Weekly Gemcitabine and Trastuzumab in the Treatment of Patients With HER2-Overexpressing Metastatic Breast Cancer

BackgroundThe use of trastuzumab in combination with either a taxane or vinorelbine has improved the efficacy of treatment for women with HER2-positive (HER+) breast cancer. We investigated the activity and toxicity of the gemcitabine/trastuzumab combination as first- or second-line treatment in women with HER2+ metastatic breast cancer (MBC).Patients and MethodsForty-one women with HER2+ MBC were treated with gemcitabine 1000 mg/m² intravenously (I.V.) days 1, 8, and 15 and trastuzumab 4-mg/kg I.V. loading dose and then 2 mg/kg weekly. Cycles were repeated every 28 days. Patients were evaluated after 8 weeks of treatment; responders/stable patients continued treatment until progression.ResultsPatients received a median of 28 weeks of treatment. Eleven of 37 evaluable patients (30%; 95% CI, 17%–46%) had major responses. The median progression-free survival (PFS) was 4 months (95% CI, 1.9–5.3 months), with a 1-year PFS of 17%. Four of 15 patients (27%) who had previously received trastuzumab for MBC had partial responses. The gemcitabine/trastuzumab combination was well tolerated.ConclusionThe combination of gemcitabine and trastuzumab is an active regimen but appears less active than trastuzumab in combination with either taxanes or vinorelbine. The role of gemcitabine/trastuzumab (versus gemcitabine alone) in women who have already received a trastuzumab-containing regimen for HER2+ MBC is not defined by this study.     

A Phase II Study of Trastuzumab Emtansine in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer Who Were Previously Treated With Trastuzumab, Lapatinib, an Anthracycline, a Taxane, and Capecitabine

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

Impact of Trastuzumab on Ipsilateral Breast Tumor Recurrence for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer after Breast-Conserving Surgery

PurposeTrastuzumab is effective in early and advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, few studies have reported the effect of trastuzumab on ipsilateral breast tumor recurrence (IBTR), whose incidence is higher in the HER2-positive subtype than in other subtypes.MethodsWe retrospectively investigated 959 patients who underwent breast-conserving surgery (BCS), chemotherapy, and radiotherapy for HER2-positive breast cancer between 2000 and 2017. IBTR was compared between the patients who received neoadjuvant or adjuvant trastuzumab (Tmab group) for a total duration of 1 year and those who received no trastuzumab (N-Tmab group).ResultsPropensity score matching designated 426 and 142 patients in the Tmab and N-Tmab groups, respectively. The median follow-up period for all patients after matching was 73.79 months. The IBTR-free survival rate was significantly higher in the Tmab group than in the N-Tmab group (10-year IBTR-free survival rate, 92.9% vs. 87.3%; p = 0.002). The multivariate analysis showed a significant association between the N-Tmab and Tmab group (hazard ratio, 3.03; 95% confidence interval, 1.07–8.59) and IBTR in addition to close or positive resection margin and hormone receptor (HR) positivity. The subgroup analysis showed that adjuvant treatment with trastuzumab significantly reduced IBTR among the patients with HR-negative or lymph node-negative breast cancer.ConclusionSignificantly reduced IBTR after BCS was observed in the patients who received 1 year of adjuvant/neoadjuvant trastuzumab treatment for HER2-positive breast cancer.     

Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE)

BackgroundPertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting.Patients and methodsIn the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8 mg/kg loading dose, then 6 mg/kg every 3 weeks (q3w)] and pertuzumab (840 mg loading dose, then 420 mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS).ResultsOverall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54 years; 29% had received prior trastuzumab. Median treatment duration was 16 months for pertuzumab and trastuzumab and 4 months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months’ median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9–22.7] months overall (19.6, 23.0 and 18.1 months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%–82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%).ConclusionsPreliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile.ClinicalTrials.govNCT01572038.     

Phase II study of trastuzumab plus gemcitabine in chemotherapy-pretreated patients with metastatic breast cancer

We evaluated the efficacy and toxicity of trastuzumab plus gemcitabine in patients with HER2-positive metastatic breast cancer (MBC). Sixty-four patients were enrolled, the majority of whom (95%) had been treated with an anthracycline and a taxane before study enrollment. Eligible women were treated with gemcitabine (1200 mg/m(2) weekly for 2 weeks with the third week off on a 21-day cycle) plus weekly doses of trastuzumab (4-mg/kg loading dose; 2 mg/kg thereafter) until disease progression. The median patient age was 55 years, and the median number of previously administered (including adjuvant) chemotherapy regimens was 3. Twenty-two patients were scored as 2+ for HER2 expression by immunohistochemistry; 39 patients scored 3+. Three patients were assessed as HER2-negative on central pathology review and were ineligible for evaluation. Fifty-nine of the 61 patients remained evaluable for response. The objective response rates were 38% in the intent-to-treat population (23 of 61) and 44% among the 39 patients with HER2 3+ expression. The median response duration was 5.8 months, median overall survival was 14.7 months, and median time to disease progression was 5.8 months. Trastuzumab plus gemcitabine was well tolerated. No cases of clinical congestive heart failure occurred. Grade 3/4 toxicities included asthenia in 4 patients, fever in 4, neutropenia in 18, dyspnea in 6, abdominal or back pain in 3, and edema and nausea in 1 patient each. The combination of trastuzumab plus gemcitabine appears to be well tolerated and effective for patients with HER2-positive MBC previously treated with chemotherapy.     

T-DM1 Efficacy in Patients With HER2-positive Metastatic Breast Cancer Progressing After a Taxane Plus Pertuzumab and Trastuzumab: An Italian Multicenter Observational Study

BackgroundT-DM1 improves progression-free survival (PFS) and overall survival (OS) in patients with metastatic human epidermal growth factor receptor 2-positive (HER2⁺) breast cancer progressing on prior trastuzumab plus a taxane. A paucity of data is available on T-DM1 efficacy after dual anti-HER2 blockade with pertuzumab and trastuzumab plus a taxane, which represents the current first-line standard of care. The present study is a retrospective/prospective evaluation of the efficacy and activity of second-line T-DM1 after front-line pertuzumab-based therapy.Patients and MethodsEligible patients were identified within the Gruppo Italiano Mammella (GIM) 14/BIOMETA study, a retrospective/prospective multicenter study on treatment patterns and outcomes of patients with metastatic breast cancer (ClinicalTrials.gov Identifier: NCT02284581). We searched for patients who received second-line T-DM1 after taxane plus trastuzumab and pertuzumab between November 15, 2013 and May 31, 2018. We calculated median PFS, median time to treatment failure (TTF), prolonged duration of therapy (PDT), objective response rate (ORR), and 1-year OS.ResultsOf 445 patients with HER2⁺ metastatic breast cancer, 77 were eligible for the analysis. At a median follow-up of 7 months, median PFS was 6.3 months (95% confidence intervals [CI], 4.8-7.7 months), and median TTF was 6.2 months (95% CI, 4-8.6 months). More than one-third of patients (37.6%; n = 29) experienced PDT with an ORR of 27.1%. At data cutoff, the median OS was not reached, and the 1-year OS was 82%.ConclusionsOur results show meaningful activity of T-DM1 after front-line pertuzumab plus trastuzumab and a taxane, with about 27% of patients having an objective response and 40% of patients achieving durable disease control.     

曲妥珠单抗辅助治疗26例HER2阳性乳腺癌患者长期心脏毒性观察

  目的   研究HER2阳性乳腺癌患者应用曲妥珠单抗治疗的心脏远期毒性反应。   方法  收集31例可手术且HER2阳性表达乳腺癌患者, HER2阳性表达定义为免疫组织化学方法(3+)或荧光原位杂交方法确认HER2基因扩增, 其中26例接受每3周1次的曲妥珠单抗治疗, 首次以负荷剂量8 mg/kg给药, 后每3周6 mg/kg维持治疗; 采用心脏二维超声定期监测左心射血分数(LVEF), 评估心脏毒性反应。   结果  曲妥珠单抗首次用药后随访期79~104个月, 中位随访90个月, 26例患者接受曲妥珠单抗治疗6个月和12个月为2例, 1年治疗为14例, 2年为10例。2例出现症状性左心射血分数下降, 降幅超过10%, 且1例伴有高血压患者出现心衰症状, 经对症处理1年后LVEF值仍为41%。辅助化疗使用过蒽环类对比未使用过蒽环类药物LVEF均值治疗前为(64.38±5.25)%, 使用1年后为(61.58±4.97)%, 使用5年后为(60.04±5.73)%(P > 0.05)。   结论   曲妥珠单抗总体安全性良好, 心脏毒性虽为可逆性, 但对具有高血压及心脏疾患的老年乳腺癌患者, 仍须注意评估与监测。      

Phase II Trial of Weekly Docetaxel,Vinorelbine, and Trastuzumab in the First-Line Treatment of Patients with HER2-Positive Metastatic Breast Cancer

BackgroundThe combinations of trastuzumab/docetaxel and trastuzumab/vinorelbine are highly active in the treatment of patients with HER2-positive metastatic breast cancer (MBC). We investigated the feasibility and safety of a 3-drug combination of trastuzumab, docetaxel, and vinorelbine as first-line therapy in this patient group.Patients and MethodsSixty patients with previously untreated, measurable HER2-positive MBC (immunohistochemistry 3+ and/or fluorescence in situ hybridization positive) were treated with docetaxel 30 mg/m² intravenously (I.V.) and vinorelbine 25 mg/m² I.V. on days 1 and 8 of each 3-week cycle. Trastuzumab was given weekly (4-mg/kg loading dose followed by 2 mg/kg/week). Patients were evaluated after 6 weeks; responders/stable patients continued treatment until progression.ResultsPatients received a median of 11 treatment cycles (range, 1–22 cycles). Forty-one of 60 patients (68%) had major responses (16 complete responses [27%], 25 partial responses [42%]). An additional 13 patients (22%) had stable disease for ≥ 6 months. After a median follow-up of 58 months, median progression-free survival was 12 months (95% CI, 9.1–16.3 months), and the median overall survival was 40.8 months (95% CI, 25-not reached). Neutropenia (72% grade 4) was the most common hematologic toxicity; 8 patients were hospitalized for febrile neutropenia. A total of 67% of patients required dose modifications for neutropenia during cycles 1 or 2. Other grade 3/4 toxicities included fatigue (12%), hyperglycemia (7%), and myalgias (7%). There were no treatment-related deaths.ConclusionThe combination of trastuzumab, docetaxel, and vinorelbine is highly active as first-line treatment for patients with HER2-positive MBC. However, this regimen offers no obvious advantages over other less myelosuppressive trastuzumab-containing regimens, and its routine use is not supported by the study.     

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.     

Use of trastuzumab beyond disease progression: observations from a retrospective review of case histories

HER2 overexpression is associated with poor breast cancer prognosis and is the target for the humanized monoclonal antibody trastuzumab. This novel agent, when administered until disease progression in combination with chemotherapy, extends the survival of women with HER2-positive metastatic breast cancer (MBC). However, the optimal duration of trastuzumab therapy remains to be confirmed. We conducted a retrospective case review study of women with HER2-positive MBC who continued to receive trastuzumab beyond disease progression. Objectives were to assess whether treatment beyond disease progression shows any evidence of efficacy and to evaluate the feasibility of this approach. One hundred five patients (median age, 47 years; range, 24-77 years) were identified in 13 centers. Women had received /=1 more trastuzumab regimen. Trastuzumab treatment beyond progression appears to be of value, producing responses and clinical benefit, and is well tolerated without significant cardiac toxicity. The feasibility of this approach warrants examination in prospective trials.     

The Global Need for a Trastuzumab Biosimilar for Patients With HER2-Positive Breast Cancer

Trastuzumab improves survival outcomes for patients with HER2-positive (HER2⁺) breast cancer, yet not all such women receive this important therapy. Trastuzumab was approved by the US Food and Drug Administration in 1998 and the European Medicines Agency in 2000 as treatment for HER2⁺ metastatic breast cancer (MBC). Observational studies between 2000 and 2015 in patients with HER2⁺ MBC suggest that nearly 12% in the United States, 27% to 54% in Europe, and 27.1% to 49.2% in China did not receive trastuzumab or any other HER2-targeted agent as first- and/or later-line for treatment of metastatic disease. In 2006, both agencies approved trastuzumab as adjuvant therapy for patients with HER2⁺ early breast cancer (EBC). Observational studies on real-world treatment patterns for HER2⁺ EBC between 2005 and 2015 suggest that 19.1% to 59.5% of patients across regions of North America, Europe, Australia, New Zealand, and China did not receive (neo)adjuvant trastuzumab. Data suggest that some patient subgroups, including older patients, those with HER2⁺/hormone receptor-positive disease, and women with small and/or node-negative HER2⁺ tumors, were less likely to receive anti-HER2 therapy. Barriers to accessing trastuzumab are multifactorial and include issues related to drug funding and high treatment costs for patients that have been reported worldwide. Herein, we review available literature on the use of, and barriers to, treatment with trastuzumab in patients with HER2⁺ breast cancer. We also discuss how the availability of safe and effective biosimilars might increase access to trastuzumab and allow greater use of anti-HER2 therapy, potentially improving patient outcomes.     

Trastuzumab-based Retreatment after Lapatinib in Heavily Pretreated HER2 Positive Metastatic Breast Cancer: an Anatolian Society of Medical Oncology Study

Background: For HER2 positive metastatic breast cancer (MBC), continuing anti-HER2 therapy beyondprogression is associated with improved outcome. However retreatment with trastuzumab after lapatinibprogression is controversial. We retrospectively analyzed the efficacy of trastuzumab-based chemotherapy inHER2+ metastatic breast cancer patients whose disease progressed after lapatinib. Materials and Methods:Between October 2010 and May 2013, 54 patients whose disease progressed after lapatinib were retreated withtrastuzumab-based chemotherapy. Efficacy and toxicity results were evaluated retrospectively. Results: Themedian age of patients was 46 (range 27-67). Fourteen patients (26%) had metastases at the time of diagnosis.All of the patients had received trastuzumab in an adjuvant or metastatic setting, while 16 (30%) had receivedtwo lines of trastuzumab. All patients had received lapatinib plus capecitabine. The median chemotherapyline for the metastatic setting was 2 (range 1-7). Cranial metastases were identified in 27 (50%) patients. 53patients received trastuzumab-based chemotherapy following lapatinib progression while one patient receivedtrastuzumab monotherapy. Combination chemotherapy consisted of navelbin (n=33), taxane (n=10), gemcitabine(n=2), platinum (n=2) and platinum with taxane (n=6). The median treatment cycle was 5 (range 1-44). Among 49patients assessed for response 2 (4%) showed CR, 12 (25%) PR, 11 (22%) SD and 24 (49%) disease progression.Asymptomatic cardiotoxicity was reported in 2 (4%) of the patients. At a median follow-up of 9 months (1-39),median progression-free survival was 5 months (95% CI 4.1-5.9) and median overall survival was 10 months(95% CI 6.9-13.0). PFS and OS were not affected by the absence/presence of cranial metastases. Conclusions:Retreatment with trastuzumab-based therapy after lapatinib progression showed efficacy in heavily treatedMBC patients.     

Final overall survival analysis of the phase 3 HERITAGE study demonstrates equivalence of trastuzumab-dkst to trastuzumab in HER2-positive metastatic breast cancer

Purpose

The phase 3 HERITAGE trial demonstrated that the biosimilar trastuzumab-dkst is well tolerated with similar efficacy (measured by overall response rate [ORR] and progression-free survival [PFS]) compared with originator trastuzumab combined with taxane followed by monotherapy in patients with HER2-positive metastatic breast cancer (MBC). Herein, we present final overall survival (OS) from HERITAGE.

Methods

HERITAGE is a multicenter, double-blind, randomized, parallel-group study. Patients were randomized 1:1 to receive trastuzumab-dkst or trastuzumab plus taxane followed by continued monotherapy until disease progression. Overall survival was to be assessed at 36 months or after 240 deaths, whichever occurred first, as observed from time of randomization of last patient.

Results

At the final analysis (36 months), 242 patients in the intention-to-treat population had died during the study: 116 and 124 in the trastuzumab-dkst and trastuzumab groups, respectively, and 1 untreated patient from each treatment group. Median OS by Kaplan–Meier analysis was 35.0 months with trastuzumab-dkst and 30.2 months with trastuzumab. Evaluation of PFS showed a median of 11.1 months in both treatment groups. No new safety concerns were reported from week 48 until the end of the survival follow-up.

