Combination of radiotherapy and double blockade HER2 with pertuzumab and trastuzumab for HER2-positive metastatic or locally recurrent unresectable and/or metastatic breast cancer: Assessment of early toxicity

Background and purposes

We evaluate the early toxicity of concurrent use of radiotherapy, pertuzumab and trastuzumab in patients with HER2-positive metastatic or locally recurrent unresectable breast cancer.

Trastuzumab combined with doublet or single-agent chemotherapy as first-line therapy for HER2-positive metastatic breast cancer

Purpose

To investigate the efficacy and safety of doublet versus single-agent chemotherapy (CT) plus trastuzumab (H) as first-line therapy for human epidermal growth factor 2 receptor (HER2)-positive metastatic breast cancer (MBC).

Methods

We searched for randomized clinical trials (RCTs) that evaluated the treatment effects of single-agent or doublet CT+H as first-line therapies for HER2-positive MBC. The main outcomes measured for this study included the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). A meta-analysis and trial sequential analysis (TSA) were performed, and the study quality was evaluated using the GRADE framework. The PROSPERO registry number of our analysis is CRD42016043766.

Results

The results from four RCTs including 1044 participants were pooled. Moderate-quality evidence indicated that compared with single-agent CT+H, doublet CT+H correlated better with prolonged PFS (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.63–0.75, P < 0.0001) and OS (HR = 0.90, 95% CI 0.88–0.92, P < 0.0001). However, moderate-quality evidence revealed no significant difference between the two regimens regarding the ORR (relative risk [RR] = 1.07, 95% CI 0.98–1.17, P = 0.157), which was confirmed by TSA, indicating that the cumulative Z-curve entered the futility area. Moderate-quality evidence indicated that treatment-related grade 3 or 4 toxicities of thrombocytopenia (RR = 4.08, P = 0.000), nausea/vomiting (RR = 4.26, P = 0.002), diarrhea (RR = 2.81, P = 0.002), and stomatitis (RR = 5.02, P = 0.003) were observed more frequently with doublet CT+H than with single-agent CT+H.

Conclusions

Compared with single-agent CT, the combination of doublet CT with trastuzumab as first-line therapy for HER2-positive MBC is associated with longer PFS and OS, but more treatment-related grade 3 or 4 toxicities. Therefore, doublet CT appears to be an appropriate regimen for HER2-positive MBC with a good performance status.

     

CLEOPATRA: a phase III evaluation of pertuzumab and trastuzumab for HER2-positive metastatic breast cancer

IntroductionPatients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer have a poor prognosis. Despite proven efficacy with the standard of care, trastuzumab, most patients with HER2-positive metastatic breast cancer (MBC) will eventually progress, requiring further intervention to prolong life. Pertuzumab, a humanized monoclonal antibody, is the first HER2 dimerization inhibitor. It binds to the dimerization site on the HER2 domain and prevents ligand-driven pairing of HER2 with other HER receptors, thus inhibiting tumor cell growth and survival. Combining trastuzumab and pertuzumab therefore provides a more comprehensive blockade of the HER signaling pathways, resulting in greater antitumor efficacy.Study DesignCLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab) is an international, randomized, double-blind, placebo-controlled phase III trial that aims to recruit approximately 800 patients from around 250 centers worldwide. Adults with HER2-positive adenocarcinoma of the breast with locally recurrent or metastatic disease will be randomized (1:1) to receive docetaxel, trastuzumab, and pertuzumab or docetaxel, trastuzumab, and placebo. The primary endpoint of the study is progression-free survival (PFS), based on tumor assessments conducted by an independent review facility. Secondary endpoints include PFS evaluated by investigator assessment, overall survival, objective response rate, duration of response, time to symptom progression, and safety. Data will also be collected to identify biomarkers that may correlate with clinical outcomes.ConclusionThe CLEOPATRA study will provide important information about the efficacy and safety of adding pertuzumab to one current standard of care in patients with HER2-positive MBC.     

Taxane versus vinorelbine in combination with trastuzumab and pertuzumab for first-line treatment of metastatic HER2-positive breast cancer: a retrospective two-center study

Breast Cancer Research and Treatment - The combination of a taxane with trastuzumab and pertuzumab is standard of care for first-line treatment of human epidermal growth factor receptor 2...     

