Adverse events induced by nivolumab and ipilimumab combination regimens

Abstract

Background: No meta-analysis has assessed the pooled frequencies of adverse events (AEs) induced by concomitant nivolumab plus ipilimumab regimen for anticancer-medications-naïve malignancies. Furthermore, no meta-analysis has compared detailed safety profiles between four doses of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks (N3I1) and four doses of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks (N1I3). Objectives of this study was estimating AE frequencies, and comparison of AE frequencies between N3I1 and N1I3 regimens. Methods: Four major electronic databases were searched; both interventional and observational studies were included. All primary cancer types were permitted. Patients should not have been previously treated with any anti-cancer medications. The frequency of AEs was pooled using a random-model meta-analysis using the generic inverse variance method. Protocol registration: UMIN000044090. Results: Forty articles representing 48 populations with 4,677 patients were included in the study. The pooled frequencies for key indicators were as follows: any AE, 81.3% (95% confidence interval (CI) 77.5-85.1); grade 3 or higher AE, 40.6% (95% CI: 35.7–45.5); serious AE, 32.7% (95% CI: 22.4–43.1); AE leading to discontinuation, 28.3% (95% CI: 23.7–32.8); and treatment-related death, 0.7% (95% CI: 0.4–1.1). AEs with the highest incidence were fatigue (27.9%, 95% CI: 22.6–33.3), followed by diarrhea (26.0%, 95% CI: 21.5–30.5), pruritus (24.6%, 95% CI: 20.3–28.8), rash (24.0% 95% CI: 19.3–28.7), and elevated aspartate aminotransferase (21.2%, 95% CI: 14.9–27.5). Subgroup analyses demonstrated that N3I1, compared to N1I3, less frequently induced any AE (N1I3 95.7%, N3I1 84.5%, p = 0.003), grade 3 or higher AE (N1I3 64.3%, N3I1 35.7%, p < 0.001), and serious AE (N1I3 61.4%, N3I1 47.8%, p = 0.004). Conclusions: Approximately 40% of patients had grade 3 or higher AE. The N3I1 regimen was substantiated to trigger fewer any AEs, high grade AEs, and serious AE than the N1I3 regimen.

Survival analysis and development of a prognostic nomogram for patients with malignant mesothelioma in different anatomic sites

“…This may be because MPM is a low tumor mutational burden (TMB) tumor ( 63 ). In addition, approximately 40% of patients treated with nivolumab plus ipilimumab experienced grade 3 or higher adverse events (AEs) ( 64 ).…”

Developments in Checkpoint Inhibitor Therapy for the Management of Deficient Mismatch Repair (dMMR) Rectal Cancer

“…In the CheckMate-142 study of ipilimumab and nivolumab, Grade 3 and 4 irAEs were observed in 32% and 13% of patients, respectively, and these led to treatment discontinuation. In a random-model meta-analysis representing 4677 patients that received nivolumab–ipilimumab regimens [ 52 ], an estimated 40.6% of patients (95% CI 35.7–45.5) experienced a grade 3 or higher adverse event, and an estimated 28.3% of patients (95% CI 23.7–32.8) discontinued their treatment due to adverse events. Common adverse events include fatigue (27.9%, CI 22.6–33.3), pruritus (24.6%, CI 20.3–28.8), rash (24.0%, CI 19.3–28.7), elevated aspartate aminotransferase (21.2%, CI 14.9–27.5), and elevated alanine aminotransferase (18.1%, CI 13.1–23.2).…”

The best dosage of nivolumab plus ipilimumab combination for melanoma brain metastases

“…Besides, our analyses revealed safety superiority of the N3I1 regimen ( Fig. 1 ) [ 3 ]. The data from Tawbi et al.…”

“…To compare the risk of adverse events caused by these two regimes, we have recently conducted a random-model meta-analysis using a generic inverse variance method and the data of patients with both melanoma and the other malignancies (RevMan ver 5.4. Cochrane Collaboration, London, UK) [ 3 ]. This analysis suggested that N3I1 regimen caused less adverse events [ 3 ].…”

“…Cochrane Collaboration, London, UK) [ 3 ]. This analysis suggested that N3I1 regimen caused less adverse events [ 3 ]. We performed additional subgroup analyses limited to advanced melanoma cases, who were treated with four doses of N1I3 regime every 3 weeks, which we considered satisfactory homogeneous to evaluate adverse events.…”