Neratinib And Trastuzumab, Protocol-defined endpoints common to

Neratinib And Trastuzumab, Protocol-defined endpoints common to both studies were analyzed. 1). In conclusion, dual anti-HER2 therapy with neratinib and trastuzumab demonstrated promising efficacy and a manageable safety profile in heavily pretreated patients with HER2 -mutated cancers. This open-label single arm phase 2 trial investigated the efficacy and safety of the dual anti-HER2 therapy, neratinib plus trastuzumab in heavily pretreated patients with HER2 mutated solid tumors excluding HER2 Apr 1, 2019 · Conclusions Neratinib in combination with trastuzumab was well-tolerated and had encouraging antitumor activity in patients with advanced trastuzumab-pretreated HER2 + breast cancer. SUMMIT has improved our understanding of the translational implications of … However, the panHER inhibitor neratinib was an effective monotherapy in HER2-low breast cancer cells and PDOs, and showed additive effects when combined with trastuzumab. Neratinib in combination with trastuzumab had a greater growth inhibitory effect than either drug alone in 4 HER2 positive cell lines. Accordingly, it may also offer benefit in T-DXd–refractory setting through combinatorial approaches. . 4 Conclusions Neratinib in combination with trastuzumab was well-tolerated and had encouraging antitumor activity in patients with advanced trastuzumab-pretreated HER2 + breast cancer. org. Background HER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). Estimated sample size is 30-36 pts using Simon 2 stage design. Electronic address: mmartin@geicam. Learn about the drug trastuzumab (Herceptin), which is used to treat metastatic breast cancer and early breast cancer (including lymph node-positive and some lymph node-negative cancers). ExteNET showed that neratinib, an irreversible pan-HER tyrosine kinase inhibitor, given for 1 year after trastuzumab-based therapy significantly impro… Therefore, neratinib is recommended if trastuzumab is the only HER2-directed adjuvant treatment a person has had, and if they had chemotherapy-based treatment before surgery to reduce tumour size (neoadjuvant treatment) they still have signs of cancer (residual invasive disease) in tissue samples from the breast or armpit (axilla). Therefore, neratinib is recommended if trastuzumab is the only HER2‑directed adjuvant treatment a person has had, and if they had chemotherapy-based treatment before surgery to reduce tumour size (neoadjuvant treatment) they still have signs of cancer (residual invasive disease) in tissue samples from the breast or armpit (axilla). TP53 mutations accelerated tumor development and reduced survival in HER2 -mutant mice. Longer follow-up is needed to ensure that the improvement in breast cancer outcome is maintained. 13 Among patients with HER2-positive breast cancer and residual disease after completing neoadjuvant therapy Neratinib-containing anti-HER2 regimen is superior to trastuzumab and pertuzumab in BT474 cell-derived xenograft model To evaluate the efficacy of different anti-HER2 treatment regimens, we first used the ER+/HER2-amplified BT474/AZ cells with high and homogeneous levels of HER2, hereafter referred to as BT474 (Supplementary Fig. These co-mutant tumors were resistant to neratinib but remained sensitive to exatecan, the topoisomerase I (TOP1) inhibitor payload in trastuzumab deruxtecan (T-DXd). ClinicalTrials. Patients receive neratinib orally (PO) once daily (QD) on days 1-21 (days 8-21 of cycle 1, then days 1-21 in cycles thereafter for PD study) of each cycle and trastuzumab deruxtecan intravenously (IV) over 30-90 minutes on day 1 of each cycle. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pretreated. Methods: Neratinib was administered 240mg p. Positive human epidermal growth factor receptor 2 (HER2) expression is associated with an increased risk of metastases especially those to the brain in patients with advanced breast cancer (BC). First-line treatment for HER2-positive metastatic breast cancer includes the anti-HER2 monoclonal antibodies trastuzumab and pertuzumab in combination with chemotherapy. We report the final analysis of overall survival in ExteNET. Human epidermal growth factor receptor (HER) 2 (HER2) is overexpressed in 20–30% of breast cancers. ESMO-MCBS table for new therapies/indications in early breast cancer a Trastuzumab has been shown to improve the survival outcomes of HER2 positive breast cancer patients. After completion of adjuvant treatment with trastuzumab, patients were randomised to receive neratinib or placebo for a period of one year. In the third-line setting and beyond, several emerging anti-HER2 therapies are becoming available, including tucatinib, fam-trastuzumab deruxtecan-nxki (DS-8201a), neratinib, and margetuximab-cmkb. In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). In case of DLTs observed with this dose, a dose of 160 mg/day for Nera will be considered. “Neratinib and trastuzumab deruxtecan showed impressive combination activity in preclinical models of HER2-mutated breast cancers, which prompted evaluation of the combination in this first-in-human clinical trial. Neratinib as a tyrosine kinase inhibitor can prevent the transduction of HER1, HER2 and HER4 signaling pathways thus playing an anticancer effect. gov: NCT01827267; NCT01953926. Adjuvant pertuzumab and neratinib are independently FDA-approved for treatment of early-stage HER2-positive breast cancer in combination with or following trastuzumab for one year, respectively. review the current standard of A phase II single-arm, open-label trial of T-DM1 (ado-trastuzumab emtansine) and neratinib for HER2-positive breast cancer with molecular residual disease (KAN-HER2 MRD). We observed intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. S. The benefit of N + F + T for HR+ HER2-mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N + F + T has been included in the National Comprehensive Cancer Network treatment guidelines. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab emtansine (T-DM1) when given in combination. The ExteNET trial randomised 2,840 patients in 41 countries with early-stage HER2+ breast cancer who had undergone surgery and adjuvant treatment with trastuzumab. However, a significant proportion of HER2-positive patients are either inherently resistant or develop resistance to trastuzumab. Preclinical data suggest that neratinib may overcome resistance to trastuzumab-emtansine (T-DM1) and that the combination has potential CNS efficacy. Trastuzumab and pertuzumab are two HER2-targeted monoclonal antibodies approved We conducted an international, randomized, double-blind trial in which the combination of tucatinib plus trastuzumab and capecitabine was compared with placebo plus trastuzumab and capecitabine. o. TKIs, such as neratinib and lapatinib, disrupt the intracellular signaling pathways activated by HER2, thereby inhibiting tumor cell proliferation. Read articles by Hector Josè Soto Parra on ScienceDirect, the world's leading source for scientific, technical, and medical research. In the non-randomized phase 3b/4 DESTINY-Breast12 study, trastuzumab deruxtecan (T-DXd) treatment of patients with HER2+ advanced breast cancer and active or stable brain metastases showed Trastuzumab is used to treat HER2-amplified metastatic gastric cancer; however, most patients become trastuzumab-resistant within a year. Trastuzumab BRCA2 mutations were correlated with neratinib and tucatinib response, and high expression of ATM, BRCA2, and BRCA1 were associated with neratinib resistance. Neratinib and ado-trastuzumab emtansine for pretreated and untreated human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases: Translational Breast Cancer Research Consortium trial 022. Furthermore, trastuzumab in combination with neratinib was growth inhibitory in SKBR3 and BT474 cells which had acquired resistance to trastuzumab as well as in a BT474 xenograft model. Affiliations 1 Instituto de Investigación Sanitaria Gregorio Marañón, Grupo Español de Investigación en Cáncer de Mama (GEICAM), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Universidad Complutense, Madrid, Spain. Wyeth, Pfizer, and Puma Biotechnology. In addition, new compounds and combinations are showing promising results in the late-line setting. Food and Drug Administration in 2017 for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, following adjuvant trastuzumab-based therapy. HER2 is a preferred target for treating HER2-positive breast cancer. Neratinib, oral was approved by the U. However, the panHER inhibitor neratinib was an effective monotherapy in HER2-low breast cancer cells and PDOs, and showed additive effects when combined with trastuzumab. 