Dataset Information

Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.

ABSTRACT: The anti-human epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody trastuzumab improves the outcome in patients with HER2-positive metastatic breast cancer. However, most cases of advanced disease eventually progress. Pertuzumab, an anti-HER2 humanized monoclonal antibody that inhibits receptor dimerization, has a mechanism of action that is complementary to that of trastuzumab, and combination therapy with the two antibodies has shown promising activity and an acceptable safety profile in phase 2 studies involving patients with HER2-positive breast cancer.We randomly assigned 808 patients with HER2-positive metastatic breast cancer to receive placebo plus trastuzumab plus docetaxel (control group) or pertuzumab plus trastuzumab plus docetaxel (pertuzumab group) as first-line treatment until the time of disease progression or the development of toxic effects that could not be effectively managed. The primary end point was independently assessed progression-free survival. Secondary end points included overall survival, progression-free survival as assessed by the investigator, the objective response rate, and safety.The median progression-free survival was 12.4 months in the control group, as compared with 18.5 months in the pertuzumab group (hazard ratio for progression or death, 0.62; 95% confidence interval, 0.51 to 0.75; P<0.001). The interim analysis of overall survival showed a strong trend in favor of pertuzumab plus trastuzumab plus docetaxel. The safety profile was generally similar in the two groups, with no increase in left ventricular systolic dysfunction; the rates of febrile neutropenia and diarrhea of grade 3 or above were higher in the pertuzumab group than in the control group.The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT00567190.).

SUBMITTER: Baselga J

PROVIDER: S-EPMC5705202 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.

Baselga José J Cortés Javier J Kim Sung-Bae SB Im Seock-Ah SA Hegg Roberto R Im Young-Hyuck YH Roman Laslo L Pedrini José Luiz JL Pienkowski Tadeusz T Knott Adam A Clark Emma E Benyunes Mark C MC Ross Graham G Swain Sandra M SM

The New England journal of medicine 20111207 2

<h4>Background</h4>The anti-human epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody trastuzumab improves the outcome in patients with HER2-positive metastatic breast cancer. However, most cases of advanced disease eventually progress. Pertuzumab, an anti-HER2 humanized monoclonal antibody that inhibits receptor dimerization, has a mechanism of action that is complementary to that of trastuzumab, and combination therapy with the two antibodies has shown promising activity an ...[more]

PMID: 22149875

Similar Datasets

Project description:BACKGROUND:NeoSphere showed significantly higher pathologic complete response (pCR) with neoadjuvant pertuzumab, trastuzumab, and docetaxel compared with trastuzumab plus docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel. We assessed associations between human epidermal growth factor receptor 2 (HER2) pathway-related biomarkers and clinical outcome in response to these regimens. METHODS:Tumor, serum, and whole blood samples were collected at baseline and post neoadjuvant treatment before surgery. Associations between biomarkers and pCR, and between biomarkers and clinical variables were assessed in the overall and estrogen receptor (ER)-positive and ER-negative populations. Changes in serum marker levels between baseline and post-neoadjuvant treatment were examined. RESULTS:No markers were associated with pCR across all groups; however, significant associations were observed for two markers in individual groups. High HER2 was significantly associated with higher pCR rates (P?=?0.001) and a significant treatment interaction (P?=?0.0236) with pertuzumab, trastuzumab, and docetaxel (odds ratio 2.07, P?=?0.01). Low serum transforming growth factor alpha (TGF?) was associated with higher pCR rates with pertuzumab plus trastuzumab (P?=?0.04) without a significant treatment interaction. Presence of truncated HER2 did not affect pCR. A non-significant decreased pCR benefit was observed consistently across groups in patients with mutated PIK3CA while the treatment benefit from pertuzumab was maintained when comparing the trastuzumab plus docetaxel and pertuzumab, trastuzumab, and docetaxel groups. Notably, PIK3CA exon 9 mutations were associated with residual disease (pooled groups), which was not found for exon 20 mutations. Serum HER2 extracellular domain levels were significantly increased between baseline and post-neoadjuvant treatment in the non-trastuzumab-treated group, and decreased in the trastuzumab-containing groups (likely due to trastuzumab's mechanism of action). Differences in biomarker profiles according to ER status were observed. CONCLUSIONS:The observed associations of HER2 protein levels with sensitivity to pertuzumab, and of PIK3CA exon 9 mutation to lack of sensitivity to HER2-targeted monoclonal antibody treatment, warrant further investigation. Previously reported findings of truncated forms of HER2 as resistance markers to HER2-targeted treatment could not be confirmed in NeoSphere. Conventional HER2 assessment should continue and HER2 remains the only biomarker suitable for patient selection in this population. TRIAL REGISTRATION:Clinicaltrials.gov, NCT00545688 . Registered on 16 October 2007.

