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

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.

The safety profile of nivolumab plus ipilimumab combination therapy in Japanese patients with renal cell carcinoma: results from post-marketing surveillance.

BACKGROUND: Nivolumab and ipilimumab combination therapy is approved in Japan for unresectable or metastatic renal cell carcinoma. Because the clinical trials supporting the approval of nivolumab and ipilimumab combination therapy included relatively few Japanese patients, post-marketing surveillance was implemented to collate further safety data for nivolumab and ipilimumab combination therapy. METHODS: Patients with unresectable or metastatic renal cell carcinoma who started nivolumab and ipilimumab combination therapy between September 2018 and December 2019 were registered in this post-marketing surveillance. The observation period was 13 weeks. Safety data included treatment-related adverse events with a particular emphasis on the gastrointestinal-related (colitis, enteritis, diarrhoea and gastrointestinal perforation) and liver-related (hepatic failure, hepatic function abnormal, hepatitis and cholangitis sclerosing) treatment-related adverse events that are listed in the risk management plan for nivolumab and ipilimumab combination therapy. RESULTS: Of the 203 patients registered, safety data were available for 159 (119 males/40 females) with a median age of 67 years (range 22-88). Seventy-one patients received nivolumab and ipilimumab combination therapy four times per usual clinical therapy, and 33 continued nivolumab monotherapy thereafter. Any-grade treatment-related adverse events were reported in 102 (64.2%) patients and grade ≥ 3 in 63 (39.6%). Hepatic function abnormalities (13.2%), rash (8.8%) and interstitial lung disease (7.5%) were the most common treatment-related adverse events. Five patients died following treatment-related adverse events. Gastrointestinal-related and liver-related treatment-related adverse events occurred in 10 (6.3%; four with grade ≥ 3 treatment-related adverse events) and 27 (17.0%; 19 with grade ≥ 3 treatment-related adverse events) patients, respectively. CONCLUSIONS: This post-marketing surveillance in patients with unresectable or metastatic renal cell carcinoma revealed a safety profile for nivolumab and ipilimumab combination therapy consistent with CheckMate 214. Furthermore, no new safety concerns were identified including gastrointestinal-related and liver-related treatment-related adverse events.

Real-world safety and efficacy data of ipilimumab in Japanese radically unresectable malignant melanoma patients: A postmarketing surveillance.

Treatment with immune checkpoint inhibitors has improved prognosis among patients with cutaneous melanoma, but there are still unmet medical needs in Japan, especially for mucosal melanoma and acral lentiginous melanoma (ALM) subtypes. Ipilimumab, a fully human monoclonal antibody that specifically blocks cytotoxic T-lymphocyte-associated antigen 4 and potentiates antitumor T-cell response, was approved in Japan in 2015 for the treatment of radically unresectable malignant melanoma. This postmarketing surveillance (prospective, non-interventional, multicenter, observational study) evaluated the safety (occurrence of adverse drug reactions [ADR]) and efficacy (overall survival [OS]) of ipilimumab in a real-world setting in Japan. All patients with radically unresectable malignant melanoma undergoing treatment with ipilimumab in Japan during the registration period between August 2015 and February 2017 were enrolled. In total, 547 patients were analyzed; 67.5% were 60 years old or more, 85.7% had an Eastern Cooperative Oncology Group performance status of 0-1, 50.3% had melanoma of the skin (mainly of the ALM subtype) and 73.5% had negative BRAF mutation status. Most patients had experienced recurrence and received multiple treatments. The overall incidence of ADR and serious ADR was 69.5% and 40.8%, respectively. The most common ADR and serious ADR were liver disorder, colitis and diarrhea. The most common ADR of special interest were liver-related ADR (22.5%), skin-related ADR (22.1%), gastrointestinal-related ADR (20.3%) and endocrine system-related ADR (16.3%). Most of these events had recovered or were in remission by the last evaluation. The median OS was 7.52 months (95% confidence interval, 6.47-8.74). Median OS was 6.31 and 8.44 months in patients with mucosal melanoma and melanoma of the skin; 9.43 and 3.75 months in patients with and without ADR; and 10.32 and 6.11 months in patients with and without serious ADR, respectively. Ipilimumab was tolerable and showed efficacy in improving OS for these patients.