1123P - Safety profile of nivolumab (NIVO) and ipilimumab (IPI) combination therapy in patients (pts) with advanced melanoma (MEL)

Date 09 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Skin Cancers
Melanoma
Presenter Mario Sznol
Citation Annals of Oncology (2016) 27 (6): 379-400. 10.1093/annonc/mdw379
Authors M. Sznol1, P.F. Ferrucci2, D. Hogg3, M. Atkins4, P. Wolter5, M. Guidoboni6, C. Lebbe7, J. Kirkwood8, J. Schachter9, G. Daniels10, J. Hassel11, J. Cebon12, W. Gerritsen13, V. Atkinson14, L. Thomas15, J. McCaffrey16, D. Power17, J. Jiang18, F..S. Hodi19, J. Wolchok20
  • 1Medical Oncology, Yale University School of Medicine Medical Oncology, 06510 - New Haven/US
  • 2Melanoma And Sarcoma, Istituto Europeo di Oncologia, 20141 - Milano/IT
  • 3Department Of Medical Oncology And Hematology, Princess Margaret Hospital, M5G 2M9 - Toronto/CA
  • 4Hematology/oncology, Lombardi Cancer Center Georgetown University, Washington/US
  • 5Department Of General Medical Oncology, University Hospitals Leuven - Campus Gasthuisberg, 3000 - Leuven/BE
  • 6Immunotherapy Unit, Istituto Tumori della Romagna I.R.S.T., Meldola/IT
  • 7Dermatology, Hôpital St. Louis, 75010 - Paris/FR
  • 8Medical Oncology And Hematology, Hillman Cancer Center, Pittsburgh/US
  • 9Ella Lemelbaum Institute Of Melanoma, Sheba Medical Center, Ramat Gan/IL
  • 10Medicine, Moores UCSD Cancer Center, La Jolla/US
  • 11Oncology, University Hospital Heidelberg, Heidelberg/DE
  • 12Cancer Immunobiology, Olivia Newton-John Cancer Research Institute, Heidelberg/AU
  • 13Department Of Medical Oncology, Radboud University Medical Centre Nijmegen, 6500 HB - Nijmegen/NL
  • 14Oncology, Gallipoli Medical Research Foundation and Princess Alexandra Hospital, Greenslopes/AU
  • 15Dermatology, Centre Hospitalier Lyon Sud, Pierre Bénite/FR
  • 16Medical Oncology, Irish Clinical Oncology Research Group, Dublin/IE
  • 17Medical Oncology, Irish Clinical Oncology Research Group, Cork/IE
  • 18Oncology, BMS, Princeton/US
  • 19Oncology, Dana-Farber Cancer Institute, Boston/US
  • 20Ludwig Center, Memorial Sloan Kettering Cancer Center, New York/US

Abstract

Background

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.

Methods

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.

Results

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 (

Conclusions

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
Skin 64 7
Rash 35 4
Pruritus 35 2
Gastrointestinal 47 16
Diarrhea 44 10
Colitis 13 9
Hepatic 29 17
Alanine aminotransferase increased 18 9
Aspartate aminotransferase increased 17 6
Hepatitis 2 2
Endocrine 30 5
Hypophysitis 9 2

Clinical trial identification

NCT01024231(CA209-004), NCT01844505 (CheckMate 067), NCT01927419 (CheckMate 069)

Legal entity responsible for the study

Bristol-Myers Squibb

Funding

Bristol-Myers Squibb

Disclosure

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.