A Phase II Study of ERK Inhibition by Ulixertinib (BVD-523) in Metastatic Uveal Melanoma

Cancer Research Communications, Год журнала: 2024, Номер 4(5), С. 1321 - 1327

Опубликована: Апрель 29, 2024

Abstract Purpose: Uveal melanoma is a rare and aggressive subset of that minimally responsive to traditional therapies. Greater than 80% uveal melanomas have mutation in GNAQ or GNA11 which lead downstream signaling through the MAPK pathway. Ulixertinib (BVD-523) potent reversible small-molecule ATP-competitive inhibitor both ERK1 ERK2 protein kinases. Materials Methods: We performed phase II study determine efficacy safety BVD-523 patients with metastatic melanoma. This was conducted as Simon two-stage design sample size 25 an initial evaluation after 13 patients. Results: From April 2018 2019, were enrolled. Patients predominantly female (69%) median age 64 years (34–76). Sites metastases included liver (84.6%) lung (30.8%). Grade 3 4 toxicities associated therapy consistent ERK inhibitors function test (LFT) elevation, hyponatremia, pruritis, amylase anemia, rash. The best response, per RECIST 1.1, stable disease patients, progression 7 Two unevaluable for response due withdrawal from study. Median time 2.0 months. There eight deaths overall survival 6.9 Conclusions: inhibition ulixertinib did not demonstrate activity observed what would be expected pathway inhibition. Significance: difficult treat minimal options. majority mutations leading activation Efforts target MEK has had mixed results. trial examined potential role this agent therapy.

Язык: Английский

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Uveal melanoma: Current evidence on prognosis, treatment and potential developments

Asia-Pacific Journal of Ophthalmology, Год журнала: 2024, Номер 13(2), С. 100060 - 100060

Опубликована: Март 1, 2024

Uveal Melanoma (UM) is a rare disease, yet it the most common primary intraocular malignancy in adult patients. Despite continuous advancements and research, risk of metastasis remains high. It possible to stratify patients according their metastases using variety known factors. Even though there no gold standard for prognostication with uveal melanoma, becoming increasingly clear that combining histo-pathological, patient-related molecular prognostic markers allows more accurate prediction metastatic than by one parameter. Primary UM eye are treated very effectively eye-sparing radiation-based techniques or enucleation. However, not prevent treat current therapeutic options. Nonetheless, efforts find new targets continue progress being made, especially field targeted therapy, as exemplified anti-gp100 bispecific molecule Tebentafusp. This review delves into history its incidence, presentation diagnosis, factors treatment options, both tumour metastases. We show different populations may have risks developing UM, each country should evaluate own

Язык: Английский

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Beyond Chemoimmunotherapy in Advanced Non–Small Cell Lung Cancer: New Frontiers, New Challenges

American Society of Clinical Oncology Educational Book, Год журнала: 2024, Номер 44(3)

Опубликована: Май 23, 2024

Chemoimmunotherapy is currently the preferred first-line treatment option for majority of patients with advanced non-small cell lung cancer without driver genetic alterations. Most these patients, however, will experience disease progression within first year after initiation and both their physicians be confronted dilemma optimal second-line treatment. Identification molecular targets, such as

Язык: Английский

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15-Gene Expression Profile and PRAME as Integrated Prognostic Test for Uveal Melanoma: First Report of Collaborative Ocular Oncology Group Study No. 2 (COOG2.1)

Journal of Clinical Oncology, Год журнала: 2024, Номер 42(28), С. 3319 - 3329

Опубликована: Июль 25, 2024

PURPOSEValidated and accurate prognostic testing is critical for precision medicine in uveal melanoma (UM). Our aims were to (1) prospectively validate an integrated classifier combining a 15-gene expression profile (15-GEP)

Язык: Английский

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Bispecific antibodies: advancing precision oncology

Trends in cancer, Год журнала: 2024, Номер 10(10), С. 893 - 919

Опубликована: Авг. 30, 2024

Bispecific antibodies (bsAbs) are engineered molecules designed to target two different epitopes or antigens. The mechanism of action is determined by the bsAb molecular targets and structure (or format), which can be manipulated create variable novel functionalities, including linking immune cells with tumor cells, dual signaling pathway blockade. Several bsAbs have already changed treatment landscape hematological malignancies select solid cancers. However, mechanisms resistance these agents understudied management toxicities remains challenging. Herein, we review principles in engineering, current understanding resistance, data for clinical application, provide a perspective on ongoing challenges future developments this field.

Язык: Английский

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Current State of Melanoma Therapy and Next Steps: Battling Therapeutic Resistance

Cancers, Год журнала: 2024, Номер 16(8), С. 1571 - 1571

Опубликована: Апрель 19, 2024

Melanoma is the most aggressive and deadly form of skin cancer due to its high propensity metastasize distant organs. Significant progress has been made in last few decades melanoma therapeutics, notably targeted therapy immunotherapy. These approaches have greatly improved treatment response outcomes; however, they remain limited their abilities hinder disease progression due, part, onset acquired resistance. In parallel, intrinsic resistance remains an issue be resolved. this review, we summarize currently available therapeutic options for focus on possible mechanisms that drive A better understanding will provide rational strategies overcome these obstacles.

Язык: Английский

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Non-Cutaneous Melanoma

Surgical Oncology Clinics of North America, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

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Tebentafusp, a T cell engager, promotes macrophage reprogramming and in combination with IL-2 overcomes macrophage immunosuppression in cancer

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 10, 2025

Uveal melanoma (UM) is the most common intraocular cancer in adults, with metastatic disease (mUM) occurring approximately half of patients. Tebentafusp, an immune-mobilizing monoclonal T cell receptor against (ImmTAC), a therapeutic shown to improve overall survival (OS) HLA-A*02:01+ adult patients mUM. Here we investigate impact tumor-associated macrophages (TAM) on ImmTAC activity. In vitro, M2 inhibit ImmTAC-mediated tumor-killing dose-dependent and contact-dependent manner. Accordingly, high baseline intratumoral TAM-to-T ratios correlate shorter OS (HR = 2.09, 95% CI, 1.31–3.33, p 0.002) tebentafusp-treated mUM from phase 2 trial. By contrast, IL-2 conditioning cells overcomes macrophage-mediated suppression while treatment leads M2-to-M1 macrophage reprogramming both vitro Overall, show that tebentafusp reshapes tumor microenvironment enhance anti-tumor activity, whilst combining may benefit levels TAM. 'T engagers promote antitumor immunity, but how modulates this activity still unclear. authors show, using biopsies uveal single analyses, engager, tebentafusp, reprograms ameliorates, synergy IL-2, immunosuppression cancer.

Язык: Английский

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Optimizing TIL therapy for uveal melanoma: lessons learned and unlearned from cutaneous melanoma

Immunotherapy, Год журнала: 2025, Номер unknown, С. 1 - 9

Опубликована: Март 18, 2025

Adoptive transfer of tumor infiltrating lymphocytes (TIL-ACT) is a personalized cancer therapy that harnesses the anti-tumor activity resident T cells through ex vivo activation and expansion. This involves infusion single dose expanded TIL together with high IL-2 following preparative lymphodepleting chemotherapy. The United States Food Drug Administration approved lifileucel in 2024 as first autologous product for patients advanced cutaneous melanoma (CM), adding to list immunotherapies this highly immunogenic cancer. However, role TIL-ACT other solid tumors unclear, especially poorly cancers low mutational burden. In review, we describe historical development TIL-ACT, summarize clinical results CM, novel application metastatic uveal (UM), prototypic immunotherapy-resistant tumor. We will highlight key biologic differences between CM UM, their consequential influence on manufacturing UM-specific products, biomarkers precision UM.

Язык: Английский

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Overall survival from tebentafusp versus nivolumab plus ipilimumab in first-line metastatic uveal melanoma: a propensity score-weighted analysis

Annals of Oncology, Год журнала: 2023, Номер 35(3), С. 317 - 326

Опубликована: Дек. 2, 2023

Tebentafusp demonstrated a superior overall survival (OS) benefit [hazard ratio (HR) 0.51] compared to investigator's choice (82% pembrolizumab) in randomized, phase III trial (IMCgp100-202; N = 378) untreated metastatic uveal melanoma (mUM). The 1-year OS rates for tebentafusp and pembrolizumab were 73% 59%, respectively. In the single-arm GEM1402 (N 52), rate nivolumab plus ipilimumab (N+I) mUM was 52%. Due limitations conducting randomized trials mUM, we on or (IMCgp100-202) N+I (GEM1402) using propensity scoring methods.

Язык: Английский

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