Postmarketing surveillance of nivolumab plus ipilimumab combination therapy in Japanese patients with unresectable malignant melanoma

J Dermatol. 2023 Sep;50(9):1108-1120. doi: 10.1111/1346-8138.16820. Epub 2023 Jun 22.


Although malignant melanoma is relatively rare in Japan, it is often diagnosed at a later stage than in Western countries. Nivolumab and ipilimumab are immune checkpoint inhibitors targeting programmed death 1 and cytotoxic T-lymphocyte-associated protein 4, respectively. Owing to their complementary anticancer effects, nivolumab and ipilimumab combination therapy (N + I) has been studied and approved for treating malignant melanoma in various countries including Japan. Real-world postmarketing surveillance was implemented to record treatment-related adverse events (TRAEs) in patients treated with N + I following its approval in Japan. Patients were eligible for registration if they had unresectable malignant melanoma and started N + I between September 2018 and August 2019. The observation period was 13 weeks from starting N + I. Only safety information was collected and evaluated. The final case report form lock was March 2021. Overall, 173 patients (median age, 66.0 years; performance status 0-1, 88.4%; skin: 53.2%; mucosal: 32.4%) were eligible for the analyses. Overall, 34.1% of patients completed 4 doses of N + I. N + I was discontinued by 63.0% (due to adverse events in 67.9% and disease progression/death in 22.9%). Any grade and grade ≥3 TRAEs were reported in 73.41% and 52.02%, respectively. TRAEs in ≥10 patients were hepatic function abnormal (any grade/grade ≥3: 23.12%/13.29%), pyrexia (10.40%/0.58%), diarrhea (9.25%/2.89%), rash (8.67%/0.58%), hypophysitis (5.78%/5.20%), interstitial lung disease (5.78%/2.89%), and liver disorder (5.78%/4.62%). TRAEs were classified as recovered (36.99% of patients), recovering (44.51%), unrecovered (13.29%), recovered with sequelae (2.31%), and death (1.73%). Overall, 24 of 34 patients (70.59%) with gastrointestinal-related and 53 of 65 (81.54%) liver-related TRAEs received treatment, such as a steroid with/without an immunosuppressant; most patients recovered within 1 to 2 months. In conclusion, this postmarketing surveillance of N + I in patients with unresectable malignant melanoma revealed no new safety concerns compared with results of prior studies. Immune-related TRAEs were generally manageable by appropriate treatment including a steroid.

Keywords: combination therapy; ipilimumab; malignant melanoma; nivolumab; postmarketing surveillance.

MeSH terms

  • Aged
  • Antineoplastic Combined Chemotherapy Protocols* / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • Disease Progression
  • East Asian People
  • Humans
  • Ipilimumab* / administration & dosage
  • Ipilimumab* / adverse effects
  • Melanoma* / drug therapy
  • Melanoma* / pathology
  • Nivolumab* / administration & dosage
  • Nivolumab* / adverse effects
  • Product Surveillance, Postmarketing
  • Skin Neoplasms* / drug therapy
  • Skin Neoplasms* / pathology


  • Ipilimumab
  • Nivolumab

Supplementary concepts

  • Melanoma, Cutaneous Malignant