Nivolumab plus Ipilimumab in Advanced Melanoma
Jedd D. Wolchok,Harriet Kluger,Margaret K. Callahan,Michael A. Postow,Naiyer A. Rizvi,Alexander M. Lesokhin,Neil H. Segal,Charlotte E. Ariyan,Ruth-Ann Gordon,Kathleen Reed,Matthew M. Burke,Anne Caldwell,Stephanie Anne Kronenberg,Blessing Agunwamba,Xiaoling Zhang,Israel Lowy,Hector David Inzunza,William Feely,Christine Horak,Quan Hong,Alan J. Korman,Jon M. Wigginton,Ashok Kumar Gupta,Mario Sznol +23 more
TLDR
Conurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy, with rapid and deep tumor regression in a substantial proportion of patients.Abstract:
A total of 53 patients received concurrent therapy with nivolumab and ipilimumab, and 33 received sequenced treatment. The objective-response rate (according to modified World Health Organization criteria) for all patients in the concurrent-regimen group was 40%. Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ≥24 weeks) was observed in 65% of patients. At the maximum doses that were associated with an acceptable level of adverse events (nivolumab at a dose of 1 mg per kilogram of body weight and ipilimumab at a dose of 3 mg per kilogram), 53% of patients had an objective response, all with tumor reduction of 80% or more. Grade 3 or 4 adverse events related to therapy occurred in 53% of patients in the concurrent-regimen group but were qualitatively similar to previous experience with monotherapy and were generally reversible. Among patients in the sequenced-regimen group, 18% had grade 3 or 4 adverse events related to therapy and the objective-response rate was 20%. CONCLUSIONS Concurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy, with rapid and deep tumor regression in a substantial proportion of patients. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; ClinicalTrials.gov number, NCT01024231.)read more
Citations
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Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination
Celine Boutros,Ahmad A. Tarhini,Emilie Routier,Olivier Lambotte,Francois Leroy Ladurie,Franck Carbonnel,Hassane Izzeddine,Aurélien Marabelle,Stéphane Champiat,Armandine Berdelou,Emilie Lanoy,M. Texier,C. Libenciuc,Alexander M.M. Eggermont,Alexander M.M. Eggermont,Jean-Charles Soria,Jean-Charles Soria,Jean-Charles Soria,Christine Mateus,Caroline Robert,Caroline Robert,Caroline Robert +21 more
TL;DR: The authors describe the adverse event profile of checkpoint inhibitors targeting CTLA-4 and PD-1, used both as monotherapies and in combination and aim to provide some general guidelines, based upon the mechanisms of action of these therapies and on the management of these immune-related adverse events.
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A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application.
TL;DR: The molecular mechanisms of the functions of PD-1, in conjunction with the mild, chronic and strain-specific autoimmune phenotypes ofPD-1-deficient mice, suggest that immunoregulation by PD- 1 is rather antigen specific and is mainly cell intrinsic.
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Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial
F. Stephen Hodi,Jason Chesney,Anna C. Pavlick,Caroline Robert,Kenneth F. Grossmann,David F. McDermott,Gerald P. Linette,Nicolas Meyer,Jeffrey K. Giguere,Sanjiv S. Agarwala,Montaser Shaheen,Marc S. Ernstoff,David R. Minor,April K.S. Salama,Matthew H. Taylor,Patrick A. Ott,Christine Horak,Paul Gagnier,Joel Jiang,Jedd D. Wolchok,Michael A. Postow +20 more
TL;DR: 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma and the proportion of patients with BRAFV600 wild-type melanoma achieving an investigator-assessed objective response is reported.
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In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target
Robert T. Manguso,Robert T. Manguso,Hans W. Pope,Hans W. Pope,Margaret D. Zimmer,Margaret D. Zimmer,Flavian D. Brown,Kathleen B. Yates,Kathleen B. Yates,Brian C. Miller,Brian C. Miller,Natalie B. Collins,Natalie B. Collins,Natalie B. Collins,Kevin Bi,Kevin Bi,Martin W. LaFleur,Vikram R. Juneja,Sarah A. Weiss,Jennifer A. Lo,David E. Fisher,Diana Miao,Diana Miao,Eliezer M. Van Allen,Eliezer M. Van Allen,David E. Root,Arlene H. Sharpe,Arlene H. Sharpe,John G. Doench,W. Nicholas Haining,W. Nicholas Haining,W. Nicholas Haining +31 more
TL;DR: Deletion of the protein tyrosine phosphatase PTPN2 in tumour cells increased the efficacy of immunotherapy by enhancing interferon-γ-mediated effects on antigen presentation and growth suppression, and a pooled in vivo genetic screening approach using CRISPR–Cas9 genome editing is used to discover previously undescribed immunotherapy targets.
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Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade.
Pei Ling Chen,Whijae Roh,Alexandre Reuben,Zachary A. Cooper,Christine N. Spencer,Peter A. Prieto,John P. Miller,Roland L. Bassett,Vancheswaran Gopalakrishnan,Khalida Wani,Mariana Petaccia de Macedo,Jacob Austin-Breneman,Hong Jiang,Qing Chang,Sangeetha M. Reddy,Wei Shen Chen,Michael T. Tetzlaff,Russell J. Broaddus,Michael A. Davies,Jeffrey E. Gershenwald,Lauren E. Haydu,Alexander J. Lazar,Sapna Pradyuman Patel,Patrick Hwu,Wen-Jen Hwu,Adi Diab,Isabella C. Glitza,Scott E. Woodman,Luis M Vence,Ignacio I. Wistuba,Rodabe N. Amaria,Lawrence N. Kwong,Victor G. Prieto,R. Eric Davis,Wencai Ma,Willem W. Overwijk,Arlene H. Sharpe,Jianhua Hu,P. Andrew Futreal,Jorge Blando,Padmanee Sharma,James P. Allison,Lynda Chin,Jennifer A. Wargo +43 more
TL;DR: It is demonstrated that adaptive immune signatures in tumor biopsy samples obtained early during the course of treatment are highly predictive of response to immune checkpoint blockade and also demonstrate differential effects on the tumor microenvironment induced by CTLA4 and PD-1 blockade.
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