Adjuvant trastuzumab therapy for HER2-positive breast cancer

HER2 is overexpressed or gene amplified in 20%-25% of breast cancers. The anti-HER2 monoclonal antibody trastuzumab targets HER2-positive tumors, inhibiting proliferation and inducing cell death via extracellular and intracellular mechanisms. The clinical benefits observed with trastuzumab in the metastatic setting provided the rationale for assessing trastuzumab in the treatment of early breast cancer. Four large phase III adjuvant trials (NSABP B-31, NCCTG N9831, HERA, and BCIRG 006) investigated the efficacy and safety of 1 or 2 years of trastuzumab given in combination with or after standard adjuvant chemotherapy. The addition of 1 year of trastuzumab to adjuvant chemotherapy significantly improved disease-free survival (DFS) by 33%-52% and overall survival by 34%-41% in the 4 trials. The DFS benefits were observed regardless of age, nodal status, hormonal status, or tumor size in all trials. The cumulative incidence of congestive heart failure or cardiac death ranged from 0-0.9% in the control arms and 0-3.8% in the trastuzumab-containing arms. These were below the safety cutoff points set by the individual studies' independent data monitoring committees, indicating acceptable cardiac safety. Risk factors associated with cardiac dysfunction included baseline left ventricular ejection fraction level, hypertension, and older age. The addition of trastuzumab to adjuvant chemotherapy provides significant survival benefits with a positive benefit/risk ratio. Ongoing and planned trials correlated with basic science will enhance our understanding of HER2-positive disease, leading to treatment optimization and further improvements in patient outcomes.     

Phase II study of bevacizumab in combination with trastuzumab and capecitabine as first-line treatment for HER-2-positive locally recurrent or metastatic breast cancer

We report the first results from a phase II, open-label study designed to evaluate the efficacy and safety of bevacizumab in combination with trastuzumab and capecitabine as first-line therapy for human epidermal growth factor receptor (HER)-2-positive locally recurrent (LR) or metastatic breast cancer (MBC). Patients were aged ≥18 years with confirmed breast adenocarcinoma, measurable LR/MBC and documented HER-2-positive disease. Patients received bevacizumab (15 mg/kg on day 1) plus trastuzumab (8 mg/kg on day 1 of cycle 1, 6 mg/kg on day 1 of each subsequent cycle) plus capecitabine (1,000 mg/m2 twice daily, days 1-14) every 3 weeks until disease progression, unacceptable toxicity, or consent withdrawal. Eighty-eight patients were enrolled; 40 (46%) are still on study treatment. The median follow-up was 8.8 months (range, 0.9-17.1 months). The overall response rate, the primary endpoint, was 73% (95% confidence interval [CI], 62%-82%), comprising 7% complete and 66% partial responses. The median progression-free survival interval was 14.4 months (95% CI, 10.4 months to not reached [NR]), with 35 events. The median time to progression was 14.5 months (95% CI, 10.5 months to NR), with 33 events. Treatment was well tolerated; main side effects were grade 3 hand-foot syndrome (22%), grade ≥3 diarrhea (9%), and grade ≥3 hypertension (7%). Overall, 44% of patients experienced grade ≥3 treatment-related adverse events and 13 patients discontinued capecitabine because of toxicity, but continued with bevacizumab and trastuzumab. Heart failure was seen in two patients. The combination of bevacizumab, trastuzumab, and capecitabine was clinically active as first-line therapy for patients with HER-2-positive MBC, with an acceptable safety profile and no unexpected toxicities.     

Trastuzumab as first-line therapy in HER2-positive metastatic breast cancer patients

Trastuzumab is a humanized monoclonal antibody against the extracellular domain of hEGF receptor-2 (HER2). Trastuzumab in combination with chemotherapy has proven efficacy in treating both early and metastatic HER2-positive breast cancer. In the metastatic setting, the addition of trastuzumab to chemotherapy is associated with a statistically significant longer time to disease progression, higher rate of objective response and improvement in overall survival. Trastuzumab efficacy is not influenced by hormone receptor status, but differences in median overall survival exist between HER2-positive and HER2-negative states. Reassessment of the benefit of re-exposing patients with metastatic breast cancer to trastuzumab following relapse in the adjuvant setting is necessary. Ongoing research into new HER2-targeted therapies and trials involving combination anti-HER2 drug therapy without chemotherapy show promise. This review is focused on the available results obtained with the use of trastuzumab in the subset of HER2-positive breast cancer patients with metastatic disease.     

Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study

BACKGROUND: The optimal trastuzumab-based chemotherapy regimen for HER2-overexpressing, metastatic breast cancer is not known. The trastuzumab and vinorelbine or taxane (TRAVIOTA) study was a prospective, multicenter, randomized trial that was designed to compare these regimens. METHODS: Eligible patients had HER2-overexpressing, metastatic breast cancer and had received no prior chemotherapy for advanced disease. Patients were randomized 1:1 to receive either trastuzumab with weekly vinorelbine therapy or weekly taxane therapy (paclitaxel or docetaxel at the investigator's choice). Originally planned for 250 patients, the study was closed because of poor accrual with 81 evaluable patients, including 41 patients who received vinorelbine and 40 patients who received taxane. RESULTS: Response rates were 51% and 40% for the vinorelbine/trastuzumab arm and the taxane/trastuzumab arm, respectively (Fisher exact test; P = .37). The median time to disease progression was 8.5 months and 6.0 months for the vinorelbine- and taxane-based arms, respectively (log-rank test; P = .09). Treatment with either regimen generally was well tolerated, yielding comparable rates of neurologic and gastrointestinal toxicity. Vinorelbine-based treatment was associated with more anemia and neutropenia and with 2 episodes of cardiotoxicity. Taxane-based therapy was associated with more dermatologic toxicity, myalgias, and fluid retention. CONCLUSIONS: Both vinorelbine/trastuzumab and taxane/trastuzumab treatments were active as first-line therapy for HER2-positive, metastatic breast cancer and had comparable rates of efficacy and tolerability. The toxicities observed were the result of recognized side effects associated with each of the chemotherapy agents and schedules. These data can inform treatment decision making in this clinical setting.     

Emerging approaches for treating HER2-positive metastatic breast cancer beyond 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.     

Pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer

Overexpression of HER2 – found in approximately 15–20% of all breast cancers – is a negative prognostic factor. Although trastuzumab significantly improves the prognosis of HER2-positive breast cancer, half of the patients with metastatic breast cancer experience disease progression within 1 year. Pertuzumab is a novel HER2-targeted humanized monoclonal antibody that binds to the dimerization domain of HER2 and acts synergically with trastuzumab in inhibiting tumor progression. The CLEOPATRA trial demonstrated that adding pertuzumab to trastuzumab plus docetaxel significantly prolonged progression-free survival and overall survival without increasing severe adverse events. Conclusively, pertuzumab was approved by the US FDA in June 2012 for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer. Furthermore, various clinical trials to evaluate the efficacy and safety of pertuzumab combined with other cytotoxic agents are ongoing at present. Thus, pertuzumab has been becoming important for the treatment of patients with HER2-positive metastatic breast cancer.     

Vinorelbine plus trastuzumab combination as first-line therapy for HER 2-positive metastatic breast cancer patients: an international phase II trial

The aim of this international phase II trial was to determine the efficacy and safety profile of weekly vinorelbine plus trastuzumab as first-line chemotherapy for women with HER 2-overexpressing metastatic breast cancer. Sixty-nine patients with tumours overexpressing HER 2 received vinorelbine: 30 mg m-2 week-1 and trastuzumab: 4 mg kg-1 on day 1 as a loading dose followed by 2 mg kg-1 week-1 starting on day 8. Sixty-two patients were evaluable for response and 69 patients were evaluable for toxicity. The overall response rate was 62.9%. The median time to response was 8.4 weeks, the median duration of response was 17.5 months, the median progression-free survival was 9.9 months (95% CI, 5.6-12.1) and the one-year progression-free survival was 39.1%. The median survival for all patients was 23.7 months (95% CI, 18.4-32.6). This regimen was safe: grade 3-4 neutropenia were observed over 17.7% of courses in 83.8% of patients, with only two episodes of febrile neutropenia (0.1%) in two patients (2.9%). Only one patient discontinued treatment due to grade 3 symptomatic cardiac dysfunction that resolved with therapy. Vinorelbine plus trastuzumab is one of the most active treatment regimens for patients with HER 2-positive metastatic breast cancer and demonstrates a very favourable safety profile allowing prolonged treatment with long-term survival. This study has been presented in part at the following conferences: The San Antonio Breast Cancer Symposium, San Antonio, TX, USA, 2003; The American Society of Clinical Oncology, Orlando, FL, USA, 2005.     

Subcutaneous trastuzumab with pertuzumab and docetaxel in HER2-positive metastatic breast cancer: Final analysis of MetaPHER,a phase IIIb single-arm safety study

Breast Cancer Research and Treatment - Intravenous trastuzumab, pertuzumab, and docetaxel are first-line standard of care for patients with HER2-positive metastatic breast cancer (mBC). MetaPHER is...     

Cardiac toxicity and efficacy of trastuzumab combined with pertuzumab in patients with trastuzumab-insensitive human epidermal growth factor receptor 2-positive metastatic breast cancer.