Conclusion

This is the first phase 3 trial of a trastuzumab biosimilar to report long-term survival data similar to originator trastuzumab in patients with MBC. The comparable long-term OS between the trastuzumab-dkst and originator trastuzumab groups further supports the similarity of trastuzumab-dkst with originator trastuzumab and establishes trastuzumab-dkst as a safe and effective treatment option for patients with HER2-positive MBC.

ClinicalTrials.gov NCT02472964; 6/16/2015

     

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.     

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.     

Incidence and Management of Diarrhea With Adjuvant Pertuzumab and Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer

BackgroundThe APHINITY (BIG 4-11) study showed that pertuzumab significantly improved the rates of invasive disease-free survival among patients with human epidermal growth factor receptor 2 (HER2)-positive, operable breast cancer when added to adjuvant trastuzumab and chemotherapy. Because diarrhea was a common adverse event that could compromise treatment administration, we evaluated the incidence and management of diarrhea in the APHINITY study.Patients and MethodsThe APHINITY trial is a prospective, randomized, multicenter, multinational, double-blind, placebo-controlled trial. The eligible patients were randomly assigned to receive standard adjuvant chemotherapy and 1 year of trastuzumab combined with pertuzumab or placebo. The diarrhea incidence, severity (National Cancer Institute common terminology criteria for adverse events, version 4.0), onset, and management were analyzed.ResultsA total of 4805 patients were randomized. Diarrhea of any grade was the most common adverse event and occurred in 71% of patients in the pertuzumab arm versus 45% in the placebo arm. Diarrhea grade 3 to 4 was observed in 10% and 4% in the pertuzumab and placebo arms, respectively. The greatest incidence of diarrhea was reported during the concomitant administration of HER2-targeted therapy and taxane (61% vs. 34% of patients experienced an event with pertuzumab vs. placebo, respectively). A marked decrease was observed on chemotherapy cessation. Antidiarrheal agents were commonly used, and diarrhea rarely caused treatment dose modifications or discontinuation.ConclusionDiarrhea was a common adverse event in the APHINITY study. Most episodes were low grade and were generally manageable with common antidiarrheal agents. The incidence of diarrhea was greater with the combination of a taxane and HER2-targeted treatment and decreased once chemotherapy was stopped.     

ABCB1, FCGR2A, and FCGR3A Polymorphisms in Patients with HER2-Positive Metastatic Breast Cancer Who Were Treated with First-Line Taxane plus Trastuzumab Chemotherapy

Objective: The aim of this study was to elucidate clinical implications of ABCB1, FCGR2A, and FCGR3A polymorphisms in patients with HER2-positive metastatic breast cancer (MBC) after taxane plus trastuzumab (TH) chemotherapy. Methods: Using genomic DNA samples extracted from mononuclear cells of consecutive patients with HER2-positive MBC who received first-line TH, we analyzed five polymorphisms (ABCB1 1236C>T, ABCB1 2677G>T/A, ABCB1 3435C>T, FCGR2A 131H/R, and FCGR3A 158V/F) and then correlated them with the response rate, progression-free survival (PFS), overall survival (OS), and adverse events of patients. Results: A total of 57 women were analyzed. The median age was 46 years (range 27-72). ABCB1 2677T carriers had a longer PFS (p = 0.037) along with a tendency toward a longer OS (p = 0.057). ABCB1 3435CC genotype carriers had a shorter PFS (p = 0.039) along with a tendency toward a shorter OS (p = 0.093). In combined analysis, PFS was significantly longer in ABCB1 1236CC and/or 2677TT carriers compared to the others (p = 0.006). FCGR2A 131H/R and FCGR3A 158V/F polymorphisms were not significantly associated with response rate, PFS, and OS. Conclusions: Our data support that ABCB1 polymorphisms may predict PFS after first-line TH chemotherapy in patients with HER2-positive MBC. In contrast, FCGR2A 131H/R and FCGR3A 158V/F polymorphisms could not predict treatment outcomes.     

