All treatment-emergent adverse events

Abstract Checkpoint-inhibitors (CPIs) improve outcomes in metastatic melanoma (MM), but resistance limits benefit. This phase I/II (NCT02706353) study evaluated intratumoral sotigalimab (an anti-CD40 agonistic antibody) with pembrolizumab in 32 CPI-naïve MM patients. Here, we report the final safety outcomes, clinical efficacy results, and comprehensive biomarker analyses from this trial. Primary endpoints included determining safety and tolerability, the recommended phase 2 dose (RP2D) of sotigalimab, and the objective response rate (ORR). The most common adverse events (AEs) related to sotigalimab were injection-site reactions, pruritus, and fatigue. Sotigalimab was well tolerated; common adverse events were injection-site reactions, and fatigue. At the RP2D, the ORR was 50% and the disease control rate (DCR) was 92%, with ORR of 67% in injected tumors and 50% in non-injected tumors. Multiomic biomarker analyses of tumor and blood samples collected before and during treatment demonstrated that sotigalimab effectively engaged the CD40 pathway, boosting the infiltration and activation of myeloid cells, including CD11c+DC-LAMP+ dendritic cells (DCs) and macrophages. The combination therapy activated innate and adaptive immunity in injected tumors and cytotoxic responses in non-injected tumors. TCR sequencing analysis showed increased T-cell clonality with expanded new clones shared across tumors. Clinical responses correlated with these immunologic changes, but not with baseline immunological features associated with response to anti-PD1 monotherapy. These findings suggest that intratumoral sotigalimab may enhance anti-PD1 therapy, supporting the need for further randomized phase 2 trials to better evaluate its therapeutic potential in the 'in situ' immunization approach. Citation Format: Salah-Eddine Bentebibel, Daniel J McGrail, Veena Kochat, Emre Arslan, Reham Abdel-Wahab, Sung-Nam Cho, Xiaodong Yang, Daniel H Johnson, Rodabe N Amaria, Isabella C Glitza, Patrick Hwu, Hussein A Tawbi, Jared K Burks, Michael A Davies, Kunal Rai, Suhendan Ekmekcioglu, Adi Diab. Intratumoral sotigalimab with pembrolizumab induces rapid activation of antigen presenting cells and drives anti-tumor responses in non-injected tumors in metastatic melanoma: A phase I/II study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT238.

Taxonomic differences from baseline between treatment arms at after antibiotic preconditioning and at C1D1

CD8 intra-tumoral infiltration percentage by IHC

Peripheral Treg populations of interest by baseline Ruminococcaceae status prior to initiating anti-PD1 therapy

Assessment of gut microbiome networks by treatment arm and across timepoints

Progression-free survival in a retrospective melanoma immunotherapy cohort by baseline Ruminococcaceae status

Summary of clinical response by treatment arm and baseline Ruminococcaceae group

Disease control and objective response rates by Ruminococcaceae status

Overview of exploratory correlative specimen availability

Best objective response by baseline Ruminococcaceae abundance levels

Longitudinal serum proteomics analysis

Patient characteristics by baseline Ruminococcaceae status

Differences in baseline peripheral immune cell populations by response and baseline Ruminococcaceae levels

Correlation between qPCR derived and WGS derived Ruminococcaceae family abundance at baseline

X50 High-parameter flow cytometry phenotypes and statistics

Gating strategy for X50 cytometric T-cell phenotyping

Ruminococcaceae family abdunance over time by stratification and arm

Intended study schema and CONSORT diagram

Patients with continued response at time of study conclusion