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
Immune checkpoint blockers (ICBs) improve outcomes in metastatic melanoma (MM), but resistance limits benefit. This phase I/II (NCT02706353) study evaluated intratumoral sotigalimab (anti-CD40 agonist) with pembrolizumab in 32 ICB-naïve MM patients. Primary endpoints were safety, and objective response rate (ORR). Sotigalimab was well tolerated. At the recommended phase 2 dose (RP2D), the ORR was 50% and the disease control rate (DCR) was 92%, with ORR of 67% in injected and 50% in non-injected tumors. Multiomic analyses of tumor and blood showed sotigalimab effectively engaged the CD40 pathway, boosting 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 showed increased T-cell clonality with expanded new clones shared across tumors. Clinical responses correlated with these immunologic changes, but not with baseline features associated with response to anti-PD1 monotherapy.
Authors
- Aaron Mayer
- Emre Arslan (ORCID: https://orcid.org/0000-0001-7224-917X)
- Jared K. Burks (ORCID: https://orcid.org/0000-0002-6173-9074)
- Barbara Nassif Rausseo (ORCID: https://orcid.org/0000-0001-7772-2456)
- Isabella C. Glitza Oliva (ORCID: https://orcid.org/0000-0002-4530-7765)
- Irene Li (ORCID: https://orcid.org/0000-0003-1942-9010)
- Salah-Eddine Bentebibel (ORCID: https://orcid.org/0000-0001-9824-107X)
- Dzifa Y. Duose (ORCID: https://orcid.org/0000-0002-6763-9736)
- Rodabe Navroze Amaria (ORCID: https://orcid.org/0000-0001-6876-278X)
- S H Cho
- Patrick Hwu (ORCID: https://orcid.org/0000-0002-8293-1313)
- Ravi Murthy (ORCID: https://orcid.org/0000-0003-1395-3890)
- Sapna Pradyuman Patel (ORCID: https://orcid.org/0000-0003-1339-1517)
- Veena Kochat (ORCID: https://orcid.org/0000-0003-2614-3790)
- Michael A. Davies (ORCID: https://orcid.org/0000-0002-0977-0912)
- Cara Haymaker (ORCID: https://orcid.org/0000-0002-1317-9287)
- Frank J. Hsu
- Chantale Bernatchez (ORCID: https://orcid.org/0000-0001-5926-3460)
- Gregory Lizée (ORCID: https://orcid.org/0000-0003-4449-7461)
- Sühendan Ekmekçioglu (ORCID: https://orcid.org/0000-0003-4079-6632)
- Khaled M. Elsayes (ORCID: https://orcid.org/0000-0003-0184-0717)
- Daniel J. McGrail (ORCID: https://orcid.org/0000-0002-6669-6069)
- Arjun Katailiha (ORCID: https://orcid.org/0000-0002-5591-3056)
- Heather M. Sonnemann (ORCID: https://orcid.org/0000-0001-5376-7203)
- Javier A. Gomez (ORCID: https://orcid.org/0000-0002-6579-744X)
- Kunal Rai (ORCID: https://orcid.org/0000-0003-2321-6894)
- Barbara Pazdrak (ORCID: https://orcid.org/0000-0002-5255-8327)
- Nourel Hoda Tahon (ORCID: https://orcid.org/0009-0002-5863-0219)
- Reham Abdel‐Wahab (ORCID: https://orcid.org/0000-0002-5432-5068)
- Daniel H. Johnson (ORCID: https://orcid.org/0000-0002-4778-686X)
- Maha K. Rahim (ORCID: https://orcid.org/0000-0002-6756-5802)
- Khalida Wani (ORCID: https://orcid.org/0000-0002-2383-3908)
- Hussein A. Tawbi (ORCID: https://orcid.org/0000-0003-1942-851X)
- Jianhua Zhang (ORCID: https://orcid.org/0009-0008-1138-9919)
- Jingjing Liu (ORCID: https://orcid.org/0009-0009-3197-2463)
Institutions
- Cleveland Clinic (US)
- The University of Texas MD Anderson Cancer Center (US)
- Ochsner Medical Center (US)
- Moffitt Cancer Center (US)
- Boston Public Schools (US)
- Universidad San Carlos (PY)
- University of Colorado Anschutz Medical Campus (US)
- Stanford University (US)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2026-04-21
- DOI
- https://doi.org/10.1158/2159-8290.cd-25-1551
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00