Medline ® Abstracts for References 36,46
of 'Toxicities associated with checkpoint inhibitor immunotherapy'
Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma.
Weber JS, Dummer R, de Pril V, LebbéC, Hodi FS, MDX010-20 Investigators
Cancer. 2013 May;119(9):1675-82. Epub 2013 Feb 7.
BACKGROUND: Ipilimumab 3 mg/kg was the first agent to demonstrate improved survival in previously treated patients with metastatic melanoma in a phase 3 trial (MDX010-20). Ipilimumab produced a characteristic spectrum of immune-related adverse events (irAEs) of special interest, consistent with its immune-based mechanism of action.
METHODS: In MDX010-20, 676 previously treated patients were randomized 3:1:1 to receive ipilimumab 3 mg/kg plus the glycoprotein 100 melanoma antigen vaccine (gp100), ipilimumab 3 mg/kg + placebo, or gp100 vaccine + placebo. For the current report, the authors conducted a detailed analysis of the time to onset and resolution of irAEs associated with ipilimumab therapy.
RESULTS: Grade 2 through 5 irAEs generally developed during the induction phase of treatment (0-12 weeks). Most, including grade 3/4 irAEs, were reversible when managed with treatment guidelines using vigilant monitoring and corticosteroids. The median time to resolution (to grade 1 or 0 or to the grade at baseline) of irAEs that had an onset during the induction phase was approximately 6 weeks for grade 2 through 4 irAEs and 8 weeks for grade 3 and 4 irAEs. Across the entire study duration, most grade 2 through 4 irAEs resolved within 12 weeks.
CONCLUSIONS: Most ipilimumab-associated irAEs, including grade 3/4 symptoms, developed within 12 weeks of initial dosing and resolved within 12 weeks of onset. IrAEs were well characterized in their evolution and could be managed using published algorithms.
Donald A. Adam Comprehensive Melanoma Research Center, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA. firstname.lastname@example.org
Systematic review with network meta-analysis: the efficacy of anti-TNF agents for the treatment of Crohn's disease.
Stidham RW, Lee TC, Higgins PD, Deshpande AR, Sussman DA, Singal AG, Elmunzer BJ, Saini SD, Vijan S, Waljee AK
Aliment Pharmacol Ther. 2014 Jun;39(12):1349-62. Epub 2014 Apr 20.
BACKGROUND: Anti-tumour necrosis factor-alpha agents (anti-TNF) are effective therapies for the treatment of Crohn's disease (CD), but their comparative efficacy is unknown.
AIM: To perform a network meta-analysis comparing the efficacy of anti-TNF therapies in CD.
METHODS: After screening 506 studies, reviewers extracted information on 10 studies. Traditional meta-analysis (TMA) was used to compare each anti-TNF agent to placebo. Bayesian network meta-analysis (NMA) was performed to compare the effects of anti-TNF agents to placebo. In addition, sample sizes for comparative efficacy trials were calculated.
RESULTS: Compared to placebo, TMA revealed that anti-TNF agents result in a higher likelihood of induction of remission and response (RR: 1.66, 95% CI: 1.17-2.36 and RR: 1.43, 95% CI: 1.17-1.73, respectively) as well as maintenanceof remission and response (RR: 1.78, 95% CI: 1.51-2.09 and RR: 1.68, 95% CI: 1.46-1.93, respectively). NMA found nonsignificant trends between infliximab and adalimumab or certolizumab pegol. Among subcutaneous therapies, NMA demonstrated superiority of adalimumab to certolizumab pegol for induction of remission (RR: 2.93, 95% CrI: 1.21-7.75). Sample size calculations suggest that adequately powered head-to-head comparative efficacy trials would require greater than 3000 patients.
CONCLUSIONS: All anti-TNF agents are effective for induction and maintenance of response and remission in the treatment of CD. Although adalimumab is superior to certolizumab pegol for induction of remission, there is no evidence of clinical superiority among anti-TNF agents. Head-to-head trials among the anti-TNF agents are impractical in terms of size and cost.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA.