288P Final results from PERUSE, a global study of pertuzumab (P), trastuzumab (H) and investigator’s chosen taxane as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer (LR/mBC)
D.W. MilesEva CiruelosAndreas SchneeweißFabio PuglisiT. Peretz-YablonskiMario CamponeIgor BondarenkoZbigniew NoweckiHassan ErrihaniShani Paluch–ShimonAndrew WardleyJean-Louis MerotYolande Du ToitDirk KlingbielValentine RevelantThomas Bachelot
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Background: Human epidermal growth factor receptor 2 (HER-2) overexpression can be found in 15-20% of breast cancers, and it strongly correlates with aggressive clinical behavior and adverse prognosis. The first-line treatment for HER-2 positive metastatic breast cancers is the combination of trastuzumab, pertuzumab, and taxane (PTH). ABP 980 is a biosimilar of the innovator trastuzumab and is characterized by highly comparable effectiveness. Methods: The group of 61 patients with HER-2 positive MBC received biosimilar ABP 980 plus pertuzumab and docetaxel from November, 18, 2018 to December, 24, 2019. The response to therapy, overall survival (OS), progression-free survival (PFS), metastases, and adverse effects among patients were determined and analyzed. Results: Initially, 42 women responded partially to the treatment and their median PFS was 27 months. Median PFS for the whole group was 18 months. Cardiotoxicity of treatment was noticed in all patients in the form of the reduction in left ventricular ejection fraction but only in 2 cases, it was the reason for withdrawing from therapy. Conclusion: Biosimilar ABP 980 is registered in the same indications as the innovator trastuzumab and their effectiveness, as well as side effects, are comparable. The costs of biosimilar make the therapy more accessible and thus more patients with MBC around the world can receive relevant treatment.
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On the basis of the results from CLEOPATRA, pertuzumab plus trastuzumab and chemotherapy is the first-line standard of care for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). However, discrepancies have been reported between clinical trial and real-world outcomes. We report real-world outcomes for patients with HER2-positive MBC treated with first-line pertuzumab plus trastuzumab and a taxane in routine clinical practice in the United States.A retrospective analysis was conducted using electronic health record-derived deidentified data from the Flatiron Health database. Patients were grouped according to the first taxane received (paclitaxel/nab-paclitaxel or docetaxel). Median real-world progression-free survival (rwPFS) and overall survival (rwOS) was estimated using Kaplan-Meier methodology. Subgroup analyses were conducted in patients treated with docetaxel who met CLEOPATRA's key eligibility criteria.We included 1,065 patients; 313 patients received paclitaxel/nab-paclitaxel and 752 received docetaxel. Patients who received paclitaxel/nab-paclitaxel were older, had a worse Eastern Cooperative Oncology Group Performance Status, and had more recurrent metastatic disease compared with the docetaxel group. After adjustment for potential confounders, similar median rwPFS (inverse probability of treatment weighted average treatment effect for the treated [IPTW-ATT] hazard ratio [HR], 1.09; 95% CI, 0.9 to 1.3; P = .365) and rwOS (IPTW-ATT HR, 1.23; 95% CI, 0.96 to 1.58; P = .101) was observed between treatment groups. In the subgroup of CLEOPATRA-eligible patients, median rwPFS and rwOS were 16.9 months and 57.8 months, respectively.There was no statistically significant difference in real-world outcomes between patients treated with paclitaxel/nab-paclitaxel and those treated with docetaxel. Selecting patients using key CLEOPATRA eligibility criteria resulted in rwPFS and rwOS similar to those observed in CLEOPATRA, highlighting the importance of ensuring similar patient populations when comparing clinical trial and real-world data.
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Pertuzumab, a humanized monoclonal antibody and the first in the class of agents called the HER2 dimerization inhibitors, impairs the ability of HER2 to bind to other members of the HER family. It has a unique and complimentary mechanism of action compared with trastuzumab, and the combination has resulted in the enhanced blockade of the HER signaling pathway. When pertuzumab was used in combination with docetaxel and trastuzumab in the first-line treatment of metastatic HER2+ breast cancer, it led to an overall survival benefit. Pertuzumab has therefore been approved by the FDA and is currently used as a standard of care for this indication. It is also the first agent in oncology to receive accelerated FDA approval in the neoadjuvant setting. Randomized trials showed that the addition of pertuzumab to trastuzumab-based chemotherapy improves pathologic complete response rates in HER2+ early-stage breast cancer. A randomized phase III clinical trial with disease-free survival as the primary end point is evaluating the safety and efficacy of pertuzumab in the adjuvant setting. This article describes the preclinical data, synthesizes available data from phase I-III clinical trials of pertuzumab in early stage and metastatic settings, and puts them into perspective with current treatment recommendations and future research developments.
