TRICK-MCC: A 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.

TPS9618 Background: Merkel cell carcinoma (MCC) is an aggressive and highly immunogenic skin cancer often associated with the Merkel cell polyomavirus (MCPyV). Immune checkpoint inhibition (ICI) via PD-(L)1 blockade can promote durable responses among patients with metastatic MCC, yet >50% of MCC patients experience disease progression. There is an unmet need for effective treatment options for these patients. One possible strategy to overcome primary and secondary resistance in PD-(L)1 refractory MCC is concurrent targeting of multiple immune checkpoints to facilitate reversal of chronic T cell exhaustion. Based on our preliminary data revealing high expression of PD-1, LAG-3 and TIM-3 on MCC-specific CD8 T cells, which appear to increase upon clinical disease progression in the context of treatment with PD-(L)1 blockade, we hypothesize that concurrent blockade of PD-1, LAG-3 and TIM-3 will overcome immune evasion in patients with PD-(L) refractory MCC. Methods: TRICK-MCC (Triple Immune Checkpoint Inhibition in MCC) is an investigator initiated, Phase 2 clinical trial investigating concurrent treatment with anti-PD-1 (retifanlimab), anti-LAG3 (INCAGN02385) and anti-TIM-3 (INCAGN02390) in patients with advanced/metastatic MCC that has progressed after treatment with anti-PD-(L)1. Target enrollment is 20 patients total, with 5 patients enrolled as of Jan 2024. Patients will receive anti-PD-1 q4w and anti-TIM-3 and LAG-3 q2w for up to 24 weeks (Induction Phase) followed by all drugs q6w (Maintenance Phase). Treatment will end 2 years after starting the study drugs, or upon disease progression, unacceptable toxicity, or study withdrawal. Primary objective is objective response rate (ORR). Secondary objectives are duration of response, progression free survival, overall survival, and incidence and severity of adverse events. Interim analysis will be done after 10 patients have been enrolled and followed sufficiently long to assess ORR. An observed ORR of 25%will be considered as clinically meaningful in this population with no reliable standard treatments. Serial tumor biopsies and blood samples will be obtained in all patients, unless deemed unsafe or not feasible. Planned correlative studies aim to better characterize the prevalence and significance of cancer-specific T cell exhaustion (through rigorous study of MCPyV-specific T cells), the immunologic effects of triple ICI, and alternative mechanisms of PD-(L)1 resistance beyond T cell exhaustion in PD-(L)1 resistant tumors. We hope to gain insights that are broadly applicable to solid tumor immunotherapy. Clinical trial information: NCT06056895 .