Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis
James Larkin,Bartosz Chmielowski,Christopher D. Lao,F. Stephen Hodi,William H. Sharfman,Jeffrey S. Weber,Karijn P M Suijkerbuijk,Sergio J Azevedo,Hewei Li,Daniel Reshef,Alexandre Avila,David A. Reardon +11 more
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Both oncologists and neurologists need to be aware of signs and symptoms of serious but uncommon neurologic irAEs associated with checkpoint inhibitors and be able to provide prompt treatment of this uncommon, but potentially serious, class of adverse events.Abstract:
Background Despite unprecedented efficacy across multiple tumor types, immune checkpoint inhibitor therapy is associated with a unique and wide spectrum of immune-related adverse events (irAEs), including neurologic events ranging from mild headache to potentially life-threatening encephalitis. Here, we summarize neurologic irAEs associated with nivolumab and ipilimumab melanoma treatment, present cases of treatment-related encephalitis, and provide practical guidance on diagnosis and management. Methods We searched a Global Pharmacovigilance and Epidemiology database for neurologic irAEs reported over an 8-year period in patients with advanced melanoma receiving nivolumab with or without ipilimumab from 12 studies sponsored by Bristol-Myers Squibb. Serious neurologic irAEs were reviewed, and relationship to nivolumab or ipilimumab was assigned. Results In our search of 3,763 patients, 35 patients (0.93%) presented with 43 serious neurologic irAEs, including neuropathy (n = 22), noninfective meningitis (n = 5), encephalitis (n = 6), neuromuscular disorders (n = 3), and nonspecific adverse events (n = 7). Study drug was discontinued (n = 20), interrupted (n = 8), or unchanged (n = 7). Most neurologic irAEs resolved (26/35 patients; 75%). Overall, median time to onset was 45 days (range 1-170) and to resolution was 32 days (2-809+). Median time to onset of encephalitis was 55.5 days (range 18-297); four cases resolved and one was fatal. Conclusion Both oncologists and neurologists need to be aware of signs and symptoms of serious but uncommon neurologic irAEs associated with checkpoint inhibitors. Prompt diagnosis and management using an established algorithm are critical to minimize serious complications from these neurologic irAEs. Implications for practice With increasing use of checkpoint inhibitors in cancer, practicing oncologists need to be aware of the potential risk of neurologic immune-related adverse events and be able to provide prompt treatment of this uncommon, but potentially serious, class of adverse events. We summarize neurologic adverse events related to nivolumab alone or in combination with ipilimumab in patients with advanced melanoma from 12 studies and examine in depth 6 cases of encephalitis. We also provide input and guidance on the existing neurologic adverse events management algorithm for nivolumab and ipilimumab.read more
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A review of cancer immunotherapy toxicity.
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TL;DR: It is found that neoadjuvant ipilimumab + nivolumab expand more tumor-resident T cell clones than adjuvant application, and warrants future evaluation with modified dosing schedules to reduce treatment-related adverse events.
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First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.
Linda M. Liau,Keyoumars Ashkan,David Tran,Jian Campian,John E. Trusheim,Charles S. Cobbs,Jason Heth,Michael Salacz,Sarah A. Taylor,Stacy D. D’Andre,Fabio M. Iwamoto,Edward J. Dropcho,Yaron A. Moshel,Kevin A. Walter,Clement Pillainayagam,Robert Aiken,Rekha Chaudhary,Samuel Goldlust,Daniela A. Bota,Paul Duic,Jai Grewal,Heinrich Elinzano,Steven A. Toms,Kevin O. Lillehei,Tom Mikkelsen,Tobias Walbert,Steven R. Abram,Andrew Brenner,Steven Brem,Matthew G. Ewend,Simon Khagi,Jana Portnow,Lyndon Kim,William G. Loudon,Reid C. Thompson,David Avigan,Karen Fink,Francois J. Geoffroy,Scott Lindhorst,Jose Lutzky,Andrew E. Sloan,Gabriele Schackert,Dietmar Krex,Hans-Jorg Meisel,Julian Wu,Raphael P. Davis,Christopher Duma,Arnold B. Etame,David Mathieu,Santosh Kesari,David Piccioni,Manfred Westphal,David S. Baskin,Pamela Z. New,Michel Lacroix,Sven-Axel May,Timothy J. Pluard,Victor Tse,Richard M. Green,John L. Villano,Michael Pearlman,Kevin Petrecca,Michael Schulder,Lynne Taylor,Anthony E. Maida,Robert M. Prins,Timothy F. Cloughesy,Paul Mulholland,Marnix L. Bosch +68 more
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Improved Survival with Ipilimumab in Patients with Metastatic Melanoma.
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Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.
James Larkin,Vanna Chiarion-Sileni,Rene Gonzalez,Jean-Jacques Grob,C. Lance Cowey,Christopher D. Lao,Dirk Schadendorf,Reinhard Dummer,Michael Smylie,Piotr Rutkowski,Pier Francesco Ferrucci,A. Hill,John Wagstaff,Matteo S. Carlino,John B A G Haanen,Michele Maio,Ivan Marquez-Rodas,Grant A. McArthur,Paolo A. Ascierto,Georgina V. Long,Margaret K. Callahan,Michael A. Postow,Michael A. Postow,Kenneth F. Grossmann,Mario Sznol,Brigitte Dréno,Lars Bastholt,Arvin Yang,Linda Rollin,Christine Horak,F. Stephen Hodi,Jedd D. Wolchok,Jedd D. Wolchok +32 more
TL;DR: Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipILimumab alone, and in patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone.
Journal ArticleDOI
Pembrolizumab versus Ipilimumab in Advanced Melanoma
Caroline Robert,Caroline Robert,Caroline Robert,Jacob Schachter,Georgina V. Long,Ana Arance,Jean-Jacques Grob,Laurent Mortier,Laurent Mortier,Adil Daud,Matteo S. Carlino,Catriona M. McNeil,Michal Lotem,James Larkin,Paul Lorigan,Bart Neyns,Christian U. Blank,Omid Hamid,Christine Mateus,Christine Mateus,Ronnie Shapira-Frommer,Ronnie Shapira-Frommer,Michele Kosh,Honghong Zhou,Nageatte Ibrahim,Scot Ebbinghaus,Antoni Ribas +26 more
TL;DR: The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma.
Journal ArticleDOI
Nivolumab in previously untreated melanoma without BRAF mutation.
Caroline Robert,Georgina V. Long,Benjamin Brady,Caroline Dutriaux,Michele Maio,Laurent Mortier,Jessica C. Hassel,Piotr Rutkowski,Catriona M. McNeil,Ewa Kalinka-Warzocha,Kerry J. Savage,Micaela Hernberg,Céleste Lebbé,Julie Charles,Catalin Mihalcioiu,Vanna Chiarion-Sileni,Cornelia Mauch,Francesco Cognetti,Ana Arance,Henrik Schmidt,Dirk Schadendorf,Helen Gogas,Lotta Lundgren-Eriksson,Christine Horak,Brian Sharkey,Ian M. Waxman,Victoria Atkinson,Paolo A. Ascierto,Abstr Act +28 more
TL;DR: Nivolumab was associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation.
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