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Javier Cortes - One of the best experts on this subject based on the ideXlab platform.
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Incidence and management of diarrhea in patients with HER2-positive breast cancer treated with Pertuzumab
Annals of oncology : official journal of the European Society for Medical Oncology, 2017Co-Authors: Sandra M Swain, Sarah Heeson, Andreas Schneeweiss, Luca Gianni, Jianjiong Gao, A. Stein, M. Waldron-lynch, Michael S. Beattie, Bongin Yoo, Javier CortesAbstract:ABSTRACT Background Pertuzumab disrupts heterodimerization between human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR), HER3, and HER4. Thus, Pertuzumab could result in adverse events similar to those observed with EGFR antagonists, such as diarrhea. We report the incidence and severity of diarrhea observed with Pertuzumab in the CLEOPATRA, NeoSphere, and TRYPHAENA studies. Patients and methods Patients (n = 1443) had metastatic [CLEOPATRA (n = 804)] or early-stage breast cancer [NeoSphere (n = 416) and TRYPHAENA (n = 223)]. The incidence and severity of diarrhea were analyzed by treatment received. The incidence of febrile neutropenia concurrent with diarrhea and the effect of pre-existing gastrointestinal comorbidities were also evaluated. Subgroup analyses were carried out using CLEOPATRA data. Results The incidence of all-grade diarrhea across studies was generally greater for Pertuzumab-based treatment, ranging from 28% to 72% (grade 1, 21%–54%; grade 2, 8%–37%; grade 3, 0%–12%; grade 4, 0%). Incidence was highest during the first Pertuzumab-containing cycle, decreasing with subsequent cycles. Dose delays or discontinuations due to diarrhea were infrequent, ranging from 0% to 8%. Among Pertuzumab-treated patients with diarrhea, 47%–67% received pharmacological intervention, most commonly with loperamide. Overlap between diarrhea and febrile neutropenia was uncommon, ranging from 0% to 11%. No relationship was observed between pre-existing gastrointestinal comorbidities and diarrhea. In CLEOPATRA, patients ≥65 years treated with Pertuzumab had a higher incidence of grade 3 diarrhea than patients Conclusions In both the metastatic and early-stage breast cancer settings, diarrhea was common but manageable for all Pertuzumab-containing regimens. Diarrheal episodes were mainly low grade and occurred most often during the first treatment cycle. Diarrheal-related drug delays or discontinuations were uncommon. ClinicalTrials.gov identifiers NCT00567190 (CLEOPATRA), NCT00545688 (NeoSphere), NCT00976989 (TRYPHAENA).
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health related quality of life assessment in cleopatra a phase iii study combining Pertuzumab with trastuzumab and docetaxel in metastatic breast cancer
Annals of Oncology, 2013Co-Authors: Javier Cortes, Jose Baselga, Xavier Pivot, Adam Knott, Graham Ross, Emma Clark, Sandra M SwainAbstract:Abstract Background The phase III CLEOPATRA study demonstrated that combining Pertuzumab with trastuzumab plus docetaxel significantly improves progression-free and overall survival in previously untreated HER2-positive metastatic breast cancer. Here, we report health-related quality-of-life (HRQoL) results from CLEOPATRA. Patients and methods Participants were randomly assigned to Pertuzumab or placebo, each given with trastuzumab plus docetaxel every 3 weeks. Pertuzumab and trastuzumab were administered until progression and six or more docetaxel cycles were recommended. Time from randomization to a ≥5-point decrease in Trial Outcome Index-Physical/Functional/Breast (TOI-PFB) of the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire was analyzed as a prespecified secondary end point. A post hoc exploratory analysis investigated time to ≥2-point deterioration in Breast Cancer Subscale (BCS) score. Results Time to ≥5-point decline in TOI-PFB did not differ significantly between the Pertuzumab and placebo arms [hazard ratio (HR), 0.97; P = 0.7161]. The median times to TOI-PFB deterioration were 18.4 and 18.3 weeks, respectively (approximately six cycles). The mean TOI-PFB declined slightly until week 18 and recovered thereafter. Pertuzumab increased time until BCS deterioration versus placebo (median 26.7 versus 18.3 weeks; HR, 0.77; P = 0.0061). Conclusions Combining Pertuzumab with trastuzumab and docetaxel had no adverse impact on HRQoL and may prolong time to worsening of breast cancer-specific symptoms.