Project description:BackgroundIn patients with metastatic breast cancer that is positive for human epidermal growth factor receptor 2 (HER2), progression-free survival was significantly improved after first-line therapy with pertuzumab, trastuzumab, and docetaxel, as compared with placebo, trastuzumab, and docetaxel. Overall survival was significantly improved with pertuzumab in an interim analysis without the median being reached. We report final prespecified overall survival results with a median follow-up of 50 months.MethodsWe randomly assigned patients with metastatic breast cancer who had not received previous chemotherapy or anti-HER2 therapy for their metastatic disease to receive the pertuzumab combination or the placebo combination. The secondary end points of overall survival, investigator-assessed progression-free survival, independently assessed duration of response, and safety are reported. Sensitivity analyses were adjusted for patients who crossed over from placebo to pertuzumab after the interim analysis.ResultsThe median overall survival was 56.5 months (95% confidence interval [CI], 49.3 to not reached) in the group receiving the pertuzumab combination, as compared with 40.8 months (95% CI, 35.8 to 48.3) in the group receiving the placebo combination (hazard ratio favoring the pertuzumab group, 0.68; 95% CI, 0.56 to 0.84; P<0.001), a difference of 15.7 months. This analysis was not adjusted for crossover to the pertuzumab group and is therefore conservative. Results of sensitivity analyses after adjustment for crossover were consistent. Median progression-free survival as assessed by investigators improved by 6.3 months in the pertuzumab group (hazard ratio, 0.68; 95% CI, 0.58 to 0.80). Pertuzumab extended the median duration of response by 7.7 months, as independently assessed. Most adverse events occurred during the administration of docetaxel in the two groups, with long-term cardiac safety maintained.ConclusionsIn patients with HER2-positive metastatic breast cancer, the addition of pertuzumab to trastuzumab and docetaxel, as compared with the addition of placebo, significantly improved the median overall survival to 56.5 months and extended the results of previous analyses showing the efficacy of this drug combination. (Funded by F. Hoffmann-La Roche and Genentech; CLEOPATRA ClinicalTrials.gov number, NCT00567190.).

