BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a 
significant proportion of patients with metastatic melanoma. New approaches to 
increase survival and to predict which patients will benefit from treatment are 
needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP) 
to assess its safety, efficacy, and to search for peripheral and tumor-based 
predictive biomarkers.
METHODS: Thirty patients with untreated unresectable/metastatic melanoma were 
treated with ipilimumab and CP. Adverse events (AEs) were monitored and response 
to treatment was evaluated. Tumor tissue and peripheral blood were collected at 
specified time points to characterize tumor immune markers by 
immunohistochemistry and systemic immune activity by multiplex assays and flow 
cytometry.
RESULTS: Eighty three percent of patients received all 5 cycles of CP and 93% 
completed ipilimumab induction. Serious AEs occurred in 13% of patients, and no 
treatment-related deaths were observed. Best Overall Response Rate (BORR) and 
Disease Control Rate (DCR) were 27 and 57%, respectively. Median overall 
survival was 16.2 months. Response to treatment was positively correlated with a 
higher tumor CD3+ infiltrate (immune score) at baseline. NRAS and BRAF mutations 
were less frequent in patients who experienced clinical benefit. Assessment of 
peripheral blood revealed that non-responders had elevated baseline levels of 
CXCL8 and CCL4, and a higher proportion of circulating late differentiated B 
cells. Pre-existing high levels of chemokines (CCL3, CCL4 and CXCL8) and 
advanced B cell differentiation were strongly associated with worse patient 
overall survival. Elevated proportions of circulating CD8+/PD-1+ T cells during 
treatment were associated with worse survival.
CONCLUSIONS: The combination of ipilimumab and CP was well tolerated and 
revealed novel characteristics associated with patients likely to benefit from 
treatment. A pre-existing systemic inflammatory state characterized by elevation 
of selected chemokines and advanced B cell differentiation, was strongly 
associated with poor patient outcomes, revealing potential predictive 
circulating biomarkers.
TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 , registered on August 29, 
2012.