Combining Nivolumab and Ipilimumab with Infliximab or Certolizumab in Patients with Advanced Melanoma: First Results of a Phase Ib Clinical Trial

Clin Cancer Res. 2021 Feb 15;27(4):1037-1047. doi: 10.1158/1078-0432.CCR-20-3449. Epub 2020 Dec 3.


Purpose: TNF blockers can be used to manage gastrointestinal inflammatory side effects following nivolumab and/or ipilimumab treatment in patients with advanced melanoma. Our preclinical data showed that anti-TNF could promote the efficacy of immune checkpoint inhibitors.

Patients and methods: TICIMEL (NTC03293784) is an open-label, two-arm phase Ib clinical trial. Fourteen patients with advanced and/or metastatic melanoma (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 antitumor activity. Adverse events (AEs) were graded according to the NCI Common Terminology Criteria for Adverse Events and response was assessed following RECIST 1.1.

Results: Only one dose-limiting toxicity 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 with certolizumab. In the certolizumab cohort, one patient was not evaluable for response. In this cohort, four of eight patients exhibited hepatobiliary disorders and seven of seven evaluable patients achieved objective response including four complete responses (CRs) and three partial responses (PRs). In the infliximab cohort, we observed one CR, two PRs, and three progressive diseases. 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 patient cohort deserves further investigations.

Trial registration: NCT03293784.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects*
  • Certolizumab Pegol / administration & dosage
  • Certolizumab Pegol / adverse effects
  • Female
  • Follow-Up Studies
  • Humans
  • Infliximab / administration & dosage
  • Infliximab / adverse effects
  • Ipilimumab / administration & dosage
  • Ipilimumab / adverse effects
  • Male
  • Melanoma / diagnosis
  • Melanoma / drug therapy*
  • Melanoma / mortality
  • Melanoma / secondary
  • Middle Aged
  • Nivolumab / administration & dosage
  • Nivolumab / adverse effects
  • Progression-Free Survival
  • Skin Neoplasms / diagnosis
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / mortality
  • Skin Neoplasms / pathology
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors


  • Ipilimumab
  • TNF protein, human
  • Tumor Necrosis Factor-alpha
  • Nivolumab
  • Infliximab
  • Certolizumab Pegol

Associated data