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Use of Pertuzumab for the Treatment of HER2-Positive Metastatic Breast Cancer
Advances in Therapy, 2013Co-Authors: Leticia De Mattos-arruda, Javier CortesAbstract:Introduction Targeting the human epidermal growth factor receptor (HER) family of tyrosine kinase receptors has proven to be effective as a therapeutic strategy for HER type 2 (HER2)-positive breast cancer. Since resistance to trastuzumab occurs relatively frequently, particularly in the metastatic setting, novel anti-HER2 targeted therapies with complementary and/or synergistic mechanisms of action have been under development. Pertuzumab, a HER2-targeted monoclonal antibody that prevents HER2 dimerisation, is the first of a class of promising targeted agents for the treatment of HER2-positive breast cancer. Methods A review of the biomedical literature published prior to February 2013 was conducted in English using PubMed. ClinicalTrials.gov was searched for appropriate clinical trials. The search terms used included breast neoplasm, Pertuzumab, dimerisation, and HER2-positive. Abstracts of studies presented at the ASCO and ESMO Annual Meetings, and San Antonio Breast Cancer Symposium were also included. Results Pertuzumab represents a novel anti-HER2 targeted therapy for HER2-positive breast cancers. In this article, we describe the mechanism of action of Pertuzumab, as well as its drug development process and preclinical testing results. Based on the results of ancillary studies, dual inhibition using Pertuzumab and trastuzumab was shown to be effective for the management of HER2-positive metastatic breast cancers pre-treated with trastuzumab-based therapy. For the first-line setting, the combination of both Pertuzumab and trastuzumab with docetaxel (CLEOPATRA trial; clinical evaluation of Pertuzumab and trastuzumab) has changed the paradigm of patient management. Conclusion Pertuzumab provided a more comprehensive inhibition of HER2-driven signalling pathways. When administered together with trastuzumab, Pertuzumab represent a significant advancement for the treatment of HER2-positive metastatic breast cancer patients.
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cardiac tolerability of Pertuzumab plus trastuzumab plus docetaxel in patients with her2 positive metastatic breast cancer in cleopatra a randomized double blind placebo controlled phase iii study
Oncologist, 2013Co-Authors: Sandra M Swain, Javier Cortes, Adam Knott, Graham Ross, Michael S Ewer, Dino Amadori, David Miles, Emma Clark, Mark C Benyunes, Jose BaselgaAbstract:INTRODUCTION We report cardiac tolerability of Pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel observed in the phase III study CLEOPATRA in patients with HER2-positive first-line metastatic breast cancer (MBC). PATIENTS AND METHODS Left ventricular ejection fraction (LVEF) ≥ 50% and ECOG performance status of 0 or 1 were required for study entry. During the study, LVEF assessments took place every 9 weeks. Pertuzumab/placebo was given at 840 mg, then 420 mg q3w; trastuzumab was administered at 8 mg/kg, then 6 mg/kg q3w, and docetaxel was initiated at 75 mg/m(2) q3w. RESULTS The incidence of cardiac adverse events (all grades) was 16.4% in the placebo arm and 14.5% in the Pertuzumab arm, with left ventricular systolic dysfunction (LVSD, all grades) being the most frequently reported event (8.3% versus 4.4% in the placebo and Pertuzumab arm). Declines in LVEF by ≥ 10% points from baseline and to <50% were reported in 6.6% and 3.8% of patients in the placebo and Pertuzumab arm, respectively. Seventy-two percent (placebo arm) and 86.7% (Pertuzumab arm) of those patients recovered to a value ≥ 50%. The incidence of symptomatic LVSD was low, occurring in 1.8% (n = 7) versus 1.0% (n = 4) of patients in the placebo and Pertuzumab arm. In 8/11 patients, the symptomatic LVSD had resolved at data cutoff. CONCLUSION The combination of Pertuzumab plus trastuzumab plus docetaxel did not increase the incidence of cardiac adverse events, including LVSD, compared with the control arm in HER2-positive MBC. The majority of cardiac adverse events were reversible.
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Absence of pharmacokinetic drug-drug interaction of Pertuzumab with trastuzumab and docetaxel.
Anti-cancer drugs, 2013Co-Authors: Javier Cortes, Sandra M Swain, V. Mcnally, Iveta Kudaba, Maik Hauschild, Taral Patel, Elza Grincuka, Norikazu Masuda, Graham Ross, Mike BrewsterAbstract:Pertuzumab is a novel antihuman epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody. Combined with trastuzumab plus docetaxel, Pertuzumab improved progression-free and overall survival versus trastuzumab plus docetaxel in the phase III CLEOPATRA trial (NCT00567190) in first-line HER2-positive metastatic breast cancer. Thirty-seven patients participated in a pharmacokinetic (PK)/corrected QT interval substudy of CLEOPATRA, which evaluated potential PK drug-drug interaction (DDI). PK parameters were calculated using noncompartmental methods, and DDI analyses were carried out. In the presence of trastuzumab and docetaxel, the mean Pertuzumab Cmin and Cmax in cycle 3 were 63.6 and 183 µg/ml, respectively. The Pertuzumab concentrations observed were consistent with simulations from a validated population PK model, indicating that trastuzumab and docetaxel did not alter Pertuzumab PK. Comparison of geometric least-squares mean PK parameters between arms showed no impact of Pertuzumab on the PK of trastuzumab or docetaxel. In conclusion, no PK DDI was observed when Pertuzumab, trastuzumab, and docetaxel were combined for the treatment of HER2-positive metastatic breast cancer.
Sandra M Swain - One of the best experts on this subject based on the ideXlab platform.
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Pertuzumab trastuzumab and docetaxel for her2 positive metastatic breast cancer cleopatra end of study results from a double blind randomised placebo controlled phase 3 study
Lancet Oncology, 2020Co-Authors: Sungbae Kim, Sandra M Swain, Andreas Schneeweiss, V F Semiglazov, E. Ciruelos, David Miles, Sherene Loi, Estefania Monturus, Emma ClarkAbstract:Summary Background CLEOPATRA was a phase 3 study comparing the efficacy and safety of Pertuzumab, trastuzumab, and docetaxel with placebo, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer. In the primary analysis and subsequent reports, progression-free and overall survival were significantly improved in the Pertuzumab group compared with the placebo group. Here, we report the end-of-study analysis of CLEOPATRA. Methods This was a double-blind, randomised, placebo-controlled, phase 3 trial that was done at 204 centres in 25 countries. Eligible patients were 18 years or older, had HER2-positive, metastatic breast cancer, had not received previous chemotherapy or biological treatment for their metastatic disease, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. All study drugs were given intravenously, every 3 weeks. Patients were assigned to receive either Pertuzumab or placebo at a loading dose of 840 mg, and 420 mg thereafter; plus trastuzumab at 8 mg/kg loading dose and 6 mg/kg thereafter; and docetaxel at 75 mg/m2, escalating to 100 mg/m2 if tolerated. Pertuzumab or placebo and trastuzumab were given until disease progression; docetaxel was given for six cycles, or longer at the investigators' discretion. Randomisation (1:1) was done by use of an interactive voice-response system and was stratified by geographical region (Asia, Europe, North America, or South America) and previous treatment (previous adjuvant or neoadjuvant chemotherapy vs none). The primary endpoint was independent review facility-assessed progression-free survival, which has been reported previously. Since the confirmatory overall survival analysis had also occurred before this prespecified end-of-study analysis, analyses presented here are descriptive. Overall survival analyses were based on the intention-to-treat population with crossover patients analysed in the placebo group; analyses were not adjusted for crossover to the Pertuzumab group and are likely to be conservative. Safety analyses were based on treatment received; crossover patients were counted in the placebo group up to the day before first Pertuzumab dose. This trial is registered with ClinicalTrials.gov, number NCT00567190. Findings Between Feb 12, 2008, and July 7, 2010, 1196 patients were assessed for eligibility, of whom 808 were enrolled and randomly assigned. 402 patients were assigned to receive docetaxel plus trastuzumab plus Pertuzumab, and 406 patients were assigned to receive docetaxel plus trastuzumab plus placebo. Clinical cutoff for this analysis was Nov 23, 2018. Between July 2012 and clinical cutoff, 50 patients crossed from the placebo to the Pertuzumab group. Median follow-up was 99·9 months in the Pertuzumab group (IQR 92·9–106·4) and 98·7 months (90·9–105·7) in the placebo group. Median overall survival was 57·1 months (95% CI 50–72) in the Pertuzumab group and 40·8 months (36–48) in the placebo group (hazard ratio 0·69, 95% CI 0·58–0·82); 8-year landmark overall survival rates were 37% (95% CI 31–42) in the Pertuzumab group and 23% (19–28) in the placebo group. The most common grade 3–4 adverse event was neutropenia (200 [49%] of 408 patients in the Pertuzumab group, 183 [46%] of 396 patients in the placebo group). Five (1%) of 408 patients in the Pertuzumab group and six (2%) of 396 patients in the placebo group had treatment-related deaths. One new serious adverse event suggestive of congestive heart failure (Pertuzumab group) and one new symptomatic left ventricular systolic dysfunction (post-crossover) occurred since the previous analysis. Interpretation Our analysis shows that the previously observed improvements in overall survival with Pertuzumab, trastuzumab, and docetaxel versus placebo, trastuzumab, and docetaxel were maintained after a median of more than 8 years of follow-up. The long-term safety and cardiac safety profiles of Pertuzumab, trastuzumab, and docetaxel were maintained in the overall safety population and within crossover patients. HER2-targeted therapy has changed the natural history of HER2-positive metastatic breast cancer, with the dual blockade of Pertuzumab and trastuzumab, with docetaxel, demonstrating an 8-year landmark overall survival rate of 37%. Funding F Hoffmann-La Roche and Genentech.
