{
  "abstract": "Background Approximately 50% of melanomas have BRAF mutations, which drive the proliferation and survival of tumor cells via constitutive activation of the MAPK pathway. BRAF inhibitors (BRAFi) ± MEK inhibitors (MEKi) may be used to treat advanced BRAF V600-mutant melanoma as first-line therapy or after progression on anti-PD-1 therapy. However, prior treatment with BRAF-directed therapy can diminish the efficacy of subsequent treatment with anti-PD-1 therapy. Vusolimogene oderparepvec (RP1; an HSV-1-based oncolytic immunotherapy) combined with nivolumab demonstrated clinically meaningful, durable antitumor activity (objective response rate [ORR], 32.9% by RECIST 1.1; median duration of response [DOR], 33.7 months) in patients with melanoma and confirmed progression on prior anti-PD-1 therapy. Here we report the impact of prior BRAFi/MEKi therapy on the efficacy of RP1 plus nivolumab.Methods Patients with melanoma and confirmed progression on anti-PD-1 ± anti-CTLA-4 therapy for ≥8 weeks as the last prior treatment were enrolled. Prior treatment with BRAFi ± MEKi therapy was allowed for BRAF V600 mutation-positive melanoma. RP1 was given intratumorally at 1×106 PFU/mL initially, then at 1×107 PFU/mL Q2W (≤7 doses) with intravenous nivolumab (240 mg), followed by nivolumab alone (240 mg Q2W or 480 mg Q4W) for up to 2 years. This post hoc analysis evaluated ORR, DOR, and progression-free survival (PFS) by RECIST 1.1 per independent review, and overall survival (OS) in patients with BRAF-mutant melanoma, stratified by prior BRAFi treatment (data cutoff: March 8, 2024).Results Of 140 enrolled patients, 53 had BRAF-mutant melanoma, including 16 (30.2%) who had received BRAFi/MEKi prior to anti-PD-1 therapy (BRAFi-exposed) and 37 (69.8%) who were BRAFi-naïve. The confirmed ORR was 12.5% in the BRAFi-exposed group vs 43.2% in the BRAFi-naïve group (table 1). Median DOR was 3.9 months in the BRAFi-exposed group vs 33.7 months in the BRAFi-naïve group. Median PFS was 1.9 months in the BRAFi-exposed group vs 5.6 months in the BRAFi-naïve group; the 12-month PFS rate was 13.3% vs 40.4%, respectively. The 12-month OS was 71.4% in BRAFi-exposed patients and 85.9% in BRAFi-naïve patients. Fifteen of the 37 BRAFi-naïve patients were subsequently treated with BRAFi ± MEKi for a median of 13.9 months with an ORR of 66.7%.Conclusions In patients with advanced BRAF-mutant melanoma that progressed on prior anti-PD-1 therapy, RP1 plus nivolumab appeared to be more effective in BRAFi-naïve patients. This finding is consistent with literature showing that BRAF-directed therapy leads to cross-resistance to subsequent immunotherapy.Trial Registration ClinicalTrials.gov NCT03767348Ethics Approval The study was conducted in accordance with the ethical principles originating from the Declaration of Helsinki and was approved by the institutional review board/ethics committee at each participating site. Written informed consent was obtained from all patients prior to the conduct of any study-related procedures.Abstract 611 Table 1Efficacy by prior BRAFi/MEKi treatmentCR, complete response; NR, not reached; PD, progressive disease; PR, partial response; SD, stable disease.",
  "authors": [
    {
      "affiliations": [
        "Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA"
      ],
      "name": "Katy K Tsai"
    },
    {
      "affiliations": [
        "Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA"
      ],
      "name": "Bartosz Chmielowski"
    },
    {
      "affiliations": [
        "University of Liverpool, Liverpool, UK",
        "The Clatterbridge Cancer Centre, Wirral, UK"
      ],
      "name": "Joseph J Sacco"
    },
    {
      "affiliations": [
        "Gustave Roussy and Paris-Saclay University, Villejuif, France"
      ],
      "name": "Caroline Robert"
    },
    {
      "affiliations": [
        "Département de Médecine Oncologique, Gustave Roussy, Villejuif, France"
      ],
      "name": "Judith Michels"
    },
    {
      "affiliations": [
        "University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA, USA"
      ],
      "name": "Gino K In"
    },
    {
      "affiliations": [
        "Vall d’Hebron Institute of Oncology (VHIO) and Vall d’Hebron Hospital Medical Oncology Department, Barcelona, Barcelona, Spain"
      ],
      "name": "Eva Muñoz Couselo"
    },
    {
      "affiliations": [
        "Department of Dermatology, West German Cancer Center, University Hospital Essen, Essen, Germany",
        "National Center for Tumour diseases (NCT-West), Campus Essen and Research Alliance Ruhr, Research Center One Health, University Duisburg-Essen, Campus Essen, Essen, Germany"
      ],
      "name": "Dirk Schadendorf"
    },
    {
      "affiliations": [
        "Duke Cancer Institute, Duke University, Durham, NC, USA"
      ],
      "name": "Georgia M Beasley"
    },
    {
      "affiliations": [
        "Banner MD Anderson Cancer Center, Gilbert, AZ, USA"
      ],
      "name": "Jiaxin Niu"
    },
    {
      "affiliations": [
        "West Cancer Center and Research Institute, Germantown, TN, USA"
      ],
      "name": "Ari M VanderWalde"
    },
    {
      "affiliations": [
        "University of Cincinnati Cancer Center, University of Cincinnati, Cincinnati, OH, USA"
      ],
      "name": "Trisha M Wise-Draper"
    },
    {
      "affiliations": [
        "Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA"
      ],
      "name": "Mohammed M Milhem"
    },
    {
      "affiliations": [
        "Intermountain Medical Center, Murray, UT, USA"
      ],
      "name": "Tawnya Lynn Bowles"
    },
    {
      "affiliations": [
        "Université Paris Cité, AP-HP Dermato-Oncology and CIC, Cancer Institute AP-HP. Nord-Université Paris Cité, INSERM U976, Saint Louis Hospital, Paris, France"
      ],
      "name": "Céleste Lebbé"
    },
    {
      "affiliations": [
        "Aix-Marseille Université, APHM, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068, CNRS, UMR7258, UM105, Hôpital Timone, CEPCM, Dermatology and Skin Cancer Department, Marseille, France"
      ],
      "name": "Caroline Gaudy-Marqueste"
    },
    {
      "affiliations": [
        "Replimune, Inc., Woburn, MA, USA"
      ],
      "name": "Junhong Zhu"
    },
    {
      "affiliations": [
        "Replimune, Inc., Woburn, MA, USA"
      ],
      "name": "Chris Tucci"
    },
    {
      "affiliations": [
        "Replimune, Inc., Woburn, MA, USA"
      ],
      "name": "Marcus Viana"
    },
    {
      "affiliations": [
        "Replimune, Inc., Woburn, MA, USA"
      ],
      "name": "Jeannie W Hou"
    },
    {
      "affiliations": [
        "Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA"
      ],
      "name": "Michael K Wong"
    }
  ],
  "title": "611 RP1 plus nivolumab in patients with and without prior BRAF-directed therapy: a subgroup analysis of patients with anti-PD-1-failed BRAF-mutant melanoma from the IGNYTE clinical trial",
  "uid": "9244e3ef-7986-59fe-a252-30c8bbd09330"
}