1 years in women with early-stage HER2-positive breast cancer. Neratinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth We previously reported central nervous system (CNS) activity for neratinib and neratinib–capecitabine. 3 Rigshospitalet, Copenhagen, Denmark. e. 2 Texas Oncology, Houston, TX, USA. Signal Transduction and Targeted Therapy - Pyrotinib plus capecitabine could significantly improve overall survival in HER2-positive metastatic breast cancer Neratinib has shown to significantly increase cellular internalization of anti-HER2 antibody drug conjugates including trastuzumab emtansine (T-DM1) and fam-trastuzumab deruxtecan (TDxd) in HER2+ cell lines and enhance release of cytotoxic payload and tumor growth inhibition. However, the efficacy o … ExteNET showed that neratinib, an irreversible pan-HER tyrosine kinase inhibitor, given for 1 year after trastuzumab-based therapy significantly improved invasive disease-free survival in women with early-stage HER2-positive breast cancer. All pts will receive standard dose mFOLFOX/trastuzumab q2w along with pembrolizumab 400 mg q6w. Here, we achieved a near-complete response in HR+ HER2 -amplified and overexpressing metastatic BC twice through molecular tumor board (MTB) discussions: initially, with trastuzumab deruxtecan (T Overall survival in the extended adjuvant setting was comparable for neratinib and placebo after a median follow-up of 8. 06, 612 and > 12 months). If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Currently, approved treatments for patients with HER2 + breast cancer include mAb therapies, such as trastuzumab and pertuzumab, the antibody–drug conjugate adotrastuzumab emtansine, and the small-molecule tyrosine kinase inhibitors (TKI) lapatinib and neratinib (3, 19–21). Exploratory genomic analyses were conducted. ExteNET showed that neratinib, an irreversible pan-HER tyrosine kinase inhibitor, given for 1 year after trastuzumab-based therapy significantly improved invasive disease-free survival in women with early-stage HER2-positive breast cancer. Primary endpoint in ORR. Interpretation: Neratinib for 12 months significantly improved 2-year invasive disease-free survival when given after chemotherapy and trastuzumab-based adjuvant therapy to women with HER2-positive breast cancer. This phase I/II trial studies the side effect and best dose of neratinib and to see how well it works with paclitaxel and with or without pertuzumab and trastuzumab before combination chemotherapy in treating patients with breast cancer that has spread to other places in the body (metastatic). Background: Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has single agent clinical activity in HER2 mutated cancer. “ HER2 Inhibitors (Trastuzumab, Pertuzumab, Lapatinib, Neratinib) Inhibit HER2 dimerization and activation HER2 breast cancer Taxane, CDK4 ”搜索结果（1923） Multiple HER2-targeted therapies have been developed over the last few years, including the tyrosine kinase inhibitors (TKI) lapatinib, neratinib, tucatinib, and pyrotinib. The combination of mAbs, such as trastuzumab and pertuzumab, has shown synergistic effects in clinical trials, leading to improved pCR and DFS. The irreversible/pan-HER inhibitor neratinib (N) has proven more potent than L. Patients received neratinib (monotherapy 4201; monotherapy SUMMIT), or neratinib with weekly temsirolimus (combination 4201), or trastuzumab every 3 weeks (combination SUMMIT). We previously reported central nervous system (CNS) activity for neratinib and neratinib–capecitabine. Nera will