Antitumor Activity and Treatment-Related Toxicity Associated With Nivolumab Plus Ipilimumab in Advanced Malignancies: A Systematic Review and Meta-Analysis

Abstract

Combining immune checkpoint inhibitors has shown its efficacy compared to monotherapy in advanced malignancies. We conducted this meta-analysis to provide latest evidence on the objective response rate (ORR) and incidence of treatment-related high-grade adverse events (AEs) during nivolumab and ipilimumab combination treatment and further explore from different drug dose level. PubMed and the 2019 American Society of Clinical Oncology (ASCO) annual meeting abstracts were searched for qualified clinical trials up to June 2019. Of the 23 clinical trials (13 from publications and 11 from ASCO abstracts) included, 2,114 and 2,674 patients were eligible for efficacy and safety analysis, respectively. Pooled analysis suggested that the overall ORR was achieved in 34.5% [95% confidence interval (CI), 29.1–40.4%] of patients. There was no significant difference between nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks (N3I1-Q3W) and nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks (N1I3-Q3W) arms in ORR [30.8% vs 41%; odds ratio (OR), 0.72; 95% CI, 0.39–1.30; P = 0.275]. Grade 3–4 AEs related to combination therapy occurred in 39.9% (95% CI, 33.5–46.7%) of patients; the most commonly reported grade 3–4 treatment-related AEs were diarrhea (5.28%), colitis (3.96%) and increased alanine aminotransferase (3.51%). Incidence of grade 3–4 AEs were significant lower in N3I1-Q3W arm than in N1I3-Q3W arm (31.3% vs 55.9%; OR 0.52; 95% CI, 0.32–0.87; P = 0.012). Treatment-related death was rare and occurred in 2.0% (95% CI, 1.5–2.7%) of patients. Our comprehensive study provides more precise data on the incidence of treatment-related high-grade AEs and ORR among patients receiving nivolumab and ipilimumab combination regimens. Patients on the N3I1-Q3W arm had comparable ORR and significantly occurred less grade 3–4 AEs than patients on the N1I3-Q3W arm. Our finding is of great importance in assisting clinical trial design and clinical medication choice.

Low-dose ipilimumab plus nivolumab combined with IL-2 and hyperthermia in cancer patients with advanced disease: exploratory findings of a case series of 131 stage IV cancers – a retrospective study of a single institution

“…However, TMB low and MSI low can be expected in the majority based on published evidence [37]. In contrast, published meta-analyses included patients with high PD-L1 expression, TMB high , and MSI high [30,38]. Therefore, in contrast to the published meta-analysis, our patient group had the following negative pre-selection factors:…”

“…Any-grade irAEs occurred in 96.8% of patients in Callahan’s study, while 58.5% of patients had grade 3 and 4 irAEs leading to discontinuation in 24.5% of patients, and one treatment-related death was also reported [ 1 ]. Similarly, grade 3–4 irAEs occurred in 39.9% of patients in the meta-analysis of Xu et al, while 2.0% treatment-related death was recorded [ 30 ].…”

“…However, TMB low and MSI low can be expected in the majority based on published evidence [ 37 ]. In contrast, published meta-analyses included patients with high PD-L1 expression, TMB high , and MSI high [ 30 , 38 ]. Therefore, in contrast to the published meta-analysis, our patient group had the following negative pre-selection factors: Antibiotic use in 24%; Low PD-1/PD-L1 expression; Only stage IV patients, with 35.1% liver metastasis, a specifically bad prognosis; Only 35% ECOG 0; Heavily pretreated patients.…”

Results from a Meta-analysis of Combination of PD-1/PD-L1 and CTLA-4 Inhibitors in Malignant Cancer Patients: Does PD-L1 Matter?

“…Gastrointestinal diseases, respiratory diseases and rashes were the most common grade 3–4 adverse reactions. Overall, the adverse effects of immunotherapy were manageable ( Xu et al, 2019 ; Yang et al, 2020 ). Since adverse events have been discussed in previous studies ( Xu et al, 2019 ; Yang et al, 2020 ), and will not be further considered here.…”

Polyendocrine Autoimmunity and Diabetic Ketoacidosis Following Anti-PD-1 and Interferon α

“…40% of patients treated with combination ICIs (anti-PD-1 and anti-CTLA-4), 9 which can manifest as immune-mediated destruction of multiple tissues (eg, skin, gut, endocrine organs, lung, heart, nervous system). IRAEs can have a significant clinical impact including interruption of cancer treatment, permanent organ dysfunction, hospitalization, and even premature death.…”