Journal ArticleDOI
Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial.
F.S. Hodi,Vanna Chiarion-Sileni,Rene Gonzalez,Jean-Jacques Grob,Piotr Rutkowski,Charles Lance Cowey,Christopher D. Lao,Dirk Schadendorf,John Wagstaff,Reinhard Dummer,Pier Francesco Ferrucci,Michael Smylie,Andrew F. Hill,David Hogg,Ivan Marquez-Rodas,Joel Jiang,Jasmine I. Rizzo,James Larkin,Jedd D. Wolchok,Jedd D. Wolchok +19 more
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TLDR
The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of May 10, 2018.Abstract:
Summary Background Previously reported results from the phase 3 CheckMate 067 trial showed a significant improvement in objective responses, progression-free survival, and overall survival with nivolumab plus ipilimumab or nivolumab alone compared with ipilimumab alone in patients with advanced melanoma. The aim of this report is to provide 4-year updated efficacy and safety data from this study. Methods In this phase 3 trial, eligible patients were aged 18 years or older with previously untreated, unresectable, stage III or stage IV melanoma, known BRAFV600 mutation status, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 1:1:1 to receive intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg every 2 weeks plus placebo, or ipilimumab 3 mg/kg every 3 weeks for four doses plus placebo. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by PD-L1 status, BRAF mutation status, and metastasis stage. The patients, investigators, study site staff, and study funder were masked to the study drug administered. The co-primary endpoints were progression-free survival and overall survival. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all patients who received at least one dose of study drug. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of May 10, 2018. This study is registered with ClinicalTrials.gov, number NCT01844505. Findings Between July 3, 2013, and March 31, 2014, 945 patients were enrolled and randomly assigned to nivolumab plus ipilimumab (n=314), nivolumab (n=316), or ipilimumab (n=315). Median follow-up was 46·9 months (IQR 10·9–51·8) in the nivolumab plus ipilimumab group, 36·0 months (10·5–51·4) in the nivolumab group, and 18·6 months (7·6–49·5) in the ipilimumab group. At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (95% CI 38·2–not reached) in the nivolumab plus ipilimumab group, 36·9 months (28·3–not reached) in the nivolumab group, and 19·9 months (16·9–24·6) in the ipilimumab group. The hazard ratio for death for the combination versus ipilimumab was 0·54 (95% CI 0·44–0·67; p Interpretation The results of this analysis at 4 years of follow-up show that a durable, sustained survival benefit can be achieved with first-line nivolumab plus ipilimumab or nivolumab alone in patients with advanced melanoma. Funding Bristol-Myers Squibb.read more
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Top 10 Challenges in Cancer Immunotherapy
Priti S. Hegde,Daniel S. Chen +1 more
TL;DR: Ten key challenges facing cancer immunotherapy are defined, which range from lack of confidence in translating pre-clinical findings to identifying optimal combinations of immune-based therapies for any given patient.
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Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma.
Caroline Robert,Jean J. Grob,Daniil Stroyakovskiy,Boguslawa Karaszewska,Axel Hauschild,Evgeny Levchenko,Vanna Chiarion Sileni,Jacob Schachter,Claus Garbe,Igor Bondarenko,Helen Gogas,Mario Mandalà,John B A G Haanen,C. Lebbé,Andrzej Mackiewicz,Piotr Rutkowski,Paul Nathan,Antoni Ribas,Michael A. Davies,Keith T. Flaherty,Paul Burgess,Monique Tan,Eduard Gasal,Maurizio Voi,Dirk Schadendorf,Georgina V. Long +25 more
TL;DR: First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation.
Journal ArticleDOI
Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study
Caroline Robert,Antoni Ribas,Jacob Schachter,Ana Arance,Jean-Jacques Grob,Laurent Mortier,Adil Daud,Matteo S. Carlino,Catriona M. McNeil,Michal Lotem,James Larkin,Paul Lorigan,Bart Neyns,Christian U. Blank,Teresa M. Petrella,Omid Hamid,Shu Chih Su,Clemens Krepler,Nageatte Ibrahim,Georgina V. Long +19 more
TL;DR: Pembrolizumab improved progression-free survival and overall survival versus ipilimumab in patients with advanced melanoma and is now a standard of care in the first-line setting, however, the optimal duration of anti-PD-1 administration is unknown.
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Challenges in liver cancer and possible treatment approaches.
TL;DR: This review presents some of the problems and current treatment options contributing to the poor outcomes for patients with liver cancer and suggests use of natural compounds and/or nanotechnology may provide patients with better outcomes