In a dose-escalating phase 1 clinical trial, 24 patients with metastatic melanoma were treated with CD40 agonist (CP-870,893) and anti-CTLA-4 (tremelimumab). The objective response rate was 27.3% (6 patients) including 2 CRs and 4 PRs. Median progression-free survival was 3.2 months and median overall survival (OS) was 23.6 months. The treatment led to systemic T cell reinvigoration, increased infiltration in the tumor, and expansion in peripheral blood of TCR clones that were expanded in the tumor. Stage IVc disease as well as elevated levels of soluble CD25 and serum C-reactive protein at baseline were all independently associated with shorter OS.
We report long-term clinical outcomes and immune responses observed from a phase 1 trial of agonist CD40 monoclonal antibody (mAb) and blocking CTLA-4 mAb in patients with metastatic melanoma. Twenty-four patients previously untreated with checkpoint blockade were enrolled. The agonistic CD40 mAb CP-870,893 and the CTLA-4 blocking mAb tremelimumab were dosed concomitantly every 3 weeks and 12 weeks, respectively, across four dose combinations. Two patients developed dose-limiting grade 3 immune-mediated colitis that led to the definition of the maximum tolerated dose (MTD). Other immune-mediated toxicity included uveitis (n = 1), hypophysitis (n = 1), hypothyroidism (n = 2), and grade 3 cytokine release syndrome (CRS) (n = 1). The estimated MTD was 0.2 mg/kg of CP-870,893 and 10 mg/kg of tremelimumab. In 22 evaluable patients, the objective response rate (ORR) was 27.3%: two patients (9.1%) had complete responses (CR) and four (18.2%) patients had partial responses (PR). With a median follow-up of 45 months, the median progression-free survival (PFS) was 3.2 months (95% CI, 1.3-5.1 months) and median overall survival (OS) was 23.6 months (95% CI, 11.7-35.5 months). Nine patients are long-term survivors (> 3 years), 8 of whom subsequently received other therapy including PD-1 mAb, surgery, or radiation therapy. Elevated baseline soluble CD25 was associated with shorter OS. Immunologically, treatment was associated with evidence of T cell activation and increased tumor T cell infiltration that was accomplished without therapeutic PD-1/PD-L1 blockade. These results suggest opportunities for immune activation and cancer immunotherapy beyond PD-1.
Author Info: (1) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. Departments of Medicine, Perelman School of Medicine, University of Pennsylv
Author Info: (1) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. Departments of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. (2) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. Departments of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. (3) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. Departments of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. (4) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. Departments of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. (5) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. (6) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. (7) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. Departments of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. (8) Departments of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. (9) Departments of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. (10) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. (11) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. (12) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. (13) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. Departments of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. (14) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. Departments of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. (15) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. Departments of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. (16) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. Departments of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. (17) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. Departments of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. (18) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. Departments of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
