Intratumoral G100, a TLR4 agonist, induces anti-tumor immune responses and tumor regression in patients with Merkel cell carcinoma.

Purpose: G100 is a toll-like receptor 4 (TLR4) agonist that triggers innate and adaptive antitumor immune responses in preclinical models. This pilot study assessed the safety, efficacy, and immunologic activity of intratumoral (IT) administration of G100 in patients with Merkel cell carcinoma (MCC). Patients and Methods: Patients with locoregional MCC (n = 3; cohort A) received neoadjuvant IT G100 (2 weekly doses at 5 mg/dose) followed by surgery and radiotherapy; patients with metastatic MCC (n = 7; cohort B) received 3 doses in a 6-week cycle and could receive additional cycles with/without radiotherapy. Results: IT G100 was safe and feasible in both neoadjuvant and metastatic settings. Treatment-related adverse events were mostly grade 1 or 2 injection-site reactions. IT G100 led to increased inflammation in the injected tumors with infiltration of CD8 thorn and CD4 thorn T cells and activation of immune-related genes. These proinflammatory changes were associated with local tumor regression and appeared to promote systemic immunity. All 3 cohort A patients successfully completed therapy; 2 patients remain recurrence free at 44thorn and 41thorn months, including 1 with a pathologic complete response after G100 alone. In cohort B, 2 patients achieved sustained partial responses, both lasting 33thorn months after 2 cycles of therapy. Conclusions: In this first-in-human study, IT G100 induced antitumor immune responses, demonstrated acceptable safety, and showed encouraging clinical activity.