title: Pilot Trial of Selecting Molecularly Guided Therapy for Patients with Non-V600 BRAF-Mutant Metastatic Melanoma: Experience of the SU2C/MRA Melanoma Dream Team.
abstract: Targeted therapies and immunotherapies have led to significant improvements in the treatment of advanced cancers, including metastatic melanoma. However, new strategies are desperately needed to overcome therapeutic resistance to these agents, as well as to identify effective treatment approaches for cancer patients that fall outside major targetable mutational subtypes (e.g., non-V600 BRAF melanoma). One such strategy is to extend the paradigm of individually tailored, molecularly targeted therapy into a broader spectrum of melanoma patients, particularly those bearing tumors without commonly recognized therapeutic targets, as well as having failed or were ineligible for immunotherapy. In this nontreatment pilot study, next-generation sequencing (NGS) technologies were utilized, including whole genome and whole transcriptome sequencing, to identify molecular aberrations in patients with non-V600 BRAF metastatic melanoma. This information was then rationally matched to an appropriate clinical treatment from a defined pharmacopeia. Five patients with advanced non-V600 BRAF metastatic melanoma were enrolled. We demonstrated successful performance of the following during a clinically relevant time period: patient tumor biopsy, quality DNA/RNA extraction, DNA/RNA-based sequencing for gene expression analysis, analysis utilizing a series of data integration methodologies, report generation, and tumor board review with formulated treatment plan. Streamlining measures were conducted based on the experiences of enrolling, collecting specimens, and analyzing the molecular signatures of patients. We demonstrated the feasibility of using NGS to identify molecular aberrations and generate an individualized treatment plan in this patient population. A randomized treatment study utilizing lessons learned from the conduct of this pilot study is currently underway.
authors.affiliation: Yale Cancer Center, New Haven, Connecticut. Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan. patricia.lorusso@yale.edu.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.affiliation: Yale Cancer Center, New Haven, Connecticut. Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Boerner
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Pilat
authors.affiliation: Yale Cancer Center, New Haven, Connecticut. Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Forman
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
authors.forename: Clarice Y
authors.initials: CY
authors.lastname: Zuccaro
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Kiefer
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: Winnie S
authors.initials: WS
authors.lastname: Liang
authors.affiliation: Biometrics Research Branch, National Cancer Institute, National Institutes of Health, Rockville, Maryland.
authors.forename: Sally
authors.initials: S
authors.lastname: Hunsberger
authors.affiliation: University of Michigan Comprehensive Cancer Center (UMCCC), Ann Arbor, Michigan.
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Redman
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Svetomir N
authors.initials: SN
authors.lastname: Markovic
authors.affiliation: Mayo Clinic, Scottsdale, Arizona.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Sekulic
authors.affiliation: Mayo Clinic, Scottsdale, Arizona.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Bryce
authors.affiliation: Mayo Clinic, Jacksonville, Florida.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Joseph
authors.affiliation: Charles A. Sammons Cancer Center/Baylor University Medical Center, Dallas, Texas.
authors.forename: C Lance
authors.initials: CL
authors.lastname: Cowey
authors.affiliation: University of Michigan Comprehensive Cancer Center (UMCCC), Ann Arbor, Michigan.
authors.forename: Leslie Anne
authors.initials: LA
authors.lastname: Fecher
authors.affiliation: Vanderbilt University, Nashville, Tennessee.
authors.forename: Jeffrey Alan
authors.initials: JA
authors.lastname: Sosman
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Chapman
authors.affiliation: Columbia University, New York, New York.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: David W
authors.initials: DW
authors.lastname: Craig
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: John D
authors.initials: JD
authors.lastname: Carpten
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Trent
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D010641:Phenotype; D010865:Pilot Projects; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D048493:Proto-Oncogene Proteins B-raf