PMID- 28817755
OWN - NLM
STAT- MEDLINE
DCOM- 20190906
LR  - 20231112
IS  - 2374-2445 (Electronic)
IS  - 2374-2437 (Print)
IS  - 2374-2437 (Linking)
VI  - 4
IP  - 1
DP  - 2018 Jan 1
TI  - Measuring Toxic Effects and Time to Treatment Failure for Nivolumab Plus 
      Ipilimumab in Melanoma.
PG  - 98-101
LID - 10.1001/jamaoncol.2017.2391 [doi]
AB  - IMPORTANCE: Nivolumab plus ipilimumab (nivo + ipi) is a standard treatment of 
      advanced melanoma. Two randomized trials describe high objective response rates 
      by Response Evaluation Criteria in Solid Tumors. The trials assessed toxic 
      effects using the Common Terminology Criteria for Adverse Events (CTCAE), which 
      may underestimate incidence of clinically significant immune-related adverse 
      events (AEs). OBJECTIVE: To describe detailed toxic effects and time to treatment 
      failure of patients with melanoma treated with nivo + ipi in a prospective 
      cohort. DESIGN, SETTING, AND PARTICIPANTS: A cohort of 64 adults with advanced or 
      unresectable melanoma were examined at a single tertiary cancer and enrolled in 
      an expanded access program of nivo + ipi conducted from December 2014 to January 
      2016. INTERVENTIONS: Intravenous nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) 
      administered every 3 weeks for up to 4 doses, followed by nivolumab (3 mg/kg) 
      every 2 weeks or pembrolizumab (2 mg/kg) every 3 weeks until unacceptable toxic 
      effects, disease progression, or complete response. MAIN OUTCOMES AND MEASURES: 
      Clinically significant immune-related AEs were defined as CTCAE grade 2 or higher 
      or any immune-related AEs requiring systemic steroids. Time to treatment failure 
      was defined as the interval between initiating therapy and the earliest of 
      clinical progression, new locally directed or systemic treatment other than 
      anti-programmed cell death 1 protein (anti-PD-1) monotherapy, or death. RESULTS: 
      Overall 64 adults with advanced or unresectable melanoma were enrolled (male to 
      female ratio, 1:1; median [range] age, 56 [22-82] years); 25 patients (39%) 
      received all 4 doses of nivo + ipi, and 31 patients (48%) received no maintenance 
      anti-PD-1 therapy. Most who discontinued treatment (n = 31 [80%]) stopped because 
      of toxic effects. Among those patients who were progression free at 12 weeks, 
      time to treatment failure was similar between those who did or did not modify 
      therapy for toxic effects. Fifty-eight patients (91%) had a clinically 
      significant immune-related AE (median, 2/patient), and 46 patients (72%) required 
      systemic steroids. Infliximab or mycophenolate was required in 16 patients (25%) 
      for steroid-refractory immune-related AEs. Seven patients (11%) developed 
      hyperglycemia, 32 patients (50%) had an emergency department visit, and 23 
      patients (36%) required a hospital admission related to an immune-related AE. 
      Four of 31 patients (13%) who stopped combination therapy early for toxic effects 
      developed a new, clinically significant immune-related AE more than 16 weeks 
      after the last treatment. CONCLUSIONS AND RELEVANCE: We observed a 91% incidence 
      of clinically significant immune-related AEs leading to frequent emergency 
      department visits, hospitalizations, and systemic immunosuppression. 
      Immuno-oncology trials should routinely report these metrics. Most patients do 
      not tolerate 4 doses of nivo + ipi; however, 4 doses may not be required for 
      clinical benefit.
FAU - Shoushtari, Alexander N
AU  - Shoushtari AN
AD  - Department of Medicine, Melanoma, and Immunotherapeutics Service, Memorial Sloan 
      Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Friedman, Claire F
AU  - Friedman CF
AD  - Department of Medicine, Melanoma, and Immunotherapeutics Service, Memorial Sloan 
      Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Navid-Azarbaijani, Pedram
AU  - Navid-Azarbaijani P
AD  - Department of Medicine, Melanoma, and Immunotherapeutics Service, Memorial Sloan 
      Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Postow, Michael A
AU  - Postow MA
AD  - Department of Medicine, Melanoma, and Immunotherapeutics Service, Memorial Sloan 
      Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Callahan, Margaret K
AU  - Callahan MK
AD  - Department of Medicine, Melanoma, and Immunotherapeutics Service, Memorial Sloan 
      Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Momtaz, Parisa
AU  - Momtaz P
AD  - Department of Medicine, Melanoma, and Immunotherapeutics Service, Memorial Sloan 
      Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Panageas, Katherine S
AU  - Panageas KS
AD  - Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer 
      Center, New York, New York.
