{
  "abstract": "Background Enfortumab vedotin plus pembrolizumab (EV/P) is the latest standard-of-care treatment for patients with advanced urothelial cancer (aUC). However, responses can be heterogeneous and real-time biomarkers to identify patients most likely to benefit are scarce. We evaluated the utility of longitudinal tumor-informed circulating tumor DNA (ctDNA) monitoring as a predictive biomarker in patients with aUC commencing EV with or without pembrolizumab.Methods We conducted a multicenter, retrospective real-world analysis of patients with aUC who received ≥1 cycle of EV/P and provided ≥1 plasma sample for commercial ctDNA testing using a tumor-informed mPCR-NGS assay (Signatera™, Natera, Inc.). Patients with either a baseline pre-treatment sample (collected within the window of 8 weeks before through 5 days after EV/P initiation) or ≥1 on-treatment sample were included. ctDNA levels were quantified during treatment time intervals (≤4, 4-12, and >12 weeks). Associations between ctDNA dynamics and clinical outcomes (progression-free survival (PFS) and overall survival (OS)) were evaluated using Cox proportional hazards models.Results Of 109 patients (547 plasma samples), 70% (76/109) had a baseline sample, and 89.5% (68/76) had ≥1 on-treatment samples. Median clinical follow-up was 60.6 (range: 2.3-316.7) weeks, and baseline ctDNA detection rate was 94.7% (72/76). ctDNA positivity at a single time point within 0–12 weeks post-treatment correlated with inferior PFS (HR 5.97, 95%CI: 2.47-14.46; p<0.001) and OS (HR 4.24, 95%CI: 1.45-12.41; p=0.008) when compared to the ctDNA-negative group. Notably, longitudinal on-treatment (>4 weeks) any time ctDNA-positivity when compared with serial ctDNA-negativity demonstrated inferior PFS (HR=11.67, 95%CI: 3.59-37.89; p<0.001) and OS (HR=4.66, 95%CI: 1.61-13.51; p=0.005). On evaluating ctDNA dynamics among patients with baseline and ≥1 on-treatment samples, rising ctDNA levels (relative to baseline) during the first 12 weeks post-treatment were associated with significantly shorter PFS (HR=11.54, 95%CI: 3.21-41.46; p<0.001) and OS (HR=7.38, 95% CI: 1.83-29.68; p=0.005) compared to patients with ctDNA clearance or persistent ctDNA negativity. Magnitude of ctDNA decline appeared modestly associated with improved PFS (strong decline ≥90%: HR=7.23, 95%CI: 1.96-26.62; p=0.003; partial decline <90%: HR=9.44, 95%CI: 2.39-37.39; p=0.001).Conclusions Tumor-informed ctDNA testing is a promising predictive biomarker for monitoring treatment response in patients with aUC receiving EV/P. Serial ctDNA negativity and early ctDNA clearance or strong decline correlate with favorable clinical outcomes, while rising ctDNA (relative to baseline) identifies patients at high risk for early progression. Prospective validation of ctDNA as a real-time biomarker is critical to guide treatment optimization with EV/P, including biologically-driven de-escalation strategies.",
  "authors": [
    {
      "affiliations": [
        "University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA"
      ],
      "name": "Ryan L Zhu"
    },
    {
      "affiliations": [
        "University of California San Francisco, San Francisco, CA, USA"
      ],
      "name": "Kevin Reyes"
    },
    {
      "affiliations": [
        "Natera, Inc., Austin, TX, USA"
      ],
      "name": "Cameron Herberts"
    },
    {
      "affiliations": [
        "Natera, Inc., Austin, TX, USA"
      ],
      "name": "Punashi Dutta"
    },
    {
      "affiliations": [
        "Natera, Inc., Austin, TX, USA"
      ],
      "name": "Ashley Wray"
    },
    {
      "affiliations": [
        "Natera, Inc., Austin, TX, USA"
      ],
      "name": "Shruti Sharma"
    },
    {
      "affiliations": [
        "Natera, Inc., Austin, TX, USA"
      ],
      "name": "Meenakshi Malhotra"
    },
    {
      "affiliations": [
        "Natera, Inc., Austin, TX, USA"
      ],
      "name": "Adam Elnaggar"
    },
    {
      "affiliations": [
        "Natera, Inc., Austin, TX, USA"
      ],
      "name": "Minetta C Liu"
    },
    {
      "affiliations": [
        "University of California San Francisco, San Francisco, CA, USA"
      ],
      "name": "Vadim Koshim"
    },
    {
      "affiliations": [
        "Stephenson Cancer Center, Oklahoma City, OK, USA"
      ],
      "name": "Adanma Ayanambakkam"
    }
  ],
  "title": "46 Association of longitudinal ctDNA dynamics with clinical outcomes in advanced urothelial carcinoma treated with enfortumab vedotin ± pembrolizumab: a real-world cohort study",
  "uid": "bf16b54c-bbd3-5fd6-a648-a25546071012"
}