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Incidence and management of diarrhea in patients with HER2-positive breast cancer treated with Pertuzumab
Annals of oncology : official journal of the European Society for Medical Oncology, 2017Co-Authors: Sandra M Swain, Sarah Heeson, Andreas Schneeweiss, Luca Gianni, Jianjiong Gao, A. Stein, M. Waldron-lynch, Michael S. Beattie, Bongin Yoo, Javier CortesAbstract:ABSTRACT Background Pertuzumab disrupts heterodimerization between human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR), HER3, and HER4. Thus, Pertuzumab could result in adverse events similar to those observed with EGFR antagonists, such as diarrhea. We report the incidence and severity of diarrhea observed with Pertuzumab in the CLEOPATRA, NeoSphere, and TRYPHAENA studies. Patients and methods Patients (n = 1443) had metastatic [CLEOPATRA (n = 804)] or early-stage breast cancer [NeoSphere (n = 416) and TRYPHAENA (n = 223)]. The incidence and severity of diarrhea were analyzed by treatment received. The incidence of febrile neutropenia concurrent with diarrhea and the effect of pre-existing gastrointestinal comorbidities were also evaluated. Subgroup analyses were carried out using CLEOPATRA data. Results The incidence of all-grade diarrhea across studies was generally greater for Pertuzumab-based treatment, ranging from 28% to 72% (grade 1, 21%–54%; grade 2, 8%–37%; grade 3, 0%–12%; grade 4, 0%). Incidence was highest during the first Pertuzumab-containing cycle, decreasing with subsequent cycles. Dose delays or discontinuations due to diarrhea were infrequent, ranging from 0% to 8%. Among Pertuzumab-treated patients with diarrhea, 47%–67% received pharmacological intervention, most commonly with loperamide. Overlap between diarrhea and febrile neutropenia was uncommon, ranging from 0% to 11%. No relationship was observed between pre-existing gastrointestinal comorbidities and diarrhea. In CLEOPATRA, patients ≥65 years treated with Pertuzumab had a higher incidence of grade 3 diarrhea than patients Conclusions In both the metastatic and early-stage breast cancer settings, diarrhea was common but manageable for all Pertuzumab-containing regimens. Diarrheal episodes were mainly low grade and occurred most often during the first treatment cycle. Diarrheal-related drug delays or discontinuations were uncommon. ClinicalTrials.gov identifiers NCT00567190 (CLEOPATRA), NCT00545688 (NeoSphere), NCT00976989 (TRYPHAENA).
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Pertuzumab for the treatment of breast cancer: a safety review
Expert opinion on drug safety, 2016Co-Authors: Jennifer Gao, Sandra M SwainAbstract:ABSTRACTIntroduction: Approximately twenty to thirty percent of newly diagnosed breast cancers are human epidermal growth factor receptor 2 (HER2) positive. The use of trastuzumab, and more recently Pertuzumab, has significantly improved the progression free survival (PFS) and overall survival (OS) in this patient population. However, Pertuzumab has side effects that can impact treatment tolerability and quality of life.Areas covered: This review describes the safety and tolerability of Pertuzumab, a monoclonal antibody targeted at HER2 approved by the United States Food and Drug Administration (FDA) for use in the neoadjuvant and first line metastatic settings.Expert opinion: The combination of trastuzumab, Pertuzumab, and chemotherapy is approved in the neoadjuvant and first line metastatic settings and should be strongly considered by providers. Further studies are needed to look at side effect prevention, novel Pertuzumab containing regimens, and re-treating patients with Pertuzumab.
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Pertuzumab trastuzumab and docetaxel in her2 positive metastatic breast cancer
The New England Journal of Medicine, 2015Co-Authors: Sandra M Swain, Sungbae Kim, Jean-marc Ferrero, Andreas Schneeweiss, V F Semiglazov, Jose Baselga, Jungsil Ro, E. Ciruelos, Mario Campone, Sarah HeesonAbstract:Background In 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 followup of 50 months. Methods We 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. Results The 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. Conclusions In patients with HER2-positive metastatic breast cancer, the addition of per tuzumab 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.)
