Combining nivolumab and ipilimumab with infliximab or certolizumab in patients with advanced melanoma: first results of a phase 1b clinical trial.

Purpose TNF blockers can be used to manage gastrointestinal inflammatory side effects following nivolumab and/or ipilimumab treatment in advanced melanoma patients. Our pre-clinical data showed that anti-TNF could promote the efficacy of immune checkpoint inhibitors. Experimental design TICIMEL (NTC03293784) is an open-label, two arms phase Ib clinical trial. Fourteen advanced and/or metastatic melanoma patients (Stage IIIc/IV) were enrolled. Patients were treated with nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) combined to infliximab (5 mg/kg, N=6) or certolizumab (400/200 mg, N=8). The primary endpoint was safety and the secondary endpoint was anti-tumor activity. Adverse events (AEs) were graded according to the NCI CTCAE criteria and response was assessed following RECIST 1.1 criteria. Results Only one DLT was observed, in the infliximab cohort. The two different combinations were found to be safe. We observed lower treatment-related AEs with infliximab as compared to certolizumab. In the certolizumab cohort, 1 patient was not evaluable for response. In this cohort, 4 out of 8 patients exhibited hepatobiliary disorders and 7 out of 7 evaluable patients achieved objective response (OR) including 4 complete responses (CR) and 3 partial responses (PR). In the infliximab cohort, we observed 1 CR, 2 PR and 3 progressive diseases (PD). Signs of activation and maturation of systemic T cell responses were seen in patients from both cohorts. Conclusions Our results show that both combinations are safe in human and provide clinical and biological activities. The high response rate in the certolizumab-treated cohort patients deserves further investigations.