Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

Abstract

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.

Keywords: CD40; CTLA4; melanoma.

Figure 1.

Clinical activity of CP-870,893 and tremelimumab in metastatic melanoma. Data are illustrated as (a) waterfall plot showing RECIST responses per dose level, * patient came off study before a second scan. (b) spider plot showing tumor measurements for each patient, and (c) swimmer plot showing long-term clinical course for each patient.

Figure 2.

Probability of OS. Data for baseline (a) sCD25 and (b) CRP, grouped according to classification and regression tree (CART) analysis. For sCD25^high/low, HR = 13.38, 95% CI 3.17 – 56.50. For CRP^high/low, HR = 4.14, 95% CI 1.39 – 12.33.

Figure 3.

Immune analysis of peripheral lymphocytes. (a) Ki67 expression in CD8 T cells, CD4 T cells, and Tregs at serial time points. ** p < 0.01, *** p < 0.001 by linear regression. (b) Expression of Eomes versus Tbet, CD45RA versus CD27, PD-1, and Granzyme B in Ki67+ CD8 T cells at cycle 1. Eomes versus Tbet analyzed using Student’s paired t-test, CD45A versus CD27 analyzed using Wilcoxon matched pairs signed rank test, * p < 0.05.

Figure 4.

Immunohistochemistry analysis of tumor. (a) Representative examples of tumor biopsies obtained at baseline and post-treatment, each stained for CD8 (top) and PD-L1 (bottom). Patient identifying numbers are shown in bottom right of each photomicrograph, corresponding to Figure 1c. (b) Quantification of CD8 cells. Mean of five high-powered fields (hpf) are shown for each sample. Whisker plots indicate mean and standard error of the group. Group differences were determined by linear regression, p = 0.009. (c) Quantification of PD-L1 expression; group differences were determined by ordinal logistic regression, p = 0.072. Lines indicate median. (d) Correlation of PD-L1 and CD8 IHC in post-treatment tumor samples. The x-axis indicates PD-L1 score as in (c) and the y-axis indicates mean CD8 cells of 5 hpf for each patient. Spearman’s correlation coefficient ρ = 0.82 with p = 0.022. Red squares indicate patients with objective responses.