71MO - Clinical and biomarker analyses of intratumoral CD40 agonist sotigalimab in combination with pembrolizumab in metastatic melanoma: A phase I/II trial

Background

Checkpoint inhibitors (CPI) provide significant clinical benefits for patients (pts) with metastatic melanoma (MM). However, resistance remains a challenge. This phase 1/2 study assessed intratumoral (IT) injection of sotigalimab (sotiga) with pembrolizumab in CPI-naïve MM.

Methods

Primary endpoints included safety and tolerability, and assessment of the objective response rate (ORR) by RECIST v1.1. Blood and tumor samples (local and distant non injected) were collected to perform in-depth analysis of immune cells using nCounter® gene expression assay, TCR sequencing, multiplex immunofluorescence imaging (mIF), and single cell multiome profiling (scRNA/scATAC).

Results

32 pts were enrolled. The most common treatment related adverse events were injection-site reactions, pruritus, and fatigue. At RP2D, ORR was 50%, with a DCR of 91%. To assess the local immune response post-IT sotiga, gene expression analysis and mIF were performed on 23 matched tumor biopsies collected before and 24 hours after treatment. Our analysis revealed that sotiga effectively engaged the CD40 pathway, increasing antigen presenting cells infiltration and activation including, cDCs and macrophages. Integrated scRNA-seq and scATAC-seq analysis on blood samples revealed early activation of cDCs, B cells and monocytes, coupled with changes in chromatin accessibility and the activity of transcription factors associated with inflammatory response, consistent with the CD40 pathway. Sotiga with pembrolizumab also induced broad innate and adaptive immune activation, extending beyond the injected tumors. TCR sequencing analysis showed increased T-cell clonality with expansion of new clones shared between local and distant tumors, correlating with clinical response. These immunological changes were recapitulated in the B16 melanoma mouse model where scRNA-seq tumor analysis demonstrated that IT CD40 activation induces unique immune responses that synergizes with anti-PD-1 therapy to suppress tumor growth.

Conclusions

This combination therapy is well tolerated, has a notable clinical response, and generated robust innate and adaptive immunologic response that extended beyond the injected tumors.

Clinical trial identification

NCT02706353.

Editorial acknowledgement

Legal entity responsible for the study

MD Anderson Cancer Center - PI Adi Diab.

Funding

Apexigen America, Inc, San Carlos, California (now a fully owned subsidiary of Pyxis Oncology, Inc.).

Disclosure

All authors have declared no conflicts of interest.