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Pertuzumab, Trastuzumab, and Docetaxel in HER2-Positive Metastatic Breast Cancer
The New England journal of medicine, 2015Co-Authors: Sandra M Swain, Sungbae Kim, Jean-marc Ferrero, Andreas Schneeweiss, V F Semiglazov, Jose Baselga, E. Ciruelos, Mario Campone, Sarah HeesonAbstract:Background In 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 followup of 50 months. Methods We 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. Results The 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
Ana Lluch - One of the best experts on this subject based on the ideXlab platform.
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Pertuzumab monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab: activity and tolerability in patients with advanced human epidermal growth factor receptor 2-positive breast cancer.
Journal of Clinical Oncology, 2012Co-Authors: Javier Cortes, Pierre Fumoleau, Giulia Valeria Bianchi, Teresa Petrella, Karen Gelmon, Xavier Pivot, Shailendra Verma, Joan Albanell, Pierfranco Conte, Ana LluchAbstract:PURPOSE: The combination of Pertuzumab and trastuzumab resulted in a clinical benefit rate (CBR) of 50% in patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer whose disease progressed during prior trastuzumab-based therapy. To define whether this previously observed encouraging activity was a result of the combination of Pertuzumab and trastuzumab or of Pertuzumab alone, we recruited a third cohort of patients who received Pertuzumab without trastuzumab. We then investigated the impact of reintroducing trastuzumab to patients whose disease progressed on Pertuzumab monotherapy. PATIENTS AND METHODS: Twenty-nine patients with HER2-positive breast cancer whose disease progressed during prior trastuzumab-based therapy received Pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) until progressive disease or unacceptable toxicity. Seventeen patients with disease progression continued to receive Pertuzumab (at the same dose), with the addition of trastuzumab (4 mg/kg loading dose and then 2 mg/kg weekly or 8 mg/kg loading dose and then 6 mg/kg every 3 weeks). RESULTS: All 29 patients enrolled for Pertuzumab monotherapy experienced disease progression. The objective response rate (ORR) and CBR were 3.4% and 10.3%, respectively, during Pertuzumab monotherapy. With the addition of trastuzumab, the ORR and CBR were 17.6% and 41.2%, respectively. Progression-free survival was longer with combination therapy than Pertuzumab monotherapy (17.4 v 7.1 weeks, respectively). Treatment was well tolerated with minimal cardiac dysfunction. CONCLUSION: Although Pertuzumab has some activity in patients with HER2-positive breast cancer that progressed during therapy with trastuzumab, the combination of Pertuzumab and trastuzumab seems to be more active than monotherapy.
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Pertuzumab monotherapy after trastuzumab based treatment and subsequent reintroduction of trastuzumab activity and tolerability in patients with advanced human epidermal growth factor receptor 2 positive breast cancer
Journal of Clinical Oncology, 2012Co-Authors: Javier Cortes, Pierre Fumoleau, Giulia Valeria Bianchi, Karen Gelmon, Xavier Pivot, Shailendra Verma, Joan Albanell, Pierfranco Conte, Teresa M Petrella, Ana LluchAbstract:Purpose The combination of Pertuzumab and trastuzumab resulted in a clinical benefit rate (CBR) of 50% in patients with human epidermal growth factor receptor 2 (HER2) –positive breast cancer whose disease progressed during prior trastuzumab-based therapy. To define whether this previously observed encouraging activity was a result of the combination of Pertuzumab and trastuzumab or of Pertuzumab alone, we recruited a third cohort of patients who received Pertuzumab without trastuzumab. We then investigated the impact of reintroducing trastuzumab to patients whose disease progressed on Pertuzumab monotherapy. Patients and Methods Twenty-nine patients with HER2-positive breast cancer whose disease progressed during prior trastuzumab-based therapy received Pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) until progressive disease or unacceptable toxicity. Seventeen patients with disease progression continued to receive Pertuzumab (at the same dose), with the addition of trastuzumab (4 mg/kg loadi...
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efficacy and safety of neoadjuvant Pertuzumab and trastuzumab in women with locally advanced inflammatory or early her2 positive breast cancer neosphere a randomised multicentre open label phase 2 trial
Lancet Oncology, 2012Co-Authors: Luca Gianni, Ana Lluch, Tadeusz Pienkowski, L Roman, Ling Ming Tseng, Mei Ching Liu, Elzbieta Staroslawska, Juan De La Habarodriguez, Jose Luiz Pedrini, Brigitte PoirierAbstract:Summary Background Studies with Pertuzumab, a novel anti-HER2 antibody, show improved efficacy when combined with the established HER2-directed antibody trastuzumab in breast cancer therapy. We investigated the combination of Pertuzumab or trastuzumab, or both, with docetaxel and the combination of Pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting. Methods In this multicentre, open-label, phase 2 study, treatment-naive women with HER2-positive breast cancer were randomly assigned (1:1:1:1) centrally and stratified by operable, locally advanced, and inflammatory breast cancer, and by hormone receptor expression to receive four neoadjuvant cycles of: trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m 2 , escalating, if tolerated, to 100 mg/m 2 every 3 weeks; group A) or Pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B) or Pertuzumab and trastuzumab (group C) or Pertuzumab plus docetaxel (group D). The primary endpoint, examined in the intention-to-treat population, was pathological complete response in the breast. Neither patients nor investigators were masked to treatment. This study is registered with ClinicalTrials.gov, number NCT00545688. Findings Of 417 eligible patients, 107 were randomly assigned to group A, 107 to group B, 107 to group C, and 96 to group D. Patients given Pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate (49 of 107 patients; 45·8% [95% CI 36·1–55·7]) compared with those given trastuzumab plus docetaxel (group A; 31 of 107; 29·0% [20·6–38·5]; p=0·0141). 23 of 96 (24·0% [15·8–33·7]) women given Pertuzumab plus docetaxel (group D) had a pathological complete response, as did 18 of 107 (16·8% [10·3–25·3]) given Pertuzumab and trastuzumab (group C). The most common adverse events of grade 3 or higher were neutropenia (61 of 107 women in group A, 48 of 107 in group B, one of 108 in group C, and 52 of 94 in group D), febrile neutropenia (eight, nine, none, and seven, respectively), and leucopenia (13, five, none, and seven, respectively). The number of serious adverse events was similar in groups A, B, and D (15–20 serious adverse events per group in 10–17% of patients) but lower in group C (four serious adverse events in 4% of patients). Interpretation Patients given Pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel, without substantial differences in tolerability. Pertuzumab and trastuzumab without chemotherapy eradicated tumours in a proportion of women and showed a favourable safety profile. These findings justify further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer. Funding F Hoffmann-La Roche.
Jose Baselga - One of the best experts on this subject based on the ideXlab platform.
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Patient-reported function, health-related quality of life, and symptoms in APHINITY: Pertuzumab plus trastuzumab and chemotherapy in HER2-positive early breast cancer
British Journal of Cancer, 2021Co-Authors: José Bines, Emma Clark, Claire Barton, Eleonora Restuccia, Marion Procter, Amir Sonnenblick, Debora Fumagalli, Damien Parlier, Amal Arahmani, Jose BaselgaAbstract:Background We assessed health-related quality of life (symptoms of therapy/patient functioning/global health status), in APHINITY (Pertuzumab/placebo, trastuzumab, and chemotherapy as adjuvant HER2-positive early breast cancer therapy). Methods Patients received 1 year/18 cycles of Pertuzumab/placebo with trastuzumab and chemotherapy and completed EORTC QLQ-C30 and BR23 questionnaires until 36 months post-randomisation/disease recurrence. Changes ≥10 points from baseline were considered clinically meaningful. Results 87–97% of patients completed questionnaires. In the Pertuzumab versus placebo arms, mean decrease in physical function scores (baseline → end of taxane) was −10.7 (95% CI −11.4, −10.0) versus −10.6 (−11.4, −9.9), mean decrease in global health status was −11.2 (−12.2, −10.2) versus −10.2 (−11.1, −9.2), and mean increase in diarrhoea scores (baseline → end of taxane) was +22.3 (21.0, 23.6) versus +9.2 (8.2, 10.2). Diarrhoea scores remained elevated versus baseline in the Pertuzumab arm throughout HER2-targeted treatment (week 25: +13.2; end of treatment: +12.2). Role functioning was maintained in both arms. Conclusions Improved invasive disease-free survival achieved by adding Pertuzumab to trastuzumab and chemotherapy did not adversely affect the ability to conduct activities of daily living versus trastuzumab and chemotherapy alone. Patient-reported diarrhoea worsened during taxane therapy in both arms, persisting during HER2-targeted treatment in the Pertuzumab arm. ClinicalTrials.gov NCT01358877.
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Pertuzumab trastuzumab and docetaxel in her2 positive metastatic breast cancer
The New England Journal of Medicine, 2015Co-Authors: Sandra M Swain, Sungbae Kim, Jean-marc Ferrero, Andreas Schneeweiss, V F Semiglazov, Jose Baselga, Jungsil Ro, E. Ciruelos, Mario Campone, Sarah HeesonAbstract:Background In 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 followup of 50 months. Methods We 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. Results The 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. Conclusions In patients with HER2-positive metastatic breast cancer, the addition of per tuzumab 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.)
