The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network.
BACKGROUND
Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers.


RESULTS
Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment.


CONCLUSIONS
The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.
Department of Dermatology, University Hospital Erlangen, Erlangen, Germany.
Caroline J
CJ
Voskens
Simone M
SM
Goldinger
Carmen
C
Loquai
Caroline
C
Robert
Katharina C
KC
Kaehler
Carola
C
Berking
Tanja
T
Bergmann
Clemens L
CL
Bockmeyer
Thomas
T
Eigentler
Michael
M
Fluck
Claus
C
Garbe
Ralf
R
Gutzmer
Stephan
S
Grabbe
Axel
A
Hauschild
Rüdiger
R
Hein
Gheorghe
G
Hundorfean
Armin
A
Justich
Ullrich
U
Keller
Christina
C
Klein
Christine
C
Mateus
Peter
P
Mohr
Sylvie
S
Paetzold
Imke
I
Satzger
Dirk
D
Schadendorf
Marc
M
Schlaeppi
Gerold
G
Schuler
Beatrice
B
Schuler-Thurner
Uwe
U
Trefzer
Jens
J
Ulrich
Julia
J
Vaubel
Roger
R
von Moos
Patrik
P
Weder
Tabea
T
Wilhelm
Daniela
D
Göppner
Reinhard
R
Dummer
Lucie M
LM
Heinzerling
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000276:immunology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use; D060908:CTLA-4 Antigen / Q000276:immunology*; D004703:Endocrine System / Q000187:drug effects; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects; D006801:Humans; D000074324:Ipilimumab; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009420:Nervous System / Q000187:drug effects; D010179:Pancreas / Q000187:drug effects; D012137:Respiratory System / Q000187:drug effects; D012189:Retrospective Studies; D012867:Skin / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy*
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; D000074324:Ipilimumab