Pertuzumab

About: Pertuzumab is a research topic. Over the lifetime, 1453 publications have been published within this topic receiving 73219 citations. The topic is also known as: 2C4 Antibody & MOAB 2C4.

Targeted neoadjuvant therapy in the HER-2-positive breast cancer patients: a systematic review and meta-analysis.

Abstract: Aim To evaluate efficacy and safety of lapatinib or trastuzumab alone or both plus chemotherapy for the treatment of breast cancer patients with positive HER-2 expression. Methods Cochrane Central Register of Controlled Trials, PubMed, MEDLINE, OVID, Embase, Chinese Biomedical Literature Database, and China Academic Journals Database were searched from 1994 through December 2017 using the keywords "breast cancer", "preoperative", "neo-adjuvant", "lapatinib", "pertuzumab", "Herceptin", and "trastuzumab". Results Meta-analysis found that pathological complete response (PCR; risk ratio [RR]=0.82, 95% CI: 0.72-0.93) and tall PCR (tPCR; RR=0.77, 95% CI: 0.67-0.88) of chemotherapy plus lapatinib were significantly less effective or safe compared to that of chemotherapy plus trastuzumab (P 0.05). Incidence of diarrhea, hepatic toxicity, and skin rash in the groups of chemotherapy plus lapatinib or chemotherapy plus both lapatinib and trastuzumab was significantly higher than that in chemotherapy plus trastuzumab (P Conclusion Efficacy of lapatinib was less than that of trastuzumab, but incidence of adverse effect of lapatinib was higher than that of trastuzumab. Combination of chemotherapy plus both lapatinib and trastuzumab could significantly increase PCR and tPCR in breast cancer patients, but rate of breast conservation, event-free survival, and overall survival was not significantly improved. Incidence of diarrhea, hepatic toxicity, and skin rash was significantly increased in the groups using lapatinib.

Abstract P4-14-21: A phase I trial of ganetespib (heat shock protein 90 inhibitor) in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 positive (HER2+) metastatic breast cancer (MBC)

Abstract: Introduction: Targeted therapies in HER2+ MBC significantly improve outcomes but efficacy is limited by therapeutic resistance. HSP90 is a molecular chaperone involved in the stability and function of multiple signaling onco-proteins. HER2 is an acutely sensitive HSP90 client and HSP90 inhibition can overcome trastuzumab resistance. Our group reported objective responses with 17-AAG plus trastuzumab in HER2+ MBC. Ganetespib, a synthetic, second generation HSP90 inhibitor has increased potency and tolerability compared with earlier agents. We reported anti-tumor activity in metastatic HER2+ and triple negative breast cancer with single agent ganetespib. Preclinically, HSP90 inhibition has synergistic anti-tumor activity with taxanes and trastuzumab. This study will define the MTD and RP2D of ganetespib plus paclitaxel and trastuzumab in HER2+ MBC. Methods: In this 3+3 phase I dose escalation study, patients with trastuzumab-resistant HER2+ MBC receive weekly trastuzumab and paclitaxel (80mg/m 2 ) with ganetespib on day 1, 8, 15 of a 28 day cycle. HR+ positive patients are required to have at least one prior line of endocrine therapy. DLT of ganetespib monotherapy is diarrhea and therefore patients receive prophylactic anti-motility agents. Based on prior experience with ganetespib plus docetaxel in NSCLC, only 3 dose levels of ganetespib were explored: 100mg/m 2 , 150mg/m 2 and a 3 rd cohort of 125mg/m 2 , if needed . Secondary endpoints include evaluation of effects of ganetespib on the pharmacokinetics (PK) of paclitaxel and preliminary efficacy assessment. Results: The dosing cohorts (100 mg/m 2 (n=3) and 150 mg/m 2 (n=6)) have been completed without any DLTs. Median age was 46 years (range 29-65), median prior lines of chemotherapy and anti-HER2 therapy were 3 (range 2-6) and 3 (range 2-4) respectively, including prior pertuzumab in 9/9 and T-DM1 in 8/9 patients. There were no grade 3/4 adverse events (AEs) related to ganetespib. Most common AEs related to ganetespib were diarrhea, fatigue, anemia and rash. Paclitaxel PK data available from 6/9 patients are not appreciably different from those reported in literature. Overall response rate was 25% (2/8 had PR in 150 mg/m 2 cohort; 1 patient was not evaluable), SD in 63% (5/8), and clinical benefit rate (CR+PR+SD>24 weeks) was 50% (4/8). 3 patients remain on study. Conclusion: The RP2D of ganetespib is 150mg/m 2 in combination with paclitaxel and trastuzumab. The combination was safe and well tolerated. Updated PFS and PK data will be presented. Despite prior taxanes, pertuzumab and T-DM1, clinical activity of this triplet regimen in this heavily pre-treated cohort is very promising and together with our prior experience with 17-AAG plus trastuzumab and single agent ganetespib warrants further study in HER2+ MBC. A phase 2 trial is being planned in trastuzumab-refractory HER2+ MBC who have progressed on prior pertuzumab and T-DM1. Additionally, the protocol is amended to assess the safety of ganetespib in combination with paclitaxel, trastuzumab and pertuzumab in the first-line setting. Citation Format: Jhaveri K, Teplinsky E, Chandarlapaty S, Solit D, Cadoo K, Speyer J, D9Andrea G, Adams S, Patil S, Haque S, Friedman K, Neville D, Esteva F, Hudis C, Modi S. A phase I trial of ganetespib (heat shock protein 90 inhibitor) in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 positive (HER2+) metastatic breast cancer (MBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-21.

European Society of Medical Oncology

Abstract: In the CLEOPATRA trial, when compared with trastuzumab and chemotherapy, a dual HER2 blockade of pertuzumab added to trastuzumab with chemotherapy increased overall survival (OS) among women with HER2-positive metastatic breast cancer. Dr. Swain, the lead investigator, called the size of the benefit “unprecedented” at an ESMO press conference. The press conference moderator, Eric Van Cutsem, MD, University of Leuven, Belgium, affirmed the importance of the CLEOPATRA findings. “I think these data are practice-changing,” he said. The dual HER2 blockade had already shown significant gains in progression-free survival (PFS) in shorter-term reporting of CLEOPATRA results. The two antibodies, Dr. Swain pointed out, bind to different sites. In CLEOPATRA, which was conducted at 204 centers in 20 countries, 406 women received placebo plus trastuzumab (8 mg/kg loading followed by 6 mg/kg maintenance) with six or more cycles of docetaxel (75 mg/m2 followed by 100 mg/m2 with escalation if tolerated) and 402 patients received pertuzumab (840 mg loading followed by 420 mg maintenance) and trastuzumab plus docetaxel. Trastuzumab and pertuzumab were dosed for a much longer period, Dr. Swain said, until progressive disease. Chemotherapy was actually administered for a median of eight cycles. After a median follow-up of 50 months, OS was 40.8 months for the arm receiving chemotherapy and trastuzumab and 56.5 months for chemotherapy with both trastuzumab and pertuzumab (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.56–0.84; P = 0.0002). Regarding the OS gain of 15.7 months, Dr. Swain said, “I have never seen that in any other trial of metastatic breast cancer.” Benefits were consistent across all subgroups. “The results, I think, are phenomenal.” An updated PFS analysis showing an improvement of 6.3 months also demonstrated a strong consistency for this measure as a good surrogate for OS, Dr. Swain commented. Adding pertuzumab raised rates of rash, mucositis, and diarrhea, but in general no new safety issues came up. While the potential for increased cardiac toxicity with the two monoclonal antibodies had been a concern, investigators actually observed lower rates of ventricular dysfunction and left ventricular ejection fraction declines of 10% or greater in less than 50% of the group receiving both trastuzumab and pertuzumab. The findings, Dr. Swain concluded, “confirm the pertuzumab regimen as first-line standard of care for patients with HER2-positive metastatic breast cancer.” She added, “Based on the study results and the consistency in the subgroups, I would recommend dual antibody therapy for all patients [with metastatic breast cancer].”

A functional signal profiling test for identifying a subset of HER2-negative breast cancers with abnormally amplified HER2 signaling activity