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HER2 overexpression occurs in about 15-20% of breast cancer cases and is associated with rapid tumor growth. The introduction in clinical practice of several drugs inhibiting the biological activity of HER2, such as trastuzumab, pertuzumab, trastuzumab emtansine (T-DM1) and lapatinib, has clearly modified the prognosis for these patients. The combination of the two inhibitors of HER2, trastuzumab and pertuzumab, with a taxane (paclitaxel or docetaxel), is currently considered the first choice treatment for patients affected by HER2-positive metastatic breast cancer, whereas T-DM1 is considered the preferred treatment after the failure of first line therapy. We present the case of a 50-year-old woman affected by HER2-positive breast cancer with bone, hepatic, pulmonary and encephalic metastases, resistant both to trastuzumab-pertuzumab double-block treatment and to T-DM1, but sensitive to third line therapy to the combination lapatinib-capecitabine with a clinical response both for visceral and cerebral metastases (Oncology).
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Abstract Background: Clinical practice guidelines recommend the combination of pertuzumab (PERJETA®), trastuzumab (Herceptin®) (PH) and a taxane for first-line treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer (HER2+ mBC) patients [Giordano et al., J Oncol Pract, 2018]. Most clinical trials investigating the efficacy and safety of pertuzumab and trastuzumab used docetaxel as the taxane (PHD) [Tian et al., Int J Clin Pharmacol Ther, 2017]. Paclitaxel used with pertuzumab and trastuzumab (PHP) is highly active and well tolerated and may be an effective alternative to docetaxel-based combination therapy (Bachelot et al., Ann Oncol, 2019; Dang et al., J Clin Oncol, 2017). We evaluated the use of taxanes with PH and patient outcomes after receiving PHP or PHD as first-line treatment for HER2+ mBC in a real-world setting. Methods: We conducted a retrospective cohort study, using the nationwide Flatiron Health Electronic Health Record (EHR)-derived de-identified database. Patients who received a taxane with PH as initial systemic therapy after mBC diagnosis between June 1, 2012 and April 30, 2019 were included. The taxane initiation and any switch was evaluated. An intention-to-treat analysis was adopted and we used Cox-proportional hazard model in the statistical analysis. Time To Last Administration (TTLA) was used as a proxy for treatment duration for PH and chemotherapy. Real world progression free survival (rwPFS) was used to describe the effectiveness of first-line therapies. Results: A total of 1054 patients received PH plus a taxane as first-line therapy for HER2+ mBC: 29.3% of patients received PHP (26.9% paclitaxel and 2.4% nab-paclitaxel) while 70.7% of patients received PHD. Patients in the PHP group at index date were significantly older (median age was 62.0 in PHP vs 58.0 in PHD group, <0.001), more likely to be recurrent patients (51.8% in PHP vs 44.3% in PHD, 0.032) and less frequently treated in the community setting (86.7% in PHP vs 96.4% in PHD, <0.001). Fifty-four (5.1%) patients switched taxane during first-line therapy. Fifteen (5.3%) switched from paclitaxel to nab-paclitaxel, 39 (5.2%) switched from docetaxel to either paclitaxel or nab-paclitaxel. No patient switched from paclitaxel or nab-paclitaxel to docetaxel. Median TTLA of the index taxane was 3.7 months (3.42, 3.91) in PHP vs 3.5 months (3.45, 3.45) in PHD. Median TTLA of PH was 10.6 months (95% CI 8.51-11.8) for PHP and 11.8 months (95% CI 10.49-13.3) for PHD. Median rwPFS was 12.9 months (95% CI 11.2, 15.8) for PHP and 14.9 months (95% CI 13.2-16.9) for PHD. No statistically significant difference was found between PHP and PHD for TTLA of PH and for rwPFS either in the unadjusted models or in the models adjusted for potential confounders. Conclusion: To our knowledge, this is the first study addressing the real world use of paclitaxel and evaluating the effectiveness of PHP vs PHD as first-line treatment in HER2+ mBC patients. PHP is used in the community practice and appears as effective as PHD. Citation Format: Letizia Polito, Jinjoo Shim, Yolande Du Toit, Thy Do, Adam Knott, Thibaut Sanglier. Use of pertuzumab in combination with taxanes for HER2+ metastatic breast cancer: Analysis of U.S. electronic health records [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-14.
