Sandro Pasquali1, Vanna Chiarion-Sileni2, Carlo Riccardo Rossi3, Simone Mocellin4. 1. Meta-Analysis Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy. Electronic address: pasqualisandro@hotmail.com. 2. Melanoma and Esophageal Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy. Electronic address: vanna.chiarion@ioveneto.it. 3. Meta-Analysis Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy. Electronic address: carlor.rossi@unipd.it. 4. Meta-Analysis Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy. Electronic address: simone.mocellin@unipd.it.
Abstract
BACKGROUND: Immune checkpoint inhibitors and targeted therapies, two new class of drugs for treatment of metastatic melanoma, have not been compared in randomized controlled trials (RCT). We quantitatively summarized the evidence and compared immune and targeted therapies in terms of both efficacy and toxicity. METHODS: A comprehensive search for RCTs of immune checkpoint inhibitors and targeted therapies was conducted to August 2016. Using a network meta-analysis approach, treatments were compared with each other and ranked based on their effectiveness (as measured by the impact on progression-free survival [PFS]) and acceptability (the inverse of high grade toxicity). RESULTS: Twelve RCTs enrolling 6207 patients were included. Network meta-analysis generated 15 comparisons. Combined BRAF and MEK inhibitors were associated with longer PFS as compared to anti-CTLA4 (HR: 0.22; 95% confidence interval [CI]: 0.12-0.41) and anti-PD1 antibodies alone (HR: 0.38; CI: 0.20-0.72). However, anti-PD1 monoclonal antibodies were less toxic than anti-CTLA4 monoclonal antibodies (RR: 0.65; CI: 0.40-0.78) and their combination significantly increased toxicity compared to either single agent anti-CTLA4 (RR: 2.06; CI: 1.45-2.93) or anti-PD1 monoclonal antibodies (RR: 3.67; CI: 2.27-5.96). Consistently, ranking analysis suggested that the combination of targeted therapies is the most effective strategy, whereas single agent anti-PD1 antibodies have the best acceptability. The GRADE level of evidence quality for these findings was moderate to low. CONCLUSIONS: The simultaneous inhibition of BRAF and MEK appears the most effective treatment for melanomas harboring BRAF V600 mutation, although anti-PD1 antibodies appear to be less toxic. Further research is needed to increase the quality of evidence.
BACKGROUND: Immune checkpoint inhibitors and targeted therapies, two new class of drugs for treatment of metastatic melanoma, have not been compared in randomized controlled trials (RCT). We quantitatively summarized the evidence and compared immune and targeted therapies in terms of both efficacy and toxicity. METHODS: A comprehensive search for RCTs of immune checkpoint inhibitors and targeted therapies was conducted to August 2016. Using a network meta-analysis approach, treatments were compared with each other and ranked based on their effectiveness (as measured by the impact on progression-free survival [PFS]) and acceptability (the inverse of high grade toxicity). RESULTS: Twelve RCTs enrolling 6207 patients were included. Network meta-analysis generated 15 comparisons. Combined BRAF and MEK inhibitors were associated with longer PFS as compared to anti-CTLA4 (HR: 0.22; 95% confidence interval [CI]: 0.12-0.41) and anti-PD1 antibodies alone (HR: 0.38; CI: 0.20-0.72). However, anti-PD1 monoclonal antibodies were less toxic than anti-CTLA4 monoclonal antibodies (RR: 0.65; CI: 0.40-0.78) and their combination significantly increased toxicity compared to either single agent anti-CTLA4 (RR: 2.06; CI: 1.45-2.93) or anti-PD1 monoclonal antibodies (RR: 3.67; CI: 2.27-5.96). Consistently, ranking analysis suggested that the combination of targeted therapies is the most effective strategy, whereas single agent anti-PD1 antibodies have the best acceptability. The GRADE level of evidence quality for these findings was moderate to low. CONCLUSIONS: The simultaneous inhibition of BRAF and MEK appears the most effective treatment for melanomas harboring BRAF V600 mutation, although anti-PD1 antibodies appear to be less toxic. Further research is needed to increase the quality of evidence.
Authors: Allison S Dobry; Cheryl K Zogg; F Stephen Hodi; Timothy R Smith; Patrick A Ott; J Bryan Iorgulescu Journal: Cancer Immunol Immunother Date: 2018-09-06 Impact factor: 6.968
Authors: Akosua A Nti; Leona W Serrano; Harpal S Sandhu; Katherine E Uyhazi; Ilaina D Edelstein; Elaine J Zhou; Scott Bowman; Delu Song; Tara C Gangadhar; Lynn M Schuchter; Sheryl Mitnick; Alexander Huang; Charles W Nichols; Ravi K Amaravadi; Benjamin J Kim; Tomas S Aleman Journal: Retina Date: 2019-03 Impact factor: 4.256
Authors: J Bryan Iorgulescu; Maya Harary; Cheryl K Zogg; Keith L Ligon; David A Reardon; F Stephen Hodi; Ayal A Aizer; Timothy R Smith Journal: Cancer Immunol Res Date: 2018-07-12 Impact factor: 11.151
Authors: Kimberley Hanson; Stephen D Robinson; Karamallah Al-Yousuf; Adam E Hendry; Darren W Sexton; Victoria Sherwood; Grant N Wheeler Journal: Oncotarget Date: 2017-12-17