Project description:ImportanceTo date, limited studies have examined the comparative outcomes of pertuzumab treatment in the real-world setting. End-of-study analyses of the CLEOPATRA trial found median overall survival (OS) of 57.1 months in patients receiving pertuzumab compared with 40.8 months in control patients, a benefit of 16.3 months. However, studies examining the real-world use of pertuzumab have found conflicting results.ObjectiveTo assess the real-world comparative effectiveness and safety of pertuzumab, trastuzumab, and chemotherapy for patients with metastatic breast cancer in Ontario, Canada.Design, setting, and participantsA population-based retrospective comparative effectiveness research study was conducted. Patients receiving first-line treatments for metastatic breast cancer from January 1, 2008, to March 31, 2018, in Ontario were identified. Data analysis was performed from November 13, 2019, to August 1, 2021. Thirteen patients had received treatment before diagnosis or were not Ontario residents and were excluded from the analysis. Of the remaining 1823 patients identified, 912 received pertuzumab and 911 were control patients. Using propensity-score methods, 579 pairs of patients receiving pertuzumab were matched to those in the control group, resulting in a total of 1158 patients in the final cohort.ExposuresPatients in the case group received pertuzumab with trastuzumab and chemotherapy and those in the control group received trastuzumab and chemotherapy.Main outcomes and measuresOverall survival (the primary outcome) and hazard ratios (HRs) were calculated using Kaplan-Meier and Cox proportional hazards regression methods. Secondary outcomes included cumulative incidence of safety end points including resource use and adverse events. Follow-up duration was up to 5 years from the start of therapy, with maximum follow-up to March 31, 2019.ResultsOf the 1158 matched patients (579 pairs) receiving pertuzumab and controls, 1151 (99%) were women (mean [SD] age, 58.2 [12.97] years). The median OS was higher in patients receiving pertuzumab (40.2; 95% CI, 35.6-47.8 months) than in the control patients (25.3; 95% CI, 22.8-27.6 months), a median OS improvement of 14.9 months. Pertuzumab was associated with reduced mortality (HR, 0.66; 95% CI, 0.57-0.79). The cumulative incidence of direct hospitalization at 1 year was lower among patients receiving pertuzumab (11.7%) compared with the control patients (19.0%) (P < .001).Conclusions and relevanceAlthough the median OS in both the pertuzumab and control groups were shorter in this study than those observed in the CLEOPATRA trial, there appears to be a similar significant OS benefit with pertuzumab in the real-world setting.

Project description:IntroductionMyocardial strain imaging and blood biomarkers have been proposed as adjuncts to left ventricular ejection fraction (LVEF) monitoring for the early detection of cardiotoxicity during cancer therapy. We report the results of a preplanned cardiac safety analysis of global longitudinal strain (GLS), and troponin-I (TnI) and brain natriuretic peptide (BNP) levels in the phase II study of paclitaxel, trastuzumab, and pertuzumab (THP) for metastatic HER2-positive breast cancer.Patients and methodsPatients with 0-1 lines of prior therapy were treated with weekly paclitaxel (80 mg/m(2)) plus trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and pertuzumab (840 mg loading dose followed by 420 mg) every 3 weeks. Exploratory endpoints were GLS measured with speckle-tracking echocardiography every 3 months and TnI and BNP levels measured every 6 weeks (immediately pre- and postchemotherapy infusion) at 6 time points.ResultsSixty-seven of 69 enrolled patients were treated with THP: 19 (28%) had hypertension, 8 (12%) had diabetes, 11 (16%) had hyperlipidemia, and 26 (38%) had smoking history. After a median follow-up of 21 months (range: 3-38 months), no patients developed symptomatic heart failure. Two patients (3.0%) experienced asymptomatic LVEF decline (grade 2). The mean GLS (±SD) was 19% ± 2% (baseline), 19% ± 2% (month 6), and 19% ± 3% (month 12). Detectable TnI (>0.06 ng/mL) and elevated BNP (>100 pg/mL) levels were observed in 3 (4.3%) and 2 (3.0%) patients, respectively, but were not associated with LVEF decline.ConclusionThe absence of any significant changes in GLS and cardiac biomarkers (TnI and BNP) further support the cardiac safety of THP in patients with metastatic HER2-positive breast cancer.Implications for practiceDual anti-HER2 therapy with trastuzumab and pertuzumab in combination with taxane-based chemotherapy improves overall survival in patients with metastatic HER2-positive breast cancer. There is a critical need to investigate the potential cardiotoxicity of dual anti-HER2 blockade, given the importance of HER2 signaling in cardiac homeostasis and stress response. Global longitudinal strain and cardiac biomarkers have been proposed as adjuncts to left ventricular ejection fraction for the early detection of cardiotoxicity. In this phase II study of combination trastuzumab and pertuzumab with paclitaxel, no clinically significant change was observed in global longitudinal strain or cardiac biomarkers. These results further support the cardiac safety of dual anti-HER2 blockade previously reported in the CLEOPATRA study. The findings in the current study also call into question the role of intensive cardiac monitoring among patients treated with anti-HER2 therapy in the absence of anthracyclines. Less frequent cardiac assessments could lead to a reduction in unnecessary treatment interruption and is an important consideration given the rise in medical expenditures, but this requires further investigation.