FAU - Wolchok, Jedd D
AU  - Wolchok JD
AD  - Department of Medicine, Melanoma, and Immunotherapeutics Service, Memorial Sloan 
      Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Chapman, Paul B
AU  - Chapman PB
AD  - Department of Medicine, Melanoma, and Immunotherapeutics Service, Memorial Sloan 
      Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
LA  - eng
GR  - P30 CA008748/CA/NCI NIH HHS/United States
PT  - Clinical Trial
PT  - Journal Article
PL  - United States
TA  - JAMA Oncol
JT  - JAMA oncology
JID - 101652861
RN  - 0 (Ipilimumab)
RN  - 31YO63LBSN (Nivolumab)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Compassionate Use Trials
MH  - Disease Progression
MH  - Disease-Free Survival
MH  - Drug-Related Side Effects and Adverse Reactions/*epidemiology
MH  - Female
MH  - Humans
MH  - Incidence
MH  - Ipilimumab/administration & dosage/*adverse effects
MH  - Male
MH  - Melanoma/*drug therapy/epidemiology/pathology
MH  - Middle Aged
MH  - Nivolumab/administration & dosage/*adverse effects
MH  - Prospective Studies
MH  - Skin Neoplasms/*drug therapy/epidemiology/pathology
MH  - Time Factors
MH  - Treatment Failure
MH  - Young Adult
PMC - PMC5833656
COIS- Conflict of Interest Disclosures: Dr Shoushtari declares institutional research 
      funding from Bristol-Myers Squibb (BMS) and Immunocore; he either presently 
      serves or has served on advisory boards for BMS, Immunocore, Vaccinex, and Castle 
      Biosciences. Dr Friedman declares institutional research funding and travel 
      expenses from BMS. Dr Postow declares honoraria from BMS, Merck; institutional 
      research funding from BMS, Novartis, Array Biopharma, Infinity Pharmaceuticals; 
      travel expenses from BMS; and presently serves or has served in advisory and/or 
      consulting roles for BMS, Novartis, and Amgen. Dr Callahan declares employment of 
      an immediate family member by BMS and Celgene; institutional research funding by 
      BMS; and presently served or has served in advisory and/or consulting roles for 
      AstraZeneca. Dr Wolchok declares stock or other ownership in Potenza 
      Pharmaceuticals and Vesuvius Pharmaceuticals; honorarium from Regeneron; 
      institutional research support from BMS; travel expenses from BMS, Chugai Pharma, 
      Roche, Janssen, Kadmon, Regeneron; and serves or has served in advisory and/or 
      consulting roles for BMS, Merck, MedImmune, ZIOPHARM Oncology, Polynoma, Polaris, 
      Jounce Therapeutics, Genentech, FStar, Beigene, Advaxis, Sellas Life Sciences, 
      Lilly, Potenza Therapeutics, Tizona Therapeutics Inc, Amgen, AstraZeneca, and 
      Chugai Pharma. Dr Chapman declares honoraria from BMS, GlaxoSmithKline, 
      Genentech/Roche, Provectus, Momenta Pharmaceuticals, and Daiichi Sankyo; research 
      funding from BMS, Genentech/Roche, GlaxoSmithKline, and Pfizer; travel expenses 
      from BMS; and serves or has served in advisory and/or consulting roles for BMS, 
      GlaxoSmithKline, Genentech/Roche, Daiichi Sankyo, Provectus, and Momenta 
      Pharmaceuticals. No other conflicts are reported.
EDAT- 2017/08/18 06:00
MHDA- 2019/09/07 06:00
PMCR- 2018/08/17
CRDT- 2017/08/18 06:00
PHST- 2017/08/18 06:00 [pubmed]
PHST- 2019/09/07 06:00 [medline]
PHST- 2017/08/18 06:00 [entrez]
PHST- 2018/08/17 00:00 [pmc-release]
AID - 2648860 [pii]
AID - cbr170016 [pii]
AID - 10.1001/jamaoncol.2017.2391 [doi]
PST - ppublish
SO  - JAMA Oncol. 2018 Jan 1;4(1):98-101. doi: 10.1001/jamaoncol.2017.2391.