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Immunomodulatory Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Mifamurtide was approved in Europe in 2009, having already been awarded orphan drug status by the FDA and EMA in 2001 and 2004, respectively. However, it was denied full approval by the FDA in 2007. Mifamurtide is approved for high-grade, non-metastatic osteosarcoma after complete surgical resection in patients aged 2–30 at initial diagnosis and is normally used in combination with multi-agent chemotherapy to kill remaining cancer cells and improve overall survival. The approval of mifamurtide was based on a Phase III clinical trial in approximately 800 newly diagnosed osteosarcoma patients who were treated with mifamurtide or placebo combined with methotrexate and doxorubicin, with or without ifosfamide and cisplatin. Mortality was 30% lower in the treated arm versus chemotherapy plus placebo, and 78% of the patients were still alive six years after treatment. This represented an overall risk reduction of 8% which was considered significant.
Primary Bone Tumors
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Jeremy S. Whelan, Rob C. Pollock, Rachael E. Windsor, Mahbubl Ahmed
Standard chemotherapy for osteosarcoma usually consists of a multi-drug regimen including methotrexate, doxorubicin, and cisplatin. Other active cytotoxic agents include ifosfamide and etoposide. There have been no important recent additions of new drugs to first-line standard of care, and clinical studies have been aimed at defining optimal treatment schedules. Intra-arterial chemotherapy has been shown to produce high rates of histological necrosis but does not improve survival and is not routinely indicated. There are relatively few randomized trials of chemotherapy for osteosarcoma that have sufficient statistical power to provide firm evidence for best practice. A large study undertaken by the Children’s Oncology Group in the USA used a 2-by-2 factorial design to investigate the addition of ifosfamide to a standard arm of cisplatin, doxorubicin, and methotrexate. A second randomization compared the addition of the biological agent, MTP-PE (mifamurtide), to chemotherapy.26,27 An unequivocal advantage for these interventions was not demonstrated although the results have attracted considerable attention. Mifamurtide has been licensed for use in patients under 30 with localized osteosarcoma in some countries but is not universally available or used. There have been no further confirmatory clinical trials.1
Drug profiles: generic names A–Z
Published in Jerome Z. Litt, Neil H. Shear, Litt's Drug Eruption & Reaction Manual, 2017
Clinically important, potentially hazardous interactions with: ACE inhibitors, adrenergic neurone blockers, aldosterone antagonists, aliskiren, alpha blockers, angiotensin II receptor antagonists, anticoagulants, aspirin, baclofen, beta blockers, calcium channel blockers, cardiac glycosides, clonidine, clopidogrel, corticosteroids, coumarins, cyclosporine, dabigatran, deferiprone, diazoxide, diuretics, enoxaparin, erlotinib, furosemide, heparins, hydralazine, iloprost, ketorolac, lithium, methotrexate, methyldopa, mifamurtide, minoxidil, moxonidine, nitrates, nitroprusside, penicillamine, pentoxifylline, phenindione, potassium canrenoate, prasugrel, rifampin, ritonavir, rivaroxaban, SSRIs, sulfonylureas, tacrolimus, thiazides, tinzaparin, venlafaxine, voriconazole, warfarin, zidovudine
Assessing the impact of single or short-term administration on a therapy’s cost-effectiveness: a hypothetical disease-agnostic model
Published in Journal of Medical Economics, 2023
Alexa C. Klimchak, Lauren E. Sedita, Katherine L. Gooch, Daniel C. Malone
The purpose of CEA is to determine a therapy’s value to inform resource allocation57, and leveraging a standard approach allows for relative valuation across a range of diseases and treatments58. Thus, it is reasonable to consider modifying approaches when assessing SSTs5,14,15 in a standardized manner10 rather than ad hoc adjustments, which have been applied on a case-by-case basis, including for mifamurtide59. Mifamurtide is indicated for a rare type of osteosarcoma and administered over 36 weeks with potential benefits lasting a lifetime, making it SST-like59. NICE found the CEA was substantially sensitive to the benefit discount rate60. Specifically, all benefits would be discounted away after 22 years with the standard UK 3.5% discount rate compared to 49 years with a 1.5% rate61. Ultimately, the 1.5% benefit discount rate was used given the curative potential of the therapy and the expected sustained benefit60.
Immunotherapy in soft tissue sarcoma: current evidence and future perspectives in a variegated family of different tumor
Published in Expert Review of Anticancer Therapy, 2022
Giacomo G Baldi, Alessandro Gronchi, Marcella Tazzari, Silvia Stacchiotti
Mifamurtide, an immunomodulant drug used in osteosarcoma patients, was reported as a stimulator of the anti-tumor activity of TAMs. Trabectedin, formally a cytotoxic agent, has been shown to exert its activity also by TAM depletion [83]. Likely, drugs targeting VEGF receptors have also shown to be able to re-polarize TAM activity in favor of their anti-cancer functions. Alternatively, drugs directly targeting these cells have been investigated: some still at the preclinical levels (e.g. anti-MARCO) other already in cancer clinical trials (e.g. anti-CSF-1 R inhibitors as pexidartinib or anti-CSF-1 R monoclonal antibody emactuzumab). However, despite the large abundance of myeloid cells in STS, and their crucial role as local regulators of therapeutic efficacy, including immunotherapy, still little has been clinically tested in these diseases, and further studies, including a better in situ classification and stratification of these players according to histotypes are essential [84]. Besides myeloid targeting agents, the active use of these cells as adoptive cell therapy also seems a smart, yet feasible, perspective . Indeed, one advantage of these cells over T cells is their ability to infiltrate the stiff tumor matrix, which fits with the high macrophage/T ratio observed in many STS. While some CAR-M-based clinical trials have started in other disease settings (NCT03608618, NCT04660929), we believe attempts to the investigation of this strategy in sarcoma should also be pursued.
State-of-the-art, approved therapeutics for the pharmacological management of osteosarcoma
Published in Expert Opinion on Pharmacotherapy, 2021
Cristina Meazza, Sebastian Dorin Asaftei
Mifamurtide is the most extensively studied immune stimulatory agent for treating OS, as mentioned earlier. Tumor cells may evade control by the immune system by targeting the so-called ‘immune checkpoints,’ with the consequent inhibition of T-cell proliferation, cytokine production, and cytolytic activity. The immune checkpoints can be blocked pharmacologically by using ‘immune checkpoint inhibitors,’ like the monoclonal antibody targeting programmed cell death protein 1 (PD1), or its ligand (PD-L1). In murine models of metastatic OS, blocking PD-1/PD-L1 interactions enhances cytotoxic T lymphocyte activity, resulting in tumor cell proliferation being inhibited and the animal surviving for longer. However, in the SARC028 study, only 1 PR was identified among 22 patients (5%) with OS by using Pembrolizumab (an anti-PD1 antibody) [111].