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.

Inhibition of focal adhesion kinase with her-2 targeted antibody pertuzumab (Omnitarg®, 2C4) in breast cancer cells

Abstract: Emel Canbay, Bala Gur-Dedeoglu, Betul Bozkurt, Melih Karabeyoglu, Bulent Unal, Osman Yıldırım, Omer Cengiz, Isik G Yulug Istanbul University, Istanbul Medical Faculty, Department of General Surgery, Capa-Istanbul, 34340 Department of Biology, Bilkent University, Faculty of Science, BilkentAnkara Ankara Numune Teaching & Research Hospital, II. Surgery Clinic, Sihhiye-Ankara 06100 Inonu University, Faculty of Medicine, Department of General Surgery, Malatya-Turkey __________________________________________________________________________________

[Targeting HER2 in colorectal cancer].

Abstract: Among the molecular subgroups of interest in metastatic colorectal cancer (mCRC), innovations are underway for tumors with overexpression of HER2 (Human Epidermal Growth Factor Receptor 2). Overexpression of the HER2 protein concerns 2 to 5% of CRC at any stage mainly located in the distal colon and rectum. Diagnosis is based on immunohistochemistry, in situ hybridization with appropriate criteria for colorectal localization, and molecular biology (NGS: next-generation sequencing). Overexpression of HER2 is a predictive factor for resistance to treatments targeting EGFR which are indicated in the case where the tumor is wild-type RAS. It seems to be associated with a poor prognosis of mCRC with a higher risk of brain metastasis. Regarding treatments targeting HER2, no randomized controlled phase III has been published to date. However, several combinations have been evaluated in phase II with clinically meaningful objective response rates: trastuzumab-deruxtecan (45%), trastuzumab-tucatinib (46%), trastuzumab-pyrotinib (45%), trastuzumab-pertuzumab (30%) ou trastuzumab-lapatinib (30%). In this literature review, we present here the current state of knowledge on the diagnostic methods of HER2 overexpression in CRC, the main clinical, molecular and prognostic characteristics, and the efficacy results of the different therapeutic combinations for the patients with HER2 overexpressed mCRC. This justifies, despite the lack of marketing authorization in France and in Europe for agents targeting HER2 in CRC, the systematic evaluation of the HER2 status, as recommended in particular by the NCCN (National Comprehensive Cancer Network).

Abstract P5-18-09: Halt-d: A randomized open label phase 2 study of crofelemer for the prevention of chemotherapy induced diarrhea (cid) in patients with breast cancer receiving trastuzumab, pertuzumab, and a taxane

Abstract: Background: CID occurs in up to 80% of patients with breast cancer who receive trastuzumab (H), pertuzumab (P), and a taxane, with grade 3 experienced by 8-12% of patients. Crofelemer is an extract of the Croton lechleri tree that inhibits luminal chloride efflux, implicated in the HP-related CID. We hypothesized crofelemer would prevent diarrhea in patients with HER2+ breast cancer receiving HP and docetaxel or paclitaxel, with/without carboplatin (THP or TCHP) in the neoadjuvant, adjuvant, or metastatic setting. Clinical trial information: NCT02910219. Methods: Adult patients with HER2+ any stage breast cancer, scheduled to receive at least 3 consecutive cycles of TCHP (docetaxel, carboplatin, trastuzumab and pertuzumab) or THP (trastuzumab and pertuzumab with paclitaxel or docetaxel), normal organ function, PS 0-2, who provided written informed consent were randomized 1:1 to receive crofelemer 125 mg PO 2x/day during cycles 1 and 2 of chemotherapy or no scheduled prophylactic medication. Randomization was stratified according to chemotherapy regimen. The primary endpoint was the incidence of CID of any grade for ≥2 consecutive days assessed by NCI CTCAE v4.0. Provider reported outcomes were collected during clinic visits and prospectively documented in clinical notes. Patient reported outcomes (PRO) were collected from patient diaries. Secondary endpoints were incidence of all grades and grade 3/4 CID by cycle/stratum; time to onset and duration of CID; stool consistency; frequency of break through anti-diarrheal medications use; and FACIT-D total score. Fisher’s exact test was used for comparing binary and categorical variables and summary statistics and Wilcoxon test for ordinal grade variables. The trial was designed to detect a 40% absolute decrease in incidence of CID (from 60% to 20%), two-sided significance level of 0.10. Results: A total of 53 patients were enrolled between 02/21/2017- 08/25/2020 on crofelemer (n=27) or control (n=26) arms. One patient withdrew consent prior to starting protocol procedures and was substituted. Early treatment discontinuation occurred in 7 cases: complications of diarrhea (n=1, control group), chemotherapy regimen changed for other cause than diarrhea (n=4) and non-compliance with trial procedures (n=2). 29 patients had early stage disease treated with TCHP; 23 patients had metastatic disease treated with THP (16 with paclitaxel and 7 with docetaxel). The primary endpoint was not statistically different between the two groups. The incidence of Grade 2 or greater diarrhea was 20.9% vs 26.4% of patients receiving crofelemer or placebo respectively in cycle 1, and 9.5% vs 41.1% in cycle 2 (Table). Results were consistent between provider assessments and patient reported outcomes (PRO). Detailed description of pooled cycle 1-2 data using correlated ordinal model and the additional secondary endpoints will be presented. Conclusions: Although there was no significant difference between crofelemer and control for diarrhea for 2 or more consecutive days in both cycles, there was a clinically meaningful difference between the crofelemer and control groups in maximum within-cycle diarrhea ordinal CTCAE grade diarrhea. These data are supportive for further testing of crofelemer in the ongoing randomized Phase 3 trial OnTARGET (NCT04538625). CycleCTCAE bCrofelemerControlPDiarrhea >= 2 consecutive days a168.069.6NS d265.272.2Maximum diarrhea grade a1Grade 0 c33.321.1NS eGrade 145.852.6Grade 216.721.1Grade 34.25.3Grade 40.00.02Grade 0 c38.117.60.0261 eGrade 152.441.2Grade 29.523.5Grade 30.017.6Grade 40.00.0Maximum diarrhea grade PRO f1Grade 0 c4.08.7NS eGrade 172.039.1Grade 216.043.5Grade 38.08.7Grade 40.00.02Grade 0 c9.10.00.0361 eGrade 181.866.7Grade 24.522.2Grade 34.511.1Grade 40.00.0aProvider assessedbCTCAE: NCI Common Terminology Criteria for Adverse Events v4.0cGrade 0: no diarrheadFisher''s exact testeWilcoxon rank sum testfPRO: Patient reported outcomes Citation Format: Paula R Pohlmann, Deena Graham, Tianmin Wu, Yvonne Ottaviano, Mahsa Mohebtash, Shweta Kurian, Donna McNamara, Filipa Lynce, Robert Warren, Asma Dilawari, Suman Rao, Candace Mainor, Nicole Swanson, Ming Tan, Claudine Isaacs, Sandra M. Swain. Halt-d: A randomized open label phase 2 study of crofelemer for the prevention of chemotherapy induced diarrhea (cid) in patients with breast cancer receiving trastuzumab, pertuzumab, and a taxane [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-09.

A randomized phase 2 study of trastuzumab and pertuzumab (TP) compared to cetuximab and irinotecan (CETIRI) in advanced/metastatic colorectal cancer (mCRC) with HER2 amplification: SWOG S1613.

Abstract: 140 Background: HER2 ( ERBB2) over-expression and amplification (HER2+) is seen in a small but distinct subset (2-3%) of mCRC and is enriched in RAS/BRAF wild type (WT) tumors. This subset is characterized by a limited response to anti-epidermal growth factor receptor monoclonal antibody-based (anti-EGFR) therapy and a promising response to dual-HER2 inhibition. Methods: In this multicenter, open label, randomized, phase 2 trial, we enrolled 54 patients with RAS/BRAF WT HER2+ mCRC who had had disease progression after 1 or 2 previous therapies. HER2 status was confirmed centrally with immunohistochemistry (IHC) and in-situ hybridization (ISH). HER2+ was defined as IHC 3+ or 2+ and ISH amplified (dual-probe HER2/CEP17 ratio > 2.0). Patients were then randomly assigned in a 1:1 ratio to receive either TP (trastuzumab [loading 8 mg/kg then 6 mg/kg] + pertuzumab [loading 840 mg then 420 mg] every 3 weeks) or CETIRI (cetuximab 500 mg/m2 + irinotecan 180 mg/m2 every 2 weeks). Crossover was allowed for patients on CETIRI arm to TP (cTP) after progression. Restaging (per RECIST v1.1) was performed at 6 and 12 weeks and then every 8 weeks until progression. The primary endpoint was progression-free survival (PFS). Key secondary endpoints were overall response rate (ORR), overall survival (OS) and safety. Results: A total of 54 (out of planned 62 due to low accrual) patients were randomized to TP (26) and CETIRI (28) between 10/2017 and 12/2021. By 8/18/2022, 20 patients had crossed over to cTP arm. One CETIRI patient was not analyzable. The results for key endpoints by protocol defined stratification factors, prior irinotecan (Piri) (yes or no) and HER2/CEP17 ratio (HCR) (>5 or ≤5), are summarized as of data cut-off of 9/6/2022. PFS did not vary significantly by treatment: medians 4.4 (95%CI: 1.9 – 7.6) months in TP group and 3.7 (95%CI: 1.6 – 6.7) months in CETIRI group (p = 0.35). Grade ≥3 adverse events occurred in 23%, 46% and 40% of patients in TP, CETIRI and cTP groups. Conclusions: Dual-HER2 inhibition with TP appears to be a safe and effective treatment option for patients with RAS/BRAF WT HER2+ mCRC with a promising response rate of 31%. Higher level of HER2 amplification may provide a greater degree of clinical benefit from TP compared to CETIRI. Future correlative efforts will explore biomarkers of response/resistance with this strategy. Clinical trial information: NCT03365882 . [Table: see text]

Abstract OT1-02-03: Trastuzumab deruxtecan (T-DXd; DS-8201) vs trastuzumab emtansine (T-DM1) in high-risk patients with HER2-positive, residual invasive early breast cancer after neoadjuvant therapy: A randomized, phase 3 trial (DESTINY-Breast05)

Abstract: Background Preoperative chemotherapy in combination with trastuzumab and pertuzumab is a preferred regimen for treating patients (pts) with HER2-positive, invasive, early breast cancer (BC). Pts who have received such treatment but still have residual invasive disease in the breast or lymph nodes at surgery are at greater risk for disease recurrence or death than those with a pathological complete response. The antibody-drug conjugate (ADC) T-DM1 is approved as a postneoadjuvant treatment for pts with residual invasive disease (in the breast and/or axillary nodes) after optimal neoadjuvant chemotherapy and trastuzumab (or trastuzumab with pertuzumab). T-DXd is a potent HER2-targeted ADC with a humanized HER2 antibody attached to a membrane-permeable topoisomerase I inhibitor payload by a cleavable tetrapeptide-based linker and a drug-to-antibody ratio of ≈8. T-DXd is approved globally for the treatment of adult pts with HER2-positive, unresectable or metastatic BC who have received ≥2 prior anti-HER2-based regimens in the metastatic setting or had prior chemotherapy and are refractory to or intolerant of standard treatments. These approvals have been supported by results from DESTINY-Breast01, an open-label, international, multicenter, phase 2 study of T-DXd in patients with HER2-positive metastatic BC. In an updated data cutoff (June 8, 2020), T-DXd demonstrated an objective response rate (ORR) of 61.4% (113/184 pts) and a duration of response of 20.8 months in pts with HER2-positive (IHC 3+ or ISH+), unresectable or metastatic BC previously treated with T-DM1 (Modi et al. Cancer Res. 2021;81[4 suppl]:PD3-06). Yet, further unmet need exists in patients who do not achieve pathologic complete response to neoadjuvant treatment, as these patients have increased risk of recurrence. Here, we describe a randomized phase 3 trial evaluating T-DXd vs T-DM1 as postneoadjuvant treatment for high-risk pts with HER2-positive primary BC who have residual invasive disease following neoadjuvant therapy. Study Description DESTINY-Breast05 is a multicenter, open-label, randomized, phase 3 trial comparing the efficacy and safety of T-DXd with those of T-DM1 in pts with HER2-positive (IHC 3+ or ISH+, centrally confirmed on pretreatment biopsy), invasive BC with pathologic evidence of residual invasive disease in the breast or axillary lymph nodes after neoadjuvant therapy. Additionally, pts must have a higher residual risk for recurrence, following standard T-DM1, defined as either presenting with inoperable disease (clinical stages T4, N0-3, M0 or T1-3, N2-3, M0) or operable BC at presentation (clinical stages T1-3, N0-1, M0) with axillary node-positive disease after neoadjuvant chemotherapy and anti-HER2 treatment. Approximately 1600 pts will be randomly assigned (1:1) to T-DXd or T-DM1 from ≈ 400 sites globally. Randomization is stratified by operative status at presentation, hormone receptor status, pathologic nodal status following neoadjuvant therapy, and type of HER2-targeted neoadjuvant therapy (single vs dual). T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg will be administered intravenously once every 3 weeks for 14 cycles. Invasive disease-free survival based on investigator assessment is the primary efficacy endpoint. Secondary endpoints are overall survival, disease-free survival, distant recurrence-free interval, and brain metastasis-free interval. The pharmacokinetics of T-DXd, biomarkers, and health-related quality of life will also be evaluated (NCT04622319). Citation Format: Charles E Geyer, Jr, Michael Untch, Aleix Prat, Priya Rastogi, Naoki Niikura, Elton Mathias, Lee Anne McLean, Yibin Wang, Sibylle Loibl. Trastuzumab deruxtecan (T-DXd; DS-8201) vs trastuzumab emtansine (T-DM1) in high-risk patients with HER2-positive, residual invasive early breast cancer after neoadjuvant therapy: A randomized, phase 3 trial (DESTINY-Breast05) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-02-03.