Abstract: // Yao Huang 1 , David J Burns 1 , Benjamin E Rich 1 , Ian A MacNeil 1 , Abhijit Dandapat 1 , Sajjad M. Soltani 1 , Samantha Myhre 1 , Brian F Sullivan 1 , Leo T Furcht 2 , Carol A Lange 3 , Sara A Hurvitz 4 , Lance G Laing 1 1 Celcuity LLC, Minneapolis, MN 55446, USA 2 Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA 3 Division of Hematology, Oncology and Transplantation, Departments of Medicine and Pharmacology and The Masonic Cancer Center, Minneapolis, MN 55455, USA 4 Division of Hematology/Oncology and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA Correspondence to: Lance G Laing, email: LLaing@Celcuity.com Keywords: HER2 negative, HER2 signaling, targeted therapy, CELx HSP test, tumor primary cells Received: June 17, 2016 Accepted: September 29, 2016 Published: October 05, 2016 ABSTRACT The results of clinical trials evaluating the efficacy of HER2 inhibitors in patients with breast cancer indicate that the correlation between HER2 receptor levels and patient outcomes is as low as 50%. The relatively weak correlation between HER2 status and response to HER2-targeting drugs suggests that measurement of HER2 signaling activity, rather than absolute HER2 levels, may more accurately diagnose HER2-driven breast cancer. A new diagnostic test, the CELx HER2 Signaling Profile (CELx HSP) test, is demonstrated to measure real-time HER2 signaling function in live primary cells. In the present study, epithelial cells extracted fresh from breast cancer patient tumors classified as HER2 negative (HER2 – , n = 34 of which 33 were estrogen receptor positive) and healthy subjects ( n = 16) were evaluated along with reference breast cancer cell lines ( n = 19). Live cell response to specific HER2 agonists (NRG1b and EGF) and antagonist (pertuzumab) was measured. Of the HER2 – breast tumor cell samples tested, 7 of 34 patients (20.5%; 95% CI = 10%–37%) had HER2 signaling activity that was characterized as abnormally high. Amongst the tumor samples there was no correlation between HER2 protein status (by cell cytometry) and HER2 signaling activity (hyperactive or normal) (Regression analysis P = 0.144, R 2 = 0.068). One conclusion is that measurement of HER2 signaling activity can identify a subset of breast cancers with normal HER2 receptor levels with abnormally high levels of HER2 signaling. This result constitutes a new subtype of breast cancer that should be considered for treatment with HER2 pathway inhibitors.

Abstract P4-21-39: Neo-adjuvant treatment with trastuzumab and pertuzumab associated with palbociclib and fulvestrant in HER2-positive and ER-positive breast cancer: Effect on Ki67 during and after treatment. A phase II Michelangelo study

Abstract: Background: In metastatic breast cancer, the CDK4,6 inhibitor palbociclib associated with fulvestrant proved superior to fulvestrant alone in HER2-negative breast cancer (NEJM 2015). In HER2-positive tumors, the dual blockade of the receptor plus an aromatase inhibitor led to a 21% rate of pCR in a neoadjuvant setting in ER+ cancers (J Clin Oncol 2013). In preclinical studies concomitant inhibition of CDK4,6 and trastuzumab led to synergistic antitumor activity (Cancer Cell 2016). The extent of early change and the persistence of Ki67 down-regulation are robust markers of the effects of endocrine treatments in hormone receptors positive breast carcinomas in the setting of neoadjuvant endocrine therapy (Ann Oncol 2012). Methods: In this exploratory Phase II trial (NCT02530424), women with invasive unilateral non metastatic ER-positive breast cancer expressing HER2 and suitable for neoadjuvant therapy were treated with every 3 wks trastuzumab and pertuzumab for 6 cycles combined with palbociclib 125 mg po q.d. x 21 q. 4 wks and fulvestrant i.m. 500 mg, both given for 5 cycles (HPPF). The primary endpoint was characterization of Ki67 changes from baseline before therapy, at 2 weeks and at surgery. Results: A total of 23 patients with centrally confirmed HER2 and ER positive breast cancer were recruited for this study. Ki67 was also assessed centrally. At baseline 30% of cases were classified as locally advanced, 43% as cN0 and 78% had Ki67 values > 20%. Objective clinical response was documented in 96% of patients and pCR (absence of invasive cells in breast and axillary nodes) was documented in 22% (pCR in breast only was 26%). The geometric means of Ki67 expression assessed at baseline, after 2 weeks of treatment and at surgery were 30.8 (SD 15.1), 3.9 (SD 15.9) and 9.2 (SD 16.6) respectively. The mean change in Ki67 values from baseline to after 2 weeks was -24.5 (paired t-test: P grade 3 were reported. The most frequent G 3 adverse events were neutropenia (26% of patients) and gastrointestinal disorders (17%). Conclusions: Neoadjuvant triple targeting of ER, HER2 and Rb in HER2+/ER+ breast cancer treatment caused a significant and rapid decrease of Ki67 that was of larger magnitude after 2 weeks than at surgery irrespective of the recorded objective clinical response. The good tolerability, the rapid effect on Ki67, the consistent clinical response, and the rate of pCR with this chemotherapy-free approach support further clinical testing and additional molecular characterization. Supported in part by an unrestricted grant from Pfizer Italia S.r.l. and from Roche S.p.a. Italia Citation Format: Gianni L, Bisagni G, Colleoni M, Del Mastro L, Zamagni C, Mansutti M, Zambetti M, Frassoldati A, De Fato R, Valagussa P, Viale G. Neo-adjuvant treatment with trastuzumab and pertuzumab associated with palbociclib and fulvestrant in HER2-positive and ER-positive breast cancer: Effect on Ki67 during and after treatment. A phase II Michelangelo study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-39.