Project description:PurposeWe aimed to improve efficacy and reduce toxicity of high-risk human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC) treatment by replacing taxanes and trastuzumab with trastuzumab emtansine (T-DM1).MethodsThe phase III KAITLIN study (NCT01966471) included adults with excised HER2-positive EBC (node-positive or node-negative, hormone receptor-negative, and tumor > 2.0 cm). Postsurgery, patients were randomly assigned 1:1 to anthracycline-based chemotherapy (three-four cycles) and then 18 cycles of T-DM1 plus pertuzumab (AC-KP) or taxane (three-four cycles) plus trastuzumab plus pertuzumab (AC-THP). Adjuvant radiotherapy/endocrine therapy was permitted. Coprimary end points were invasive disease-free survival (IDFS) in the intention-to-treat node-positive and overall populations with hierarchical testing.ResultsThe median follow-up was 57.1 months (interquartile range, 52.1-60.1 months) for AC-THP (n = 918) and 57.0 months (interquartile range, 52.1-59.8 months) for AC-KP (n = 928). There was no significant IDFS difference between arms in the node-positive (n = 1,658; stratified hazard ratio [HR], 0.97; 95% CI, 0.71 to 1.32) or overall population (n = 1846; stratified HR, 0.98; 95% CI, 0.72 to 1.32). In the overall population, the three-year IDFS was 94.2% (95% CI, 92.7 to 95.8) for AC-THP and 93.1% (95% CI, 91.4 to 94.7) for AC-KP. Treatment completion rates (ie, 18 cycles) were 88.4% for AC-THP and 65.0% for AC-KP (difference driven by T-DM1 discontinuation because of laboratory abnormalities [12.5%]). Similar rates of grade ≥ 3 (55.4% v 51.8%) and serious adverse events (23.3% v 21.4%) occurred with AC-THP and AC-KP, respectively. KP decreased clinically meaningful deterioration in global health status versus THP (stratified HR, 0.71; 95% CI, 0.62 to 0.80).ConclusionThe primary end point was not met. Both arms achieved favorable IDFS. Trastuzumab plus pertuzumab plus chemotherapy remains the standard of care for high-risk HER2-positive EBC.

Project description:PurposeIntravenous trastuzumab, pertuzumab, and docetaxel are first-line standard of care for patients with HER2-positive metastatic breast cancer (mBC). MetaPHER is the first study assessing the safety and tolerability of subcutaneous trastuzumab plus intravenous pertuzumab and chemotherapy in a global patient population with HER2-positive mBC.MethodsIn this open-label, single-arm, multicenter, phase 3b study, eligible patients were ≥ 18 years old with histologically/cytologically confirmed previously untreated HER2-positive mBC. All received ≥ 1 subcutaneous trastuzumab 600 mg fixed dose plus intravenous pertuzumab (loading dose: 840 mg/kg; maintenance: 420 mg/kg) and docetaxel (≥ 6 cycles; initial dose 75 mg/m2) every 3 weeks. The primary objective was safety and tolerability; secondary objectives included efficacy.ResultsAt clinical cutoff, 276 patients had completed the study; median duration of follow-up was 27 months. The most common any-grade adverse events were diarrhea, alopecia, and asthenia; the most common grade ≥ 3 events were neutropenia, febrile neutropenia, and hypertension. There were no cardiac deaths and mean left ventricular ejection fraction was stable over time. Median investigator-assessed progression-free survival was 18.7 months; objective response rate was 75.6%.ConclusionsSafety and efficacy with subcutaneous trastuzumab plus intravenous pertuzumab and docetaxel in mBC are consistent with historical evidence of intravenous trastuzumab with this combination. Findings further support subcutaneous administration not affecting safety/efficacy profiles of trastuzumab in HER2-positive BC with increased flexibility in patient care. A fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection has recently been approved for the treatment of HER2-positive early/mBC, further addressing the increasing relevance of and need for patient-centric treatment strategies.Trial registrationNCT02402712.

Dataset Information

Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.

Publications

Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets