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Chemoprevention agents for melanoma: A path forward into phase 3 clinical trials.

ABSTRACT: Recent progress in the treatment of advanced melanoma has led to unprecedented improvements in overall survival and, as these new melanoma treatments have been developed and deployed in the clinic, much has been learned about the natural history of the disease. Now is the time to apply that knowledge toward the design and clinical evaluation of new chemoprevention agents. Melanoma chemoprevention has the potential to reduce dramatically both the morbidity and the high costs associated with treating patients who have metastatic disease. In this work, scientific and clinical melanoma experts from the national Melanoma Prevention Working Group, composed of National Cancer Trials Network investigators, discuss research aimed at discovering and developing (or repurposing) drugs and natural products for the prevention of melanoma and propose an updated pipeline for translating the most promising agents into the clinic. The mechanism of action, preclinical data, epidemiological evidence, and results from available clinical trials are discussed for each class of compounds. Selected keratinocyte carcinoma chemoprevention studies also are considered, and a rationale for their inclusion is presented. These data are summarized in a table that lists the type and level of evidence available for each class of agents. Also included in the discussion is an assessment of additional research necessary and the likelihood that a given compound may be a suitable candidate for a phase 3 clinical trial within the next 5 years.

SUBMITTER: Jeter JM

PROVIDER: S-EPMC6860362 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Chemoprevention agents for melanoma: A path forward into phase 3 clinical trials.

Jeter Joanne M JM Bowles Tawnya L TL Curiel-Lewandrowski Clara C Swetter Susan M SM Filipp Fabian V FV Abdel-Malek Zalfa A ZA Geskin Larisa J LJ Brewer Jerry D JD Arbiser Jack L JL Gershenwald Jeffrey E JE Chu Emily Y EY Kirkwood John M JM Box Neil F NF Funchain Pauline P Fisher David E DE Kendra Kari L KL Marghoob Ashfaq A AA Chen Suephy C SC Ming Michael E ME Albertini Mark R MR Vetto John T JT Margolin Kim A KA Pagoto Sherry L SL Hay Jennifer L JL Grossman Douglas D Ellis Darrel L DL Kashani-Sabet Mohammed M Mangold Aaron R AR Markovic Svetomir N SN Meyskens Frank L FL Nelson Kelly C KC Powers Jennifer G JG Robinson June K JK Sahni Debjani D Sekulic Aleksandar A Sondak Vernon K VK Wei Maria L ML Zager Jonathan S JS Dellavalle Robert P RP Thompson John A JA Weinstock Martin A MA Leachman Sancy A SA Cassidy Pamela B PB

Cancer 20181003 1

Recent progress in the treatment of advanced melanoma has led to unprecedented improvements in overall survival and, as these new melanoma treatments have been developed and deployed in the clinic, much has been learned about the natural history of the disease. Now is the time to apply that knowledge toward the design and clinical evaluation of new chemoprevention agents. Melanoma chemoprevention has the potential to reduce dramatically both the morbidity and the high costs associated with treat ...[more]

PMID: 30281145

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Project description:BackgroundPeripheral blood parameters are correlated to immune-checkpoint inhibitor efficacy in solid tumors, such as melanoma and non-small cell lung cancer. Few data are currently available on the prognostic role of these immune-inflammatory biomarkers for other solid tumors and immunotherapy combinations.Material and methodsFrom August 2014 to May 2019, 153 patients with metastatic solid tumors were enrolled in phase I clinical trials testing immunotherapy both as single agents and as combinations. Primary endpoint was to evaluate the impact of baseline blood parameters on progression-free survival (PFS) and overall survival (OS).ResultsThe most common tumor types were gastrointestinal, breast, and gynecological cancers (22.9%, 22.2%, and 15.0%, respectively). Higher lactate dehydrogenase (LDH) and derived neutrophil-to-lymphocyte ratio (dNLR) were independently associated with reduced PFS (hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.30-2.99; p = .001, and HR, 2.29; 95% CI, 1.39-3.77; p = .001, respectively) and reduced OS (HR, 2.04; 95% CI, 1.26-3.28; p = .004, and HR, 2.06; 95% CI, 1.12-3.79; p = .02, respectively). In the subgroup analysis, (single agent vs. combination), patients at "good" (dNLR <3 and LDH < upper limit of normal [ULN]) and "intermediate and poor" (dNLR >3 and/or LDH > ULN) risk had higher and lower PFS, respectively (p for interaction = .002). Conversely, patients receiving monotherapy presented statistically significant difference in OS according to the risk group, whereas this effect was not observed for those treated with combinations (p for interaction = .004).ConclusionElevated LDH and dNLR are associated with poorer survival outcomes in patients treated with immunotherapy in phase I clinical trials, regardless of tumor type. These parameters represent an easy tool that might be considered as stratification factors in immunotherapy-based clinical trials.Implications for practiceIn this retrospective cohort study of 153 patients with metastatic solid tumors treated with immunotherapy in the context of phase I clinical trials, elevated baseline lactate dehydrogenase and derived neutrophil-to-lymphocyte ratio were associated with reduced survival regardless of tumor subtype. If prospectively validated, these parameters might represent low-cost and easy biomarkers that could help patient selection for early phase immunotherapy trials and be applied as a stratification factor in randomized studies testing immunotherapy agents.

Dataset Information

Chemoprevention agents for melanoma: A path forward into phase 3 clinical trials.

Publications

Chemoprevention agents for melanoma: A path forward into phase 3 clinical trials.

Similar Datasets

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