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.

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.