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.

Pharmacovigilance Analysis of Heart Failure Associated With Anti-HER2 Monotherapies and Combination Regimens for Cancer

Abstract: Trastuzumab improves outcomes in patients with HER2-overexpressing malignancies but is associated with decreases in left ventricular ejection fraction. Heart failure (HF) risks from other anti-HER2 therapies are less clear.Using World Health Organization pharmacovigilance data, the authors compared HF odds across anti-HER2 regimens.In VigiBase, 41,976 patients had adverse drug reactions (ADRs) with anti-HER2 monoclonal antibodies (trastuzumab, n = 16,900; pertuzumab, n = 1,856), antibody-drug conjugates (trastuzumab emtansine [T-DM1], n = 3,983; trastuzumab deruxtecan, n = 947), and tyrosine kinase inhibitors (afatinib, n = 10,424; lapatinib, n = 5,704; neratinib, n = 1,507; tucatinib, n = 655); additionally, 36,052 patients had ADRs with anti-HER2-based combination regimens. Most patients had breast cancer (monotherapies, n = 17,281; combinations, n = 24,095). Outcomes included comparison of HF odds with each monotherapy relative to trastuzumab, within each therapeutic class, and among combination regimens.Of 16,900 patients with trastuzumab-associated ADRs, 2,034 (12.04%) had HF reports (median time to onset 5.67 months; IQR: 2.85-9.32 months) compared with 1% to 2% with antibody-drug conjugates. Trastuzumab had higher odds of HF reporting relative to other anti-HER2 therapies collectively in the overall cohort (reporting OR [ROR]: 17.37; 99% CI: 14.30-21.10) and breast cancer subgroup (ROR: 17.10; 99% CI: 13.12-22.27). Pertuzumab/T-DM1 had 3.4 times higher odds of HF reporting than T-DM1 monotherapy; tucatinib/trastuzumab/capecitabine had similar odds as tucatinib. Among metastatic breast cancer regimens, HF odds were highest with trastuzumab/pertuzumab/docetaxel (ROR: 1.42; 99% CI: 1.17-1.72) and lowest with lapatinib/capecitabine (ROR: 0.09; 99% CI: 0.04-0.23).Trastuzumab and pertuzumab/T-DM1 had higher odds of HF reporting than other anti-HER2 therapies. These data provide large-scale, real-world insight into which HER2-targeted regimens would benefit from left ventricular ejection fraction monitoring.

Clinical Pharmacology Strategies in the Development of Antibody–Drug Conjugates

Abstract: The development of antibody–drug conjugates (ADCs) represents a novel approach to improving the therapeutic index of cytotoxic agents by selectively delivering potent cytotoxic drugs to tumors while minimizing exposure and toxicity to normal tissues. The past decade has seen a significant progress in the development of ADCs as anticancer therapeutics. Although there are more than 40 ADCs currently being evaluated in clinical trials, the clinical pharmacology roadmap for the development of ADCs is not well defined. With the example of T-DM1, an ADC comprised of a unique combination of trastuzumab, linker, and cytotoxic agent DM1, some development challenges unique to ADCs are discussed in this chapter. A clinical pharmacology strategy, comprised of both large and small molecule drug development paradigms, including population pharmacokinetics and exposure–response (safety/efficacy) analysis, QTc, drug interaction, organ dysfunction, and integrated metabolism strategies, was applied to characterize the clinical pharmacology of T-DM1. Antitherapeutic antibody responses to molecular components of the ADC were also assessed. T-DM1 is currently being tested in multiple Phase Ib/II and III studies, either as a single agent or in combination with taxane and pertuzumab in HER2+ MBC and gastric cancer patients. This chapter focuses primarily on clinical pharmacology assessments in the development of T-DM1 for HER2+ metastatic breast cancer.

Abstract A22: Augmentation of a novel adenoviral vaccine strategy by checkpoint inhibitors

Abstract: The immunologic hurdles for a vaccine targeting cancer are much higher than for those targeting an infectious disease. The profoundly immunosuppressive tumor microenvironment, the lack of microbial danger signals, and the need to break tolerance without causing catastrophic autoimmunity are all considerations that must be made when designing an effective anti-cancer vaccine. Immune checkpoint blockade (ICB) including programmed death 1 (PD1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibodies have revolutionized cancer treatment as a whole, including the potential for a successful cancer vaccine. Human epidermal growth factor receptor 2 (HER2) is an oncogene that is overexpressed in 20-25% of breast cancers and has been successfully targeted with therapeutic anti-HER2 therapies, particularly antibody combinations like trastuzumab and pertuzumab. However, even the most potent anti-HER2 therapy available is often accompanied by a high rate of recurrence, with the many responders eventually becoming resistant. Given the relative success of combination therapy using antibodies targeting different epitopes of HER2, we hypothesized that a HER2 targeting vaccine approach could further broaden the immune repertoire and reduce rates of resistance and recurrence. We developed both an implantable and a mammary specific spontaneous tumor model driven by an oncogenic isoform of HER2 (HER2Δ16). Using these models we tested a novel adenoviral vaccine platform encoding an inactive HER2Δ16 variant. We have shown that this isoform is significantly more oncogenic than full length HER2 and plays a role in anti-HER2 therapeutic resistance. Using the implantable tumor model, we found that therapeutic vaccination elicits a robust anti-HER2 specific cellular and humoral response, as well as significantly inhibits tumor growth of HER2Δ16-positive tumors. While effective at reducing tumor growth, we observed that our vaccine was typically not capable of eliciting tumor regression in mice, due to the immunosuppressive tumor microenvironment of established tumors. As such, we tested our vaccine platform in combination with two recently approved checkpoint inhibitors anti-CTLA-4 and anti-PD-1. This combination greatly enhanced the HER2-specific immune response as well as the antitumor effect seen post vaccination, with many tumors exhibiting complete regression. Our spontaneous model provides the ideal setting to test our vaccine platform as it is tolerant to human HER2, driven by HER2 expression, and grows at a rate that provides sufficient time to intervene with an immune targeting therapy. Using this model we have further shown that vaccination against HER2Δ16 can prevent spontaneous tumor formation and work is ongoing to test therapeutic vaccine strategies in combination with ICB. Future studies will be focused on determining the exact mechanism of regression and evaluating the impact on de novo and acquired resistance by combining this novel therapeutic platform with current standard of care HER2 targeted therapies. We conclude that the incorporation of ICB can help overcome the immunologic hurdles and augment the utility of therapeutic cancer vaccines. Citation Format: Erika J. Crosby, Gangjun Lei, Junping Wei, Xiao Yi Yang, Tao Wang, Cong-Xiao Liu, H Kim Lyerly, Zachary C. Hartman. Augmentation of a novel adenoviral vaccine strategy by checkpoint inhibitors [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A22.