Cumulative data indicate greater tumor response from the addition of IPI (anti-CTLA-4 antibody) to NIVO (anti-PD-1 antibody) in MEL pts, but with a higher frequency of adverse events (AEs) than observed with either agent alone. The objective of this pooled analysis is to describe the safety profile of NIVO + IPI across MEL studies in which established guidelines for AE management were utilized.
A retrospective safety review was conducted for three phase 1-3 trials in which all MEL pts who received at least 1 dose of the standard regimen, NIVO 1 mg/kg + IPI 3 mg/kg Q3W x 4, then NIVO 3 mg/kg Q2W until disease progression or unacceptable toxicity. Analyses included AEs, select (immune-related) AEs, time to onset and resolution, use of immune-modulating agents (IMs) for management of toxicity, and effect of IMs on outcome.
Among 448 pts, median age was 61 (range:18-87) and 25% had ECOG PS > 0. Median duration of follow-up was 13.2 months. Treatment-related grade 3–4 AEs occurred in 55% of pts, and led to discontinuation in 28%. The most frequent treatment-related select AEs of any grade were skin (64%) and gastrointestinal (47%); the most frequent grade 3–4 select AEs were hepatic (17%) and gastrointestinal (16%; Table). 30% developed a grade 2-4 select AE in >1 organ category. Median time to onset of grade 3–4 treatment-related select AEs ranged from 3.1 wks (skin) to 16.3 wks (renal). Excluding endocrine AEs, median time to resolution of grade 3–4 select AEs with IMs ranged from 1.1 wks (renal) to 7.3 wks (pulmonary). Resolution rates for non-endocrine grade 3–4 select AEs ranged between 79─100% using IMs. 4 (
The frequency of grade 3–4 treatment-related AEs was higher with NIVO + IPI and time to onset of select AEs occurred earlier than with either agent alone. Resolution rates of select AEs were similar to those previously reported with IPI monotherapy.
|NIVO + IPI-treated pts (N = 448)|
|Select AEs, %||Any grade||Grade 3–4|
|Alanine aminotransferase increased||18||9|
|Aspartate aminotransferase increased||17||6|
Clinical trial identification
NCT01024231(CA209-004), NCT01844505 (CheckMate 067), NCT01927419 (CheckMate 069)
Legal entity responsible for the study
M. Sznol: Consultant: BMS, Genentech-Roche, AZ-Medimmune, Anaeropharma, Merus, Symphogen, Nektar, Amgen, Kyowa-Kirin, Astellas-Agensys, Lion Biotech, Neostem, Seattle Genetics, Pfizer, TRM Oncology, Physicians Education Resource, Imedex, Research to Practice. P.F. Ferrucci: Honoraria from Delcath Systems, consultant for GSK, Roche, and BMS, provided expert testimony for GSK, Roche, and BMS, received travel support from GSK, Roche, and BMS. D. Hogg: Served as a consultant for BMS, Roche, Novartis, and GSK. M. Atkins: Served as a consultant for BMS, Merck, Novartis, Genentech Roche, Pfizer, Nektar, Caladrius, SAB for Merck, DSMB for Novartis and GSK. P. Wolter: Served as a consultant for GSK and BMS, received research funding from GSK, Pfizer, and Novartis. M. Guidoboni: Advisor for BMS, Novartis, Amgen, travel support from BMS, Novartis, research support from MSD. C. Lebbe: Advisory boards for BMS, MSD, Roche, GSK, and Novartis. J. Kirkwood: Consultant for BMS, Merck, GSK, Amgen, Green Peptide, Roche, Genentech. G. Daniels: Dr. Daniels institution received research funding from BMS and Site Pl. J. Hassel: Received honoraria from BMS, GSK, Roche, MSD, and Amgen, served as a consultant for Amgen and GSK, participated in speakers bureau for BMS, GSK, Roche, MSD, and Amgen, received reimbursements on travel, accommodations, expenses from Amgen and BMS. W. Gerritsen: Advisory boards and speaker's bureau for BMS. V. Atkinson: Received honoraria from Glasko Smith Kline, BMS, Merck, and Sharp & Dohme, served as a consultant for Merck, Sharp & Dohme, and BMS, received reimbursements on travel, accommodations, expenses from BMS and Roche. J. Jiang: Employee of BMS. F.S. Hodi: Institution served as a consultant for BMS (non-paid), institution received research funding from BMS, and institution has a patent pending on immune target. J. Wolchok: Honoraria: EMD Serono, Janssen Oncol; consultant: BMS, Merck, MedImmune, Ziapharm, Polynoma, Polaris, Jounce, GSK; institutional research funding: BMS, MedImmune, GSK, Merck; co-investor on patent for DNA vaccines of cancer in animals; travel support: BMS. All other authors have declared no conflicts of interest.