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Practice PointsTreatment decision in HER2-positive metastatic breast cancer patients must be based on patient factors including evaluation of extent of disease, assessment of performance status, review of cardiac status and consideration of previous treatment including adjuvant taxanes and trastuzumab.Generally, taxanes, along with trastuzumab, remain the standard first-line approach.However, recent evidence suggests that patients may be considered for vinorelbine and trastuzumab based on superior toxicity profile and possible improved efficacy.Pertuzumab, along with docetaxel and trastuzumab, has demonstrated improved progression-free survival and may be the new standard therapy; however, appropriate cost-effectiveness studies need to be conducted.HER2-and hormone receptor-positive metastatic breast cancer patients with low-burden visceral disease and a prolonged disease-free interval may be candidates for treatment with either anastrozole and trastuzumab or lapatinib and letrozole.There is a need for prospective studies and predictive biomarkers to determine which patients could be treated with anti-HER2 and endocrine therapy instead of chemotherapy.Lapatinib and capecitabine should be considered for those patients who have progressed while on adjuvant trastuzumab and have evidence of brain metastases or for those do not have a significant response or have a shortened progression-free survival with chemotherapy and trastuzumab.Dramatic developments have occurred in the management of HER2-positive metastatic breast cancer in the past two decades.New regimens must focus not only on improved efficacy but also on superior toxicity profiles compared with current standard options.
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Aim To carry out a cost-minimization analysis including a comparison of the costs arising from first-line treatment by trastuzumab plus docetaxel versus trastuzumab plus paclitaxel in patients with metastatic breast cancer. Methods All consecutive patients with human epidermal growth receptor 2-postive metastatic breast cancer who were treated at Besançon University Hospital and Saint Vincent private hospital between 2001 and 2010 by first-line therapy containing trastuzumab plus taxane were retrospectively studied. Economic analysis took into account costs related to drugs, hospitalization, and healthcare travel. Results Progression-free survival difference between the two treatments was not significant ( p = 0.65). First-line treatment by trastuzumab plus taxane was estimated at approximately €68,000 ( p = 0.74). The drug costs represented around 70–75% of the total cost, mainly related to the use of trastuzumab. Conclusion Our economic analysis shows that although the costs of the two trastuzumab plus taxane regimens are similar, they may contribute to the on-going debate about the availability and use of innovative chemotherapy drugs, in particular in human epidermal growth factor receptor 2-positive metastatic breast cancer with new therapies such as trastuzumab-DM1 and pertuzumab.
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•Final safety and efficacy results from PERUSE with ∼6 years' median follow-up are consistent with CLEOPATRA results.•Results provide reassurance that paclitaxel is a valid alternative to docetaxel with first-line pertuzumab and trastuzumab.•In exploratory analyses, presence of both visceral disease and prior trastuzumab identified a subgroup with worse PFS. BackgroundThe phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting.Patients and methodsEligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors.ResultsOf 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade ≥3 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months).ConclusionsMature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design. The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade ≥3 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design.
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The standard first-line treatment for patients with human epidermal growth factor 2-positive metastatic breast cancer is a combination therapy of trastuzumab, pertuzumab and docetaxel, and the standard second-line treatment is trastuzumab emtansine. However, it may be difficult for the elderly to maintain sufficient intensity of treatment due to severe adverse events of trastuzumab, pertuzumab and docetaxel. The aim of this trial is to confirm the non-inferiority of trastuzumab emtansine over trastuzumab, pertuzumab and docetaxel in terms of overall survival in elderly (65-year-old or more) patients with human epidermal growth factor 2-positive metastatic breast cancer. If improved overall survival and fewer toxicities are observed, trastuzumab emtansine may be a feasible new standard first-line treatment for elderly patients with human epidermal growth factor 2-positive metastatic breast cancer. A planned total 330 patients will be enrolled from 45 institutions over 6.5 years. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000030783 [http://www.umin.ac.jp/ctr/index.htm].
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