Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions

Neuro-Oncology, Год журнала: 2020, Номер 22(8), С. 1073 - 1113

Опубликована: Апрель 20, 2020

Abstract Glioblastomas are the most common form of malignant primary brain tumor and an important cause morbidity mortality. In recent years there have been advances in understanding molecular pathogenesis biology these tumors, but this has not translated into significantly improved outcomes for patients. consensus review from Society Neuro-Oncology (SNO) European Association (EANO), current management isocitrate dehydrogenase wildtype (IDHwt) glioblastomas will be discussed. addition, novel therapies such as targeted therapies, agents targeting DNA damage response metabolism, immunotherapies, viral reviewed, well challenges future directions research.

Язык: Английский

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Longitudinal molecular trajectories of diffuse glioma in adults

Nature, Год журнала: 2019, Номер 576(7785), С. 112 - 120

Опубликована: Ноя. 20, 2019

Язык: Английский

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Antibody–Drug Conjugates: The Last Decade

Pharmaceuticals, Год журнала: 2020, Номер 13(9), С. 245 - 245

Опубликована: Сен. 14, 2020

An armed antibody (antibody–drug conjugate or ADC) is a vectorized chemotherapy, which results from the grafting of cytotoxic agent onto monoclonal via judiciously constructed spacer arm. ADCs have made considerable progress in 10 years. While 2009 only gemtuzumab ozogamicin (Mylotarg®) was used clinically, 2020, 9 Food and Drug Administration (FDA)-approved are available, more than 80 others active clinical studies. This review will focus on FDA-approved late-stage ADCs, their limitations including toxicity associated resistance mechanisms, as well new emerging strategies to address these issues attempt widen therapeutic window. Finally, we discuss combination with conventional chemotherapy checkpoint inhibitors, design for applications beyond oncology, make magic bullet that Paul Ehrlich dreamed of.

Язык: Английский

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The current state of molecular testing in the treatment of patients with solid tumors, 2019

CA A Cancer Journal for Clinicians, Год журнала: 2019, Номер 69(4), С. 305 - 343

Опубликована: Май 22, 2019

The world of molecular profiling has undergone revolutionary changes over the last few years as knowledge, technology, and even standard clinical practice have evolved. Broad is now nearly essential for all patients with metastatic solid tumors. New agents been approved based on testing instead tumor site origin. Molecular methodologies likewise changed such that tests were performed a ago are no longer complete possibly inaccurate today. As rapid change, medical providers can quickly fall behind or struggle to find up-to-date sources ensure he she provides optimum care. In this review, authors provide current state art profiling/precision medicine, standards, view into future ahead.

Язык: Английский

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INTELLANCE 2/EORTC 1410 randomized phase II study of Depatux-M alone and with temozolomide vs temozolomide or lomustine in recurrent EGFR amplified glioblastoma

Neuro-Oncology, Год журнала: 2019, Номер 22(5), С. 684 - 693

Опубликована: Ноя. 19, 2019

Abstract Background Depatuxizumab mafodotin (Depatux-M) is a tumor-specific antibody–drug conjugate consisting of an antibody (ABT-806) directed against activated epidermal growth factor receptor (EGFR) and the toxin monomethylauristatin-F. We investigated Depatux-M in combination with temozolomide or as single agent randomized controlled phase II trial recurrent EGFR amplified glioblastoma. Methods Eligible were patients centrally confirmed glioblastoma at first recurrence after chemo-irradiation temozolomide. Patients to either 1.25 mg/kg every 2 weeks intravenously, this treatment combined 150–200 mg/m2 day 1–5 4 weeks, lomustine The primary endpoint study was overall survival. Results Two hundred sixty randomized. In efficacy analysis 199 events (median follow-up 15.0 mo), hazard ratio (HR) for arm compared control 0.71 (95% CI = 0.50, 1.02; P 0.062). monotherapy comparable that (HR 1.04, 95% 0.73, 1.48; 0.83). most frequent toxicity treated reversible corneal epitheliopathy, occurring grades 3–4 adverse 25–30% patients. long-term median 28.7 months, HR comparison versus 0.66 0.48, 0.93). Conclusion This suggests possible role use glioblastoma, especially relapsing well end first-line adjuvant treatment. (NCT02343406)

Язык: Английский

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Recent advances of antibody drug conjugates for clinical applications

Acta Pharmaceutica Sinica B, Год журнала: 2020, Номер 10(9), С. 1589 - 1600

Опубликована: Апрель 24, 2020

Antibody drug conjugates (ADCs) normally compose of a humanized antibody and small molecular via chemical linker. After decades preclinical clinical studies, series ADCs have been widely used for treating specific tumor types in the clinic such as brentuximab vedotin (Adcetris®) relapsed Hodgkin's lymphoma systemic anaplastic large cell lymphoma, gemtuzumab ozogamicin (Mylotarg®) acute myeloid leukemia, ado-trastuzumab emtansine (Kadcyla®) HER2-positive metastatic breast cancer, inotuzumab (Besponsa®) most recently polatuzumab vedotin-piiq (Polivy®) B malignancies. More than eighty investigated different stages from approximately six hundred trials to date. This review summarizes key elements highlights recent advances ADCs, well important lessons learned data, future directions.

Язык: Английский

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Targeting cancer with antibody-drug conjugates: Promises and challenges

mAbs, Год журнала: 2021, Номер 13(1)

Опубликована: Янв. 1, 2021

Antibody-drug conjugates (ADCs) are a rapidly expanding class of biotherapeutics that utilize antibodies to selectively deliver cytotoxic drugs the tumor site. As May 2021, U.S. Food and Drug Administration (FDA) has approved ten ADCs, namely Adcetris®, Kadcyla®, Besponsa®, Mylotarg®, Polivy®, Padcev®, Enhertu®, Trodelvy®, Blenrep®, Zynlonta™ as monotherapy or combinational therapy for breast cancer, urothelial myeloma, acute leukemia, lymphoma. In addition, over 80 investigational ADCs currently being evaluated in approximately 150 active clinical trials. Despite growing interest challenges remain expand their therapeutic index (with greater efficacy less toxicity). Recent advances manufacturing technology antibody, payload, linker combined with new bioconjugation platforms state-of-the-art analytical techniques helping shape future development ADCs. This review highlights current status marketed those under investigation focus on translational strategies improve product quality, safety, efficacy.

Язык: Английский

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Stepping forward in antibody-drug conjugate development

Pharmacology & Therapeutics, Год журнала: 2021, Номер 229, С. 107917 - 107917

Опубликована: Июнь 24, 2021

Язык: Английский

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Depatuxizumab mafodotin in EGFR-amplified newly diagnosed glioblastoma: A phase III randomized clinical trial

Neuro-Oncology, Год журнала: 2022, Номер 25(2), С. 339 - 350

Опубликована: Июль 15, 2022

Abstract Background Approximately 50% of newly diagnosed glioblastomas (GBMs) harbor epidermal growth factor receptor gene amplification (EGFR-amp). Preclinical and early-phase clinical data suggested efficacy depatuxizumab mafodotin (depatux-m), an antibody–drug conjugate comprised a monoclonal antibody that binds activated EGFR (overexpressed wild-type EGFRvIII-mutant) linked to microtubule-inhibitor toxin in EGFR-amp GBMs. Methods In this phase III trial, adults with centrally confirmed, GBM were randomized 1:1 radiotherapy, temozolomide, depatux-m/placebo. Corneal epitheliopathy was treated combination protocol-specified prophylactic supportive measures. There 85% power detect hazard ratio (HR) ≤0.75 for overall survival (OS) at 2.5% 1-sided significance level (ie traditional two-sided p ≤ 0.05) by log-rank testing. Results 639 patients (median age 60, range 22–84; 62% men). Prespecified interim analysis found no improvement OS depatux-m over placebo 18.9 vs. 18.7 months, HR 1.02, 95% CI 0.82–1.26, = 0.63). Progression-free longer than 8.0 6.3 months; 0.84, confidence interval [CI] 0.70–1.01, 0.029), particularly among those EGFRvIII-mutant 8.3 5.9 0.72, 0.56–0.93, 0.002) or MGMT unmethylated (HR 0.77, 0.61–0.97; 0.012) tumors but without improvement. occurred 94% depatux-m-treated (61% grade 3–4), causing 12% discontinue. Conclusions Interim demonstrated benefit treating GBM. No new important safety risks identified.

Язык: Английский

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Antibody-Drug Conjugates Targeting the Human Epidermal Growth Factor Receptor Family in Cancers

Frontiers in Molecular Biosciences, Год журнала: 2022, Номер 9

Опубликована: Фев. 28, 2022

Members of the human epidermal growth factor receptor (HER) family, which includes HER1 (also known as EGFR), HER2, HER3 and HER4, have played a central role in regulating cell proliferation, survival, differentiation migration. The overexpression HER family has been recognized one most common cellular dysregulation associated with wide variety tumor types. Antibody-drug conjugates (ADCs) represent new promising class anticancer therapeutics that combine cancer specificity antibodies cytotoxicity chemotherapeutic drugs. Two HER2-directed ADCs, trastuzumane-emtansine (T-DM1) trastuzumab-deruxtecan (DS-8201a), approved for HER2-positive metastatic breast by U.S. Food Drug Administration (FDA) 2013 2019, respectively. A third ADC, disitamab vedotin (RC48), locally advanced or gastric gastroesophageal junction NMPA (National Medical Products Administration) China 2021. total 11 ADCs target receptors (EGFR, HER2 HER3) are currently under clinical trials. In this review article, we summarize three (T-DM1, DS-8201a RC48), together investigational EGFR-directed (ABT-414, MRG003 M1231), (SYD985, ARX-788, A166, MRG002, ALT-P7, GQ1001 SBT6050) HER3-directed ADC (U3-1402). Lastly, discuss major challenges development highlight possible future directions to tackle these challenges.

Язык: Английский

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