Purpose: Identifying baseline patient biomarkers that predict clinical outcomes to cancer immunotherapy is a major goal for the field. In a phase I dose escalation study of αCD40 CP-870,893 (0.1-0.2 mg/kg) and tremelimumab (6-15 mg/kg) for patients (pts) with metastatic melanoma, we determined associations between pre-treatment clinical (stage, LDH) and immune variables and tumor response, progression-free survival (PFS) and overall survival (OS).
Methods: Twenty-two metastatic melanoma pts (6 stage 4a, 6 stage 4b and 10 stage 4c) enrolled and contributed serum specimens for immunologic evaluation, which included: soluble CD25 (sCD25), C-reactive protein (CRP), EGF, HGF, VEGF, IFNα, IFNγ, TNFα, G-/GM-CSF, MIP1A/1B, MIG, MCP1, IL1B, IL1RA, IL2, IL4, IL5, IL6, IL8, IL10, IL12 and IL13. There were 6 responders (2 CR, 4 PR) and 16 nonresponders (3 SD, 13 PD). With a median follow-up of 26 months (mos), 13 pts have died. Median PFS and OS were 2.5 and 26.1 mos, respectively. Associations with continuous and binary immune variables were tested, cut points for the latter were determined by median or classification and regression tree (CART) analysis. Univariate logistic or Cox regression analyses determined predictors for response or PFS and OS, respectively. Variables with univariate significance <0.05 were then tested in multivariable models using stepwise regression.
Results: Tumor Response. Response was associated with stage (50% in 12 stage 4a/b pts vs 0% in 10 stage 4c pts, p=0.02). Baseline LDH was not associated with response or PFS. No immune variables predicted response. Overall Survival. sCD25 (p=0.01), CRP (p=0.005), LDH (p=0.006) and stage (p=0.01) were highly significant predictors of OS. Natural log transformed sCD25 was highly correlated with CRP (r=0.56, p=0.006) and moderately correlated with LDH (r=0.41, p=0.06) and stage (rho=0.32, p=0.09). CART analysis identified sCD25 >110 and CRP >7 as the optimal cut points for OS. Accordingly, binary sCD25 (>110 vs <110, HR=13.4, p<0.001) and binary CRP (>7 vs <7, HR=7.2, p=0.003) were highly significant predictors. These cut points defined very similar risk groups. Of 6 pts with sCD25 >110, 5 had CRP >7 and of 16 pts with sCD25 <110, 14 had CRP <7. Thus, these CART-defined binary variables were strongly associated (p=0.004). In multivariate modeling, only binary sCD25 remained statistically significant since it was slightly superior to binary CRP, although both variables produced identical estimates of median OS. For pts with sCD25 <110 (or CRP <7), median OS was 27.1 mos while for pts with sCD25 >110 (or CRP >7), median OS was 4.6 mos. Moreover, binary sCD25 remained highly significant (HR=11.2, p=0.002) after adjusting for LDH (p=0.06). Progression-free Survival. Stage (p=0.01) and sCD25 (p=0.02), but not CRP (p=0.10), were significant predictors of PFS. Binary sCD25 defined by median (>60 vs <60, HR=3.1, p=0.02) and binary CRP (>7 vs <7, HR=3.1, p=0.02) were also significant predictors. Binary CRP (p=0.001), but not binary sCD25 (p=0.20), was associated with stage. In multivariable modeling, only stage remained significant. For stage 4a/b pts, median PFS was 4.8 mos while for stage 4c pts, median PFS was 2.3 mos. sCD25, CRP and IL6. IL6 was not correlated with sCD25 (p=0.99) or CRP (p=0.83) nor was it associated with response (p=0.26), PFS (p=0.48) or OS (p=0.74).
Conclusion: sCD25 and CRP are both highly significant predictors for OS, although they are not independent predictors due to their strong co-linearity. sCD25 remains a significant predictor for OS after adjusting for baseline LDH. To confirm these findings, sCD25 and CRP should be investigated as possible predictive biomarkers in future studies of immune checkpoint inhibitors.
Citation Format: Rosemarie Mick, David Bajor, Lee Richman, Robert Vonderheide. Soluble CD25 and C-reactive protein predict overall survival in melanoma patients receiving anti-CD40 monoclonal antibody CP-870,893 (αCD40) and anti-CTLA4 monoclonal antibody tremelimumab. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A10.