimen of HER2-targeted agents as first-line treatment for metastatic HER2-positive breast cancer.

Methods: We searched the Medline, Embase, and Cochrane Library electronic databases (through December 2016) for phase II/III randomized controlled trials that compared regimens of one or two HER2-targeted agents combined with trastuzumab or chemotherapy. A network meta-analysis including direct and indirect analyses was conducted in WinBUGS using fixed and random effects. Study quality was assessed following the Grading of Recommendations, Assessment, Development and Evaluations method. The primary outcome was overall survival.

Results: The network meta-analysis incorporated nine HER2-targeted regimens with 9 direct comparisons and 28 indirect comparisons for the main outcomes (8 studies; n = 3976). Combining direct and indirect effects showed significant increased efficacy of trastuzumab and docetaxel plus pertuzumab (TDP) over other regimens as first-line treatment. With indirect comparison of overall safety, TDP, TDM-1, and TDM-1 plus pertuzumab demonstrated a lower risk of grade 3–4 adverse events compared to other regimens.

Conclusions: TDPs are a preferred first-line treatment for HER2-positive metastatic breast cancer compared with other target agent regimens.     

New and developing chemical pharmacotherapy for treating hormone receptor-positive/HER2-negative breast cancer

Introduction: Endocrine therapy is the mainstay of treatment for a substantial proportion of hormone receptor positive (HR+) breast cancer (BC). Indeed, patients with metastatic disease not immediately life threatening may experience long disease control across several lines of endocrine therapy. The major limitation of this therapeutic approach is primary or acquired resistance. A better understanding of endocrine resistance has resulted in newer targeted agents to be added to endocrine therapy.

Areas covered: This review highlights new findings in the treatment of HR+/HER2- BC, with a particular focus on new drugs from phase 3 development onwards.

Expert opinion: Combining endocrine therapy with agents targeting putative mechanisms of endocrine resistance is a newer treatment paradigm in HR+ BC. Adding a biologically targeted agent to endocrine therapy results in improved response rate, and clinical benefit rate, and prolonged progression-free survival. A clear advantage in overall survival has not yet been reported. Combination therapy allows to delay chemotherapy but increases toxicities and costs, which are critical factors in decision making in the clinical practice. Moreover, identification and validation of biomarkers of response are needed. Ongoing and future trials should elucidate the role of these compounds in the treatment of HR+/HER2- BC.     

Ribociclib for post-menopausal women with HR+/HER2- advanced or metastatic breast cancer

Introduction: The introduction of CDK4/6 inhibitors, such as ribociclib, has changed the treatment landscape for post-menopausal women with HR+/HER2- advanced or metastatic breast cancer. As first-line treatment of HR+/HER2- MBC, the addition of a CDK4/6 inhibitor to an aromatase inhibitor improves progression-free survival compared to an aromatase inhibitor alone.

Areas covered: In this drug profile, we review the current market for HR+/HER2- MBC, as well as the characteristics, mechanism, pharmacology, pharmacodynamics, pharmacokinetics, metabolism, clinical efficacy, toxicities, monitoring, and dosing modification of the CDK4/6 inhibitor ribociclib.

Expert commentary: CDK4/6 inhibitors, such as ribociclib, improve outcomes in post-menopausal women with HR+/HER2- MBC. The most common toxicity of ribociclib is neutropenia, which is generally not complicated and can be managed with dose modification and/or supportive care measures. Additional research will help better define the optimal clinical use of ribociclib.