{
  "abstract": "Background Neutralization of interferon (IFN)-γ abrogates the efficacy of anti-programmed death-ligand 1 (PD-(L)1) checkpoint inhibitors. Most epithelial cells do not constitutively express major histocompatibility complex (MHC) class II but can be induced to do so by IFN-γ. Inducible tumor-specific MHC class II (tsMHC-II) underlies responsiveness to anti-PD-(L)1. Retrospective studies show that tsMHC-II positivity associates with improved outcomes in patients treated with anti-PD-(L)1. The ANICCA-Class II single-arm Bayesian phase II trial prospectively explored whether positive tsMHC-II status could be a useful selection marker for anti-programmed cell death protein-1 (PD-1) in proficient mismatch repair colorectal cancer (pMMR CRC). In parallel, we retrospectively evaluated the potential predictive power of immunoscore-immune checkpoint (IS-IC) for outcome with single-agent immune checkpoint blockade.Methods Patients with histologically confirmed locally advanced/metastatic pMMR CRC with >1% MHC class II expression, Eastern Cooperative Oncology Group performance status 0–2, aged ≥18 years were eligible. Participants received 480 mg nivolumab every 28 days for up to 24 cycles. The primary outcome was durable clinical benefit (DCB) defined as participants remaining progression-free at their third trial-specific scan since treatment start (ie, at approximately 27 weeks). Secondary outcomes included progression-free survival time (PFS) and overall survival time (OS).Results 35 participants were treated: 65.7% of participants’ cancers were tsMHC-II ≥5%. 3/35 patients achieved DCB (8.6%), estimating the true DCB rate (R) of 11% (95% credible interval 3% to 22%) with 0.002 probability that the true DCBR was >30%, below the required 0.5 to warrant further research. The higher tsMHC-II cut-point ≥5% was not more useful in predicting duration of disease stabilization. All three participants who achieved DCB had no evidence of liver metastases (LM); DCBR 23.1% in those without versus 0% in those with LM. PFS and OS were significantly greater in those without LM. There was no evidence that IS-IC high predicted for prolonged time on treatment or improved tumor growth inhibition.Conclusions In pMMR CRC, tsMHC-II positivity fails to identify a subset of patients with metastatic pMMR CRC obtaining potentially meaningful benefit from single-agent anti-PD-1. Although numbers are limited, there is no clear evidence that IS-IC is predictive of outcome with single-agent anti-PD-1. The poor outcome in those with LM underscores the need for therapies that overcome the systemic immunosuppression driven by LM.",
  "authors": [
    {
      "affiliations": [
        "Department of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK",
        "University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK"
      ],
      "name": "Gary Middleton"
    },
    {
      "affiliations": [
        "University of Birmingham Cancer Research UK Clinical Trials Unit, Birmingham, UK"
      ],
      "name": "Charlotte Gaskell"
    },
    {
      "affiliations": [
        "University of Birmingham Cancer Research UK Clinical Trials Unit, Birmingham, UK"
      ],
      "name": "Joshua Savage"
    },
    {
      "affiliations": [
        "University College London Hospitals NHS Foundation Trust, London, UK"
      ],
      "name": "John Bridgewater"
    },
    {
      "affiliations": [
        "Guy’s Hospital, London, UK"
      ],
      "name": "Paul Ross"
    },
    {
      "affiliations": [
        "Christie Hospital, Manchester, UK"
      ],
      "name": "Mark Saunders"
    },
    {
      "affiliations": [
        "Clatterbridge Cancer Centre NHS Foundation Trust, Bebington, UK"
      ],
      "name": "Daniel Palmer"
    },
    {
      "affiliations": [
        "Newcastle University, Northern Centre for Cancer Care, Newcastle upon Tyne, UK"
      ],
      "name": "Ruth Plummer"
    },
    {
      "affiliations": [
        "Western General Hospital, Edinburgh, UK"
      ],
      "name": "Sally Clive"
    },
    {
      "affiliations": [
        "Belfast City Hospital, Belfast, UK"
      ],
      "name": "Vicky Coyle"
    },
    {
      "affiliations": [
        "Leicester Royal Infirmary, Leicester, UK"
      ],
      "name": "Anne Thomas"
    },
    {
      "affiliations": [
        "Royal Marsden Hospital NHS Trust, London, UK"
      ],
      "name": "David Cunningham"
    },
    {
      "affiliations": [
        "University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK"
      ],
      "name": "Phillipe Taniere"
    },
    {
      "affiliations": [
        "University of Birmingham Cancer Research UK Clinical Trials Unit, Birmingham, UK"
      ],
      "name": "Lucinda Billingham"
    }
  ],
  "title": "Final results of ANICCA-Class II, a single arm, open-label phase II trial assessing nivolumab in tissue-specific class II expressing metastatic microsatellite stable colorectal cancer, with a parallel assessment of the immunoscore-immune checkpoint as a predictive biomarker for single-agent anti-PD-1",
  "uid": "3e0f6c10-c01e-5784-95d6-78d571a517a5"
}