Phase II Multicenter Study of Docetaxel and Bevacizumab With or Without Trastuzumab as First-Line Treatment for Patients With Metastatic Breast Cancer

BackgroundAdding bevacizumab to docetaxel or paclitaxel in the first-line improves the progression-free survival (PFS) of metastatic breast cancer (MBC) patients. Docetaxel has been studied with bevacizumab at the maximally tolerated dose of 100 mg/m². We investigated the effects of combining bevacizumab with docetaxel (75 mg/m²) with or without trastuzumab for human epidermal growth factor receptor 2–positive (HER2⁺) and HER2–negative (HER2⁻) patients, respectively.Patients and MethodsWe conducted a phase II study, stratified by HER2 status, of patients with locally advanced breast cancer or MBC who had received no prior chemotherapy for metastatic disease and showed no evidence or history of central nervous system metastases. Stratum 1 (HER2⁻) treatment consisted of bevacizumab (15 mg/kg) followed by docetaxel (75 mg/m²) administered every 3 weeks; stratum 2 (HER2⁺) treatment was the same as that of stratum 1 with the addition of trastuzumab (8 mg/kg loading dose on day 2 of cycle 1, and 6 mg/kg on day 1 of all subsequent cycles).ResultsThe trial accrued 73 patients (stratum 1, 52 patients; stratum 2, 21 patients). The most common grade 3 or 4 adverse event (all strata) was fatigue (stratum 1, 11.5%; stratum 2, 10%). The incidence of grade 3 hypertension was 6% for stratum 1 and 5% for stratum 2. The median PFS was 8.4 months (95% CI, 5.2-10.4 months) in stratum 1; the median PFS in stratum 2 was 13.3 months (95% CI, 11.9-35.4 months). The overall response rate for stratum 1was 58% and for stratum 2 was 81%, and the clinical benefit rates were 67% and 81%, respectively.ConclusionIn first-line treatment of MBC, adding docetaxel (75 mg/m²) to bevacizumab administered every 3 weeks in HER2⁻ patients, and docetaxel plus trastuzumab plus bevacizumab treatment in HER2⁺ patients are feasible and safe, with high response rates and promising PFS compared with those of bevacizumab-naive historic controls.     

Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer.

BACKGROUND: Trastuzumab provides significant clinical benefits in HER2-positive metastatic breast cancer patients when administered in combination with chemotherapy. Chemotherapy has also been shown to be beneficial in some patients with advanced non-small-cell lung cancer (NSCLC). The present randomized phase II trial examined the effect of adding trastuzumab to a standard chemotherapeutic combination (gemcitabine-cisplatin) in patients with HER2-positive NSCLC. PATIENTS AND METHODS: Patients with untreated stage IIIB/IV HER2-positive NSCLC received up to six 21-day cycles of gemcitabine 1250 mg/m(2) (days 1 and 8) and cisplatin 75 mg/m(2) (day 1). Patients in the trastuzumab arm received trastuzumab 4 mg/kg intravenously (i.v.) followed by 2 mg/kg/week i.v. until progression. RESULTS: Of 619 patients screened, 103 were eligible. Fifty-one patients were treated with trastuzumab plus gemcitabine-cisplatin and 50 with gemcitabine-cisplatin alone. Efficacy was similar in the trastuzumab and control arms: response rate 36% versus 41%; median time to progression 6.3 versus 7.2 months; and median progression-free survival (PFS) 6.1 versus 7 months. Response rate (83%) and median PFS (8.5 months) appeared relatively good in the six trastuzumab-treated patients with HER2 3+ or fluorescence in situ hybridization (FISH)-positive NSCLC. Addition of trastuzumab to gemcitabine-cisplatin was well tolerated, side-effects were as expected, and trastuzumab did not exacerbate the known toxicity of gemcitabine and cisplatin. Symptomatic cardiotoxicity was observed in one trastuzumab-treated patient. Serum trastuzumab concentrations in the presence of gemcitabine-cisplatin were comparable to those of trastuzumab alone. CONCLUSIONS: Trastuzumab plus gemcitabine-cisplatin is well tolerated. Clinical benefit was not observed. Although HER2 3+/FISH-positive patients may benefit from trastuzumab, the subgroup is too small to provide definitive information. No significant effect of gemcitabine-cisplatin on trastuzumab pharmacokinetics was observed.