PURPOSE: To evaluate safety and efficacy of trastuzumab with pertuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who had progressive disease on trastuzumab-based therapy. EXPERIMENTAL DESIGN: Patients with measurable HER2(+) metastatic breast cancer, < or = 3 trastuzumab-based regimens, and left ventricular ejection fraction (LVEF) > or = 55% received 8 or 6 mg/kg trastuzumab and 840 mg pertuzumab i.v. followed by 6 mg/kg trastuzumab and 420 mg pertuzumab every 3 weeks. Cardiac evaluation and tumor response were assessed every 3 and 6 weeks, respectively. RESULTS: Eleven patients received 64 cycles of trastuzumab plus pertuzumab. A total of 92 echocardiograms and 8 cardiac magnetic resonance imaging studies were done. With the lower limit of normal LVEF 55%, left ventricular systolic dysfunction was observed in six patients, three grade 1, two grade 2, and one grade 3 according to the National Cancer Institute Common Terminology Criteria for Adverse Events. The objective response rate was 18%. Two patients had partial responses, three had stable disease, and six had progressive disease. The median time to progression was 6 weeks. In baseline tumors from formalin-fixed paraffin-embedded primary and/or metastatic tumor biopsies, pHER2-Y1248 trended toward an increase in patients with partial response compared with those with stable disease/progressive disease (P = 0.095). CONCLUSION: Trastuzumab plus pertuzumab may have clinical benefit in selected patients who have previously been treated with trastuzumab. Cardiac toxicity, although asymptomatic in most cases, was associated with this treatment. Further evaluation of efficacy of this combination is required to define the overall risks and benefits.     

Similar survival with single-agent capecitabine or taxane in first-line therapy for metastatic breast cancer

Capecitabine is often offered as a first-line chemotherapy option for metastatic breast cancer (MBC). In this study, we compare characteristics of and survival among women prescribed first-line capecitabine or taxane monotherapy for MBC. Women receiving first-line chemotherapy for MBC from 1998 to 2005 were identified from the North Carolina tumor registry linked with Medicaid and Medicare claims records, and were followed through the end of 2005 with survival data from the National Death Index. T Tests and Chi-square tests were used to compare baseline characteristics. Overall survival and cancer-specific survival were examined using Cox proportional hazard modeling. There were 257 patients with MBC starting first-line chemotherapy with capecitabine (n=71) or a taxane (n=186). No differences in age, race, or Charlson comorbidity status were observed between groups. Hormone receptor negative tumors (31.0 vs. 17.7%, p=0.02) and patients insured by Medicaid (28 vs. 12%, p=0.002) were more prevalent in the capecitabine group. Time from metastasis to first-line chemotherapy was longer in the capecitabine group (52 vs. 26% began after 3 months, p<0.001). In multivariate analysis, treatment received was not associated with overall or cancer-specific survival. Among standard demographics, age was the only factor significantly associated with overall survival (HR 1.02, p=04). In this population-based study, women who received capecitabine as first-line treatment for MBC were more often hormone receptor negative and insured by Medicaid. In multivariate analysis, first-line capecitabine and taxane for MBC yielded similar overall and cancer-specific survival outcomes.     

Efficacy and safety of trastuzumab plus capecitabine in heavily pretreated patients with HER2-positive metastatic breast cancer

Purpose We retrospectively evaluated the efficacy and safety of combination therapy of trastuzumab plus capecitabine in heavily pretreated patients with HER2-positive metastatic breast cancer (MBC). Methods Patients with HER2-positive MBC who had been administered the combination therapy between July 2003 and July 2006 at the Cancer Institute Hospital, Tokyo, were retrospectively reviewed. Capecitabine (828 mg/m²) was given twice daily for 3 weeks followed by a 1-week rest period; this was repeated every 4 weeks. Trastuzumab was given at 4 mg/kg as an initial loading dose intravenously, followed by 2 mg/kg weekly. We investigated objective response rate (ORR), clinical benefit rate (CBR), and time-to-treatment failure (TTF) according to the Response Evaluation Criteria in Solid Tumors guidelines. Adverse events were graded according to the National Cancer Institute, Common Toxicity Criteria, version 3.0. Results A total of 49 patients were assessed and median follow-up time of patients was 16.2 months (1.4–43.5 months). ORR was 16% (95% confidence interval: 7–30%) and CBR was 47% (95% confidence interval: 32–62%). Median TTF was 5.4 months. Common adverse effects were hand–foot syndrome, liver dysfunction, and bone marrow suppression. Grade 3 adverse events were observed in nine patients (18%). One patient (2%) suffered from symptomatic chronic heart failure, which improved after discontinuation of trastuzumab. Conclusions The combination therapy of trastuzumab plus capecitabine is effective and tolerable for heavily pretreated patients with HER2-positive MBC.