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
Middleton, Gary Gaskell, Charlotte Savage, Joshua Bridgewater, John Ross, Paul Saunders, Mark Palmer, Daniel Plummer, Ruth Clive, Sally Coyle, Vicky
Middleton, Gary
Gaskell, Charlotte
Savage, Joshua
Bridgewater, John
Ross, Paul
Saunders, Mark
Palmer, Daniel
Plummer, Ruth
Clive, Sally
Coyle, Vicky
Affiliation
University of Birmingham; University Hospitals Birmingham NHS Foundation Trust; University College London Hospitals NHS Foundation Trust; Guy's and St Thomas' NHS Foundation Trust; The Christie NHS Foundation Trust; Clatterbridge Cancer Centre NHS Foundation Trust; Newcastle University; NHS Lothian; Belfast City Hospital; University Hospitals of Leicester NHS Trust; Royal Marsden Hospital NHS Trust
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Publication date
2025-12-17
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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.
Citation
Middleton G, Gaskell C, Savage J, Bridgewater J, Ross P, Saunders M, Palmer D, Plummer R, Clive S, Coyle V, Thomas A, Cunningham D, Taniere P, Billingham L. 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. J Immunother Cancer. 2025 Dec 17;13(12):e012749. doi: 10.1136/jitc-2025-012749.
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Article