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.

Novel pharmaceutical composition containing at least one dolastatin 10 derivative

Abstract: The present invention is directed to a pharmaceutical composition, comprising at least one compound of formula (I), in combination with capecitabine, trastuzumab, pertuzumab, cisplatin or irinotecan for simultaneous, sequential or separate administration in the treatment of cancer.

Abstract P5-19-23: A phase I clinical trial of ganetespib (heat shock protein 90 inhibitor) in combination with paclitaxel and trastuzumab in human epidermal growth factor receptor-2 positive (HER2+) metastatic breast cancer

Abstract: Introduction: Targeted therapies in HER2+ metastatic breast cancer (MBC) have significantly improved survival, however efficacy is limited by development of 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. Ganetespib is a novel, synthetic HSP90 inhibitor with increased potency and tolerability compared with earlier agents. Our group has conducted a single agent ganetespib trial in unselected patients which showed anti-tumor activity in HER2+ and triple negative breast cancer. In addition, preclinical data suggests HSP90 inhibition is synergistic with taxanes with potential for significant clinical activity. Ganetespib has been combined with docetaxel in non-small cell lung cancer, it has not previously been combined with paclitaxel and trastuzumab. This study will define the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of ganetespib when given with paclitaxel and trastuzumab for patients with HER2+ MBC. Methods: In this 3+3 phase I dose escalation study, patients with trastuzumab resistant HER2+ MBC receive trastuzumab (4mg/kg loading dose, then 2mg/kg) and paclitaxel weekly (80mg/m2) with ganetespib day 1, 8 ,15 of 28 day cycle. Patients are required to have prior pertuzumab and T-DM1 (prior pertuzumab and T-DM1 are not mandated if heavily pretreated prior to their respective FDA approvals). Hormone receptor positive patients are required to have at least one prior line of endocrine therapy. The single agent dose limiting toxicity (DLT) of ganetespib is diarrhea and therefore patients receive prophylactic anti-motility agents. The anticipated MTD of ganetespib in this combination has been informed by experience with docetaxel and based on this only three dose levels of ganetespib are being explored 100mg/m2, 150mg/m2 and a third intermediate cohort of 125mg/m2, if needed. Secondary endpoints include evaluation of effects of ganetespib on the pharmacokinetics of paclitaxel and preliminary assessment of efficacy of the combination (scans at 8 weeks and every 12 weeks thereafter, RECIST 1.1). Results: The first dosing cohort has fully enrolled and there were no significant toxicities or DLTs reported. Median age was 48 years (range 39-49), median prior lines of chemotherapy were 4 (range 3-7) and included prior pertuzumab and T-DM1 in all 3 patients. 5 adverse events have been defined as possibly/probably related to ganetespib – grade 2 anemia and leukopenia, grade 1 diarrhea (2 patients), fatigue, and rash. Enrollment to the second and potentially final cohort is underway. Conclusion: This study will define the RP2D of ganetespib in combination with paclitaxel and trastuzumab. Final safety, pharmacokinetic and preliminary response data for all patients will be presented. This combination, with a novel anti-HER2 agent, has encouraging potential for activity in HER2+ breast cancer which is refractory to other HER2 targeting agents. Citation Format: Komal Jhaveri, Karen Cadoo, Sarat Chandarlapaty, Eleonora Teplinsky, James Speyer, Gabriella D9 Andrea, Sujata Patil, Sofia Haque, Kent Friedman, Scott Heese, Deirdre Neville, Francisco Esteva, Clifford Hudis, Shanu Modi. A phase I clinical trial of ganetespib (heat shock protein 90 inhibitor) in combination with paclitaxel and trastuzumab in human epidermal growth factor receptor-2 positive (HER2+) metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-23.

Abstract PD3-05: Co-occurring gain-of-function mutations in HER2 and HER3 cooperate to enhance HER2/HER3 binding, HER-dependent signaling, and breast cancer growth

Abstract: ERBB2, the gene encoding HER2, is mutated in 2-4% of breast cancers. The HER2 tyrosine kinase inhibitor neratinib has shown clinical activity against breast cancers harboring HER2 activating mutations, suggesting these tumors depend on HER2 signaling. Co-occurring HER2 and HER3 (ERBB3) mutations have been reported in patients who respond to neratinib (Hanker et al., Cancer Discov. 2017) suggesting the possibility of cooperativity of both oncogenes. Co-expression of the mutant intracellular domains of HER2 and HER3 in HEK293 cells enhanced phosphorylation of HER3 and ERK compared to expression of either mutant alone, which was blocked by 100 nM neratinib. Interrogation of TCGA, METABRIC, Project GENIE, and Foundation Medicine datasets revealed that gain-of-function mutations in ERBB2 and ERBB3 co-occur with a statistically significant frequency. For example, in GENIE, ERBB2 mutations co-occur with mutations in ERBB3 (8.3% of ERBB2-mutant vs 2.3% of ERBB2 WT; q=1.37x10-10). We hypothesized that co-occurring mutations in HER2 and HER3 cooperate to enhance HER2 signaling and dependence and breast cancer progression. Thirty-four unique breast cancers were found to harbor co-occurring mutations in HER2 and HER3, the most common of which were ERBB2L755S/ERBB3E928G (n=10), ERBB2V777L/ERBB3E928G(n=6), and ERBB2L869R/Q/ERBB3E928G (n=4). Using co-immunoprecipitation assays with HER2 and HER3 antibodies in transfected HEK293 cells, we found that co-expression of HER3E928G with wild type (WT) HER2, or co-expression of HER2L755S or HER2L869R with HER3WT, slightly increased HER2-HER3 dimerization. However, binding was strongest between double mutants. This was accompanied by the highest levels of Y1289 p-HER3 in cells expressing both HER3E928G and each HER2L755S, HER2V777L, or HER2L869R compared to cells expressing each HER2 or HER3 mutant with a respective WT heterodimer partner. Structural modeling of the HER2L869R/HER3E928G double-mutant predicted that the HER3 mutation, located at the dimer interface, may enhance heterodimerization of the kinase domains through decreased bulk and electrostatic repulsion. We also noted that the HER2L755S mutation is predicted to be in close proximity to HER3E928G ( MCF7 “knock-in” cells incorporating HER2L755S, HER2V777L, or HER2L869R (or HER2WT) were stably transduced with HER3E928G or HER3WT. Co-expression of double mutants strongly enhanced estrogen-independent growth in 3D Matrigel over cells expressing either mutant alone. We are currently testing inhibitors of HER2/HER3 signaling, including neratinib ± trastuzumab, trastuzumab + pertuzumab, and the ERBB1-3 antibody mixture Sym013, to determine therapeutic strategies to block the cooperative growth induced by co-occurring HER2 and HER2 mutations. Conclusions: Co-expression of mutant HER2 and mutant HER3 promotes HER2/HER binding, HER3 phosphorylation, and breast tumor cell proliferation. We aim to identify therapeutic vulnerabilities for patients with co-occurring HER2 and HER3 mutations. Citation Format: Hanker AB, Koch JP, Ye D, Sliwoski G, Sheehan J, Kinch LN, Red Brewer M, He J, Miller VA, Lalani AS, Cutler, Jr. RE, Croessmann S, Zabransky DJ, Meiler J, Arteaga CL. Co-occurring gain-of-function mutations in HER2 and HER3 cooperate to enhance HER2/HER3 binding, HER-dependent signaling, and breast cancer growth [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD3-05.