Trick-MCC: Final results from the proof-of-concept investigator-initiated study of combination therapy with anti–PD-1, anti–LAG-3, and anti–TIM-3 in participants with advanced or metastatic PD-(L)1 refractory Merkel cell carcinoma (NCT06056895).

9531 Background: Merkel cell carcinoma (MCC) is an aggressive and highly immunogenic skin cancer associated with the Merkel cell polyomavirus. Over 50% of patients with metastatic MCC do not derive durable benefit from PD-(L)1 therapy alone. High expression of additional immune checkpoints LAG-3 and TIM-3 on MCC-specific CD8 T cells suggested that concurrent triple checkpoint blockade may overcome immune evasion in patients with PD-(L)1 refractory MCC. Methods: TRICK-MCC (Triple Immune Checkpoint Inhibition in MCC) is an investigator initiated, single center, proof-of-concept clinical trial studying concurrent treatment with anti-PD-1 (retifanlimab, q4w), anti-LAG3 (tuparstobart, q2w) and anti-TIM-3 (verzistobart, q2w) in patients with advanced/metastatic MCC that progressed after PD-(L)1 therapy. After receiving standard frequency dosing for the first 24w, benefitting patients are transitioned to reduced frequency dosing at q6w for up to 2 years total or until disease progression, unacceptable toxicity, or study withdrawal. Primary endpoint is objective response rate (ORR). Secondary endpoints include duration of response, disease control rate, progression free and overall survival, and incidence and severity of adverse events (AE). Serial tumor biopsies and blood samples are obtained in all patients, unless not feasible/safe. Results: Twelve (out of planned 20) patients were enrolled between Nov 2023 and Jan 2025, before the study was closed to enrollment for administrative reasons by the funding sponsor. At the time of abstract submission, ORR and AE data are available for 10 patients. Two of 10 patients (20%) have partial response and one (10%) has stable disease (26% decrease in tumor size) per RECIST 1.1. Therapy has generally been well tolerated, with immune-related AEs observed in 4 (40%) patients, all Grade 1-2. One patient discontinued therapy due to an AE, grade 5 encephalopathy (anti-IgLON5 disease) diagnosed 7 mo into treatment with unclear relationship to study agents. Correlative studies of pre- and post-treatment tumor and blood specimens are ongoing to characterize the prevalence and significance of cancer-specific T cell exhaustion markers (including PD-1, LAG-3 and TIM-3), and additional mechanisms of PD-(L)1 resistance. Updated translational and clinical results will be presented at the meeting. Conclusions: Concurrent triple immune checkpoint blockade of PD-1, LAG-3 and TIM-3 appears to be generally well tolerated and associated with clinical activity in our cohort of patients with PD-(L)1 refractory MCC. Our data suggests TIM-3 and LAG-3 are contributing to immune evasion in a subset of patients with PD-(L)1 resistant MCC, providing support for further investigation of these pathways in larger trials. Clinical trial information: NCT06056895 .