be dosed at 240 mg daily. daily with trastuzumab biosimilar (Herzuma) every 3 weeks. The ExteNET trial showed that 1 year of extended adjuvant therapy with neratinib after completion of adjuvant trastuzumab-based therapy reduces the risk of invasive breast cancer recurrence, with no evidence of increased cardiotoxicity. Methods: Patients with early-stage HER2+ breast cancer received oral neratinib 240 mg/day or placebo for 1 year after standard trastuzumab-based (neo)adjuvant therapy. Here, Swain et al. Neratinib plus trastuzumab is superior to pertuzumab plus trastuzumab in HER2-positive breast cancer xenograft models Jamunarani Veeraraghavan, Carolina Gutierrez, Vidyalakshmi Sethunath, We previously reported central nervous system (CNS) activity for neratinib and neratinib–capecitabine. Lapatinib (L) plus trastuzumab (T), with endocrine therapy for estrogen receptor (ER)+ tumors, but without chemotherapy, yielded meaningful response in HER2+ breast cancer (BC) neoadjuvant trials. Second-line therapy includes T-DM1, an antibody-drug conjugate (ADC) consisting of trastuzumab conjugated to maytansinoid (DM1). Furthermore, our exploratory analysis of ctDNA as a prognostic biomarker offers a practical tool to optimize patient selection and monitor treatment response. This open-label single arm phase 2 trial investigated the efficacy and safety of the dual anti-HER2 therapy, neratinib plus trastuzumab in heavily pretreated patients with HER2 mutated solid tumors excluding HER2 amplifications. We assessed the effects of neratinib, an irreversible panHER inhibito … Neratinib, an irreversible pan-HER inhibitor, with chemotherapy, anti-HER2 or HER2 ADC consistently yielded favorable patient outcomes in the trastuzumab-refractory patients (11 – 14). Knowledge of the mechanisms underlying trastuzumab Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. OUTLINE: This is a dose-escalation study of neratinib followed by a dose-expansion (PD) study. Here, we report results of neratinib plus T-DM1 in pts with HER2+ BCBM. Moreover, clinical bene ts fi were also observed in locally advanced or metastatic trastuzumab pre-treated HER2-positive breast cancers with the combination of neratinib and trastuzumab [18]. Moreover, neratinib has a certain efficacy to reverse “ HER2 Inhibitors (Trastuzumab, Pertuzumab, Lapatinib, Neratinib) Inhibit HER2 dimerization and activation HER2 breast cancer Taxane, CDK4 ”搜索结果（1897） Over the past 2 decades, there has been an extraordinary progress in the regimens developed for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Neratinib plus trastuzumab is superior to pertuzumab plus trastuzumab in HER2-positive breast cancer xenograft models Jamunarani Veeraraghavan, Carolina Gutierrez, Vidyalakshmi Sethunath, Neratinib-containing anti-HER2 regimen is superior to trastuzumab and pertuzumab in BT474 cell-derived xenograft model To evaluate the efficacy of different anti-HER2 treatment regimens, we first used the ER+/HER2-amplified BT474/AZ cells with high and homogeneous levels of HER2, hereafter referred to as BT474 (Supplementary Fig. “ HER2 Inhibitors (Trastuzumab, Pertuzumab, Lapatinib, Neratinib) Inhibit HER2 dimerization and activation HER2 breast cancer Taxane, CDK4 ”搜索结果（1897） Specific anti-EGFR therapies include compounds acting as TKIs such as gefitinib, erlotinib, afatinib, lapatinib, osimertinib, neratinib, canertinib, tucatinib and pyrotinib as well as monoclonal antibodies (mAb) trastuzumab, pertuzumab, cetuximab, panitumumab, and necitumumab. iDFS, the primary study endpoint, was examined in subgroups categorized according to the interval between completing trastuzumab and randomization (i. Both agents reduce the risk of recurrence; however, the We previously reported central nervous system (CNS) activity for neratinib and neratinib–capecitabine. The discovery of the monoclonal antibody trastuzumab almost 25 years ago revolutionized treatment and drug development for HER2+ breast cancer. Durable responses can be achieved in some patients. h7wjn, vkfn6o, q93l, f69rh, u94oj, vog4d, 3muyd, n5ad7, n6w3g, d4vub,