The treatment of breast cancer that is driven by amplification and overexpression of human epidermal growth factor receptor 2 (HER2) has been drastically improved by the development of HER2-targeted therapies including trastuzumab and lapatinib. While outcomes for patients diagnosed with HER2-positive breast cancer have been greatly impacted by these therapies, treatment resistance is common and toxicity to standard regimens remains a therapeutic challenge. Trastuzumab emtansine (T-DM1) is a novel antibody drug conjugate that consists of the HER2-targeted monoclonal antibody, trastuzumab, joined via a stable linker to a derivative of maytansine, a highly potent cytotoxic chemotherapy. While other antibody drug conjugates have been developed clinically, this is the first in its class that maintains the antitumor properties of the HER2-targeted antibody, trastuzumab, and also avoids release of the chemotherapy until the molecule is taken up inside the HER2-overexpressing cancer cell. Several phase I studies have shown T-DM1 is safe, tolerable and has activity in trastuzumaband lapatinib-pretreated breast cancer. Moreover, phase II studies are now being reported that confirm its safety and clinical efficacy in both the frontline and heavily pretreated settings. Preliminary data from phase II studies evaluating its use in combination with other cytotoxics have also been reported and several large phase III trials are underway to evaluate its use in the HER2-positive metastatic breast cancer setting. This paper aims to provide a detailed review of the preclinical and clinical evidence relating to the mechanism of action, efficacy and safety of T-DM1 for the treatment of HER2-positive breast cancer.
Purpose: This review aims to present the preclinical and clinical data regarding efficacy and safety of lapatinib alone and in combination with other agents in the treatment of human epidermal growth factor receptor-2 (HER2)-overexpressing breast cancer. Background: HER2-positive (HER2+) breast cancer remains a treatment challenge. It is more aggressive than other breast cancers and it is associated with a poor outcome. Targeted therapy for HER2+ breast cancer has significantly changed the clinical course of the disease. Despite advances in therapy, there remains an unmet need in the treatment of HER2+ breast cancer. Lapatinib is a novel, orally bioavailable epidermal growth factor receptor/HER2+ targeted agent. Many trials have investigated the efficacy and safety of lapatinib alone and in conjunction with other agents in the treatment of HER2+ breast cancer. Methods and results: Preclinical and clinical trials of lapatinib have shown that it is effective in the treatment on HER2+ breast cancer. More important, studies show that it is effective in the setting of trastuzumab resistance and in the treatment of central nervous system metastases, both of which are current treatment challenges. Furthermore, lapatinib is effective in conjunction with trastuzumab in the treatment of early breast cancer. Data regarding the safety of lapatinib show that it is generally well tolerated; however, multiple studies have shown significant (grade 3 and 4) diarrhea and rash associated with lapatinib, thereby limiting its use. Carditoxicity has not been a significant adverse event associated with the use of lapatinib. Conclusion: Lapatinib is effective alone and in conjunction with other agents in the treatment of HER2+ breast cancer. However, its use is limited by significant diarrhea and rash.
Background:Activation and expansion of regulatory T cells (Tregs) has been proposed as a strategy to treat autoimmunity. When administered in low doses, IL-2 expands and activates Tregs leading to clinical response in several autoimmune diseases. However, the narrow therapeutic window of IL-2 results in loss of selectivity for Tregs and concurrent activation of conventional T cells (Tconv) and NK cells, limiting its clinical utility. This loss of selectivity may negate the clinical benefit of Treg activation and lead to dose-limiting side effects. PT101 is a novel engineered variant of IL-2 fused to an Fc protein backbone which in preclinical studies selectively activates Tregs without expanding Tconv or NK cells. PT101 is in clinical development for the treatment of patients with autoimmune diseases.Objectives:To assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of PT101 after a single dose in healthy human volunteers.Methods:We conducted a randomized, double-blind, single-ascending dose trial of PT101 or placebo (3:1 allocation). Five dose levels from 1 mg to 10 mg were administered by subcutaneous injection. Adverse events, physical examination findings, and clinical laboratory results were assessed for 29 days. Serum PT101 levels and antidrug antibody were assessed. Changes in mononuclear cell populations were measured in peripheral blood by flow cytometry.Results:56 subjects were administered PT101 or placebo. All subjects completed the study. There were no deaths, serious adverse events, dose limiting toxicities, or clinically significant changes in vital sign, ECG, or laboratory results. All adverse events were Grade 1 or 2 and self-limited. Injection site reactions were the most common adverse event. Transient increases in eosinophil counts were observed in some subjects, consistent with the known class effect of IL-2. Peak levels of PT101 occurred 11.0 to 14.6 hours after administration, and declined with a mean half-life of 20.4 to 28.3 hours, demonstrating linear exposure through the dose range. No anti-drug antibodies were induced. PT101 caused dose-related expansion of Tregs that plateaued at doses between 3.5 and 10 mg. Mean maximum expansion above baseline was 3.6-fold for total Tregs and 72.5-fold for the CD25bright subset of Tregs. Maximal expansion was observed by Day 8-10 with a return toward baseline by Day 29. Over 80% of subjects achieved a 2-fold or greater expansion of total Tregs (Table 1). No significant expansion of Tconv or NK cells was observed at any dose level.Table 1.Percent Total Treg RespondersFold Change Total TregsPlacebo(n=14)1 mg(n=6)3.5 mg(n=12)5 mg(n=12)7.5 mg(n=6)10 mg(n=6)≥ 2X7%33%83%83%100%100%≥ 3X0%0%58%75%33%50%≥ 4X0%0%24%42%33%17%Conclusion:PT101 was safe and well tolerated after a single dose in healthy volunteers. Marked expansion of both total Treg and CD25bright Treg cells was observed. High selectivity for Tregs was observed with no significant expansion of pro-inflammatory Tconv and NK cells even at the highest dose studied. These results support the therapeutic potential of PT101 in planned multiple dose studies in systemic lupus erythematosus, ulcerative colitis, and other autoimmune diseases.References:[1]Klatzmann, D., Abbas, A. The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat Rev Immunol 15, 283–294 (2015)Acknowledgements:Pandion Therapeutics acknowledges the participants and research staff who contributed to this clinical trialDisclosure of Interests:John S Sundy Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Kevin L. Otipoby Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Nathan Higginson-Scott Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Jyothsna Visweswaraiah Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Erik Sampson Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Katalin Kis-Toth Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Adrianne Monsef Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Parika Petaipimol Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, David Essayan Consultant of: Pandion Therapeutics, Mary Ellen Cosenza Consultant of: Pandion Therapeutics, Rahul Kakkar Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Jo Viney Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics
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