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

Abstract

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.

Signal pathways of melanoma and targeted therapy

“…Besides, other immunomodulatory molecules, TLR, TNFα and IL-10 are also appealing for potential combination with ICBs to treat melanoma. 704 , 705 …”

Editorial: TNFR Superfamily Oligomerization and Signaling

“…Inhibition of TNF-induced TNFR1 signaling is sufficient to overcome resistance to immune checkpoint inhibitors, restoring the anti-tumoral immune response. The ongoing clinical trials translating this finding are promising (Montfort et al, 2021), showing high response rates in advanced and/or metastatic melanoma patients. Finally, despite the fact that most family members have been known for more than two decades, including TNF and TNFR1, new therapeutic opportunities may emerge as a result of our better understanding of TNF/TNFR family members.…”

Predicting and Preventing Immune Checkpoint Inhibitor Toxicity: Targeting Cytokines

“…An ongoing Phase Ib trial will evaluate the safety and tolerance of nivolumab and ipilimumab in combination with infliximab or certolizumab (anti-TNF-α Ab) in advanced melanoma patients (NCT03293784) iii . Preliminary results from this trial indicate that the addition of infliximab appears to show equivalent safety profiles to combination nivolumab and ipilimumab (NCT03293784) iii [61]. However, the addition of certolizumab displayed both increased irAEs, particularly pertaining to hepatic disorders, and higher objective responses when treated alongside nivolumab and ipilimumab, relative to combination CPI-treated patients without certolizumab (NCT03293784) iii [61].…”

“…Preliminary results from this trial indicate that the addition of infliximab appears to show equivalent safety profiles to combination nivolumab and ipilimumab (NCT03293784) iii [61]. However, the addition of certolizumab displayed both increased irAEs, particularly pertaining to hepatic disorders, and higher objective responses when treated alongside nivolumab and ipilimumab, relative to combination CPI-treated patients without certolizumab (NCT03293784) iii [61]. Examining the mechanism(s) by which differential TNF inhibitors can initiate alternative therapeutic outcomes will be important to reconcile.…”

“…Cytokine inhibitors have shown merit in the treatment of some irAEs, particularly in steroid-refractory disease [28,108,109]. However, their potential treatment either concurrently at CPI treatment initiation or preceding corticosteroid use has also been suggested (NCT03293784 iii , NCT03999749 iv , NCT04258150 v ) [61].…”