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Pertuzumab, Trastuzumab, and Docetaxel in HER2-Positive Metastatic Breast Cancer
The New England journal of medicine, 2015Co-Authors: Sandra M Swain, Sungbae Kim, Jean-marc Ferrero, Andreas Schneeweiss, V F Semiglazov, Jose Baselga, E. Ciruelos, Mario Campone, Sarah HeesonAbstract:Background In 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 followup of 50 months. Methods We 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. Results The 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
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health related quality of life assessment in cleopatra a phase iii study combining Pertuzumab with trastuzumab and docetaxel in metastatic breast cancer
Annals of Oncology, 2013Co-Authors: Javier Cortes, Jose Baselga, Xavier Pivot, Adam Knott, Graham Ross, Emma Clark, Sandra M SwainAbstract:Abstract Background The phase III CLEOPATRA study demonstrated that combining Pertuzumab with trastuzumab plus docetaxel significantly improves progression-free and overall survival in previously untreated HER2-positive metastatic breast cancer. Here, we report health-related quality-of-life (HRQoL) results from CLEOPATRA. Patients and methods Participants were randomly assigned to Pertuzumab or placebo, each given with trastuzumab plus docetaxel every 3 weeks. Pertuzumab and trastuzumab were administered until progression and six or more docetaxel cycles were recommended. Time from randomization to a ≥5-point decrease in Trial Outcome Index-Physical/Functional/Breast (TOI-PFB) of the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire was analyzed as a prespecified secondary end point. A post hoc exploratory analysis investigated time to ≥2-point deterioration in Breast Cancer Subscale (BCS) score. Results Time to ≥5-point decline in TOI-PFB did not differ significantly between the Pertuzumab and placebo arms [hazard ratio (HR), 0.97; P = 0.7161]. The median times to TOI-PFB deterioration were 18.4 and 18.3 weeks, respectively (approximately six cycles). The mean TOI-PFB declined slightly until week 18 and recovered thereafter. Pertuzumab increased time until BCS deterioration versus placebo (median 26.7 versus 18.3 weeks; HR, 0.77; P = 0.0061). Conclusions Combining Pertuzumab with trastuzumab and docetaxel had no adverse impact on HRQoL and may prolong time to worsening of breast cancer-specific symptoms.
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cardiac tolerability of Pertuzumab plus trastuzumab plus docetaxel in patients with her2 positive metastatic breast cancer in cleopatra a randomized double blind placebo controlled phase iii study
Oncologist, 2013Co-Authors: Sandra M Swain, Javier Cortes, Adam Knott, Graham Ross, Michael S Ewer, Dino Amadori, David Miles, Emma Clark, Mark C Benyunes, Jose BaselgaAbstract:INTRODUCTION We report cardiac tolerability of Pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel observed in the phase III study CLEOPATRA in patients with HER2-positive first-line metastatic breast cancer (MBC). PATIENTS AND METHODS Left ventricular ejection fraction (LVEF) ≥ 50% and ECOG performance status of 0 or 1 were required for study entry. During the study, LVEF assessments took place every 9 weeks. Pertuzumab/placebo was given at 840 mg, then 420 mg q3w; trastuzumab was administered at 8 mg/kg, then 6 mg/kg q3w, and docetaxel was initiated at 75 mg/m(2) q3w. RESULTS The incidence of cardiac adverse events (all grades) was 16.4% in the placebo arm and 14.5% in the Pertuzumab arm, with left ventricular systolic dysfunction (LVSD, all grades) being the most frequently reported event (8.3% versus 4.4% in the placebo and Pertuzumab arm). Declines in LVEF by ≥ 10% points from baseline and to <50% were reported in 6.6% and 3.8% of patients in the placebo and Pertuzumab arm, respectively. Seventy-two percent (placebo arm) and 86.7% (Pertuzumab arm) of those patients recovered to a value ≥ 50%. The incidence of symptomatic LVSD was low, occurring in 1.8% (n = 7) versus 1.0% (n = 4) of patients in the placebo and Pertuzumab arm. In 8/11 patients, the symptomatic LVSD had resolved at data cutoff. CONCLUSION The combination of Pertuzumab plus trastuzumab plus docetaxel did not increase the incidence of cardiac adverse events, including LVSD, compared with the control arm in HER2-positive MBC. The majority of cardiac adverse events were reversible.
Giulia Valeria Bianchi - One of the best experts on this subject based on the ideXlab platform.
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Biomarker analysis of the NeoSphere study: Pertuzumab, trastuzumab, and docetaxel versus trastuzumab plus docetaxel, Pertuzumab plus trastuzumab, or Pertuzumab plus docetaxel for the neoadjuvant treatment of HER2-positive breast cancer.
Breast cancer research : BCR, 2017Co-Authors: Giampaolo Bianchini, Giulia Valeria Bianchi, Tadeusz Pienkowski, Ling Ming Tseng, Mei Ching Liu, Astrid Kiermaier, Mitch Dowsett, Lila Zabaglo, Sarah KirkAbstract: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. 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. 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 (TGFα) 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. 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. Clinicaltrials.gov, NCT00545688 . Registered on 16 October 2007.
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Pertuzumab monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab: activity and tolerability in patients with advanced human epidermal growth factor receptor 2-positive breast cancer.
Journal of Clinical Oncology, 2012Co-Authors: Javier Cortes, Pierre Fumoleau, Giulia Valeria Bianchi, Teresa Petrella, Karen Gelmon, Xavier Pivot, Shailendra Verma, Joan Albanell, Pierfranco Conte, Ana LluchAbstract:PURPOSE: The combination of Pertuzumab and trastuzumab resulted in a clinical benefit rate (CBR) of 50% in patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer whose disease progressed during prior trastuzumab-based therapy. To define whether this previously observed encouraging activity was a result of the combination of Pertuzumab and trastuzumab or of Pertuzumab alone, we recruited a third cohort of patients who received Pertuzumab without trastuzumab. We then investigated the impact of reintroducing trastuzumab to patients whose disease progressed on Pertuzumab monotherapy. PATIENTS AND METHODS: Twenty-nine patients with HER2-positive breast cancer whose disease progressed during prior trastuzumab-based therapy received Pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) until progressive disease or unacceptable toxicity. Seventeen patients with disease progression continued to receive Pertuzumab (at the same dose), with the addition of trastuzumab (4 mg/kg loading dose and then 2 mg/kg weekly or 8 mg/kg loading dose and then 6 mg/kg every 3 weeks). RESULTS: All 29 patients enrolled for Pertuzumab monotherapy experienced disease progression. The objective response rate (ORR) and CBR were 3.4% and 10.3%, respectively, during Pertuzumab monotherapy. With the addition of trastuzumab, the ORR and CBR were 17.6% and 41.2%, respectively. Progression-free survival was longer with combination therapy than Pertuzumab monotherapy (17.4 v 7.1 weeks, respectively). Treatment was well tolerated with minimal cardiac dysfunction. CONCLUSION: Although Pertuzumab has some activity in patients with HER2-positive breast cancer that progressed during therapy with trastuzumab, the combination of Pertuzumab and trastuzumab seems to be more active than monotherapy.
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Pertuzumab monotherapy after trastuzumab based treatment and subsequent reintroduction of trastuzumab activity and tolerability in patients with advanced human epidermal growth factor receptor 2 positive breast cancer
Journal of Clinical Oncology, 2012Co-Authors: Javier Cortes, Pierre Fumoleau, Giulia Valeria Bianchi, Karen Gelmon, Xavier Pivot, Shailendra Verma, Joan Albanell, Pierfranco Conte, Teresa M Petrella, Ana LluchAbstract:Purpose The combination of Pertuzumab and trastuzumab resulted in a clinical benefit rate (CBR) of 50% in patients with human epidermal growth factor receptor 2 (HER2) –positive breast cancer whose disease progressed during prior trastuzumab-based therapy. To define whether this previously observed encouraging activity was a result of the combination of Pertuzumab and trastuzumab or of Pertuzumab alone, we recruited a third cohort of patients who received Pertuzumab without trastuzumab. We then investigated the impact of reintroducing trastuzumab to patients whose disease progressed on Pertuzumab monotherapy. Patients and Methods Twenty-nine patients with HER2-positive breast cancer whose disease progressed during prior trastuzumab-based therapy received Pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) until progressive disease or unacceptable toxicity. Seventeen patients with disease progression continued to receive Pertuzumab (at the same dose), with the addition of trastuzumab (4 mg/kg loadi...
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Pertuzumab – a HER-2 Dimerisation Inhibitor – for the Treatment of Breast and Other Cancers
Drugs for HER-2-positive Breast Cancer, 2010Co-Authors: Giulia Valeria Bianchi, Luca GianniAbstract:Pertuzumab is a recombinant humanised monoclonal antibody targeting the extracellular domain of human epidermal growth factor receptor 2 (HER-2) to block HER-2 dimerisation with other HER family members. Preclinical Pertuzumab data showed activity in a number of solid tumour types, and synergistic or additive activity was also observed when Pertuzumab was combined with chemotherapy or with other targeted agents, including trastuzumab and erlotinib. Pertuzumab has also been studied in the clinical setting, both as monotherapy and in combination with other agents in a variety of tumour types. Following encouraging results of a Phase II trial of Pertuzumab and trastuzumab in patients with HER-2-positive metastatic breast cancer, this indication has become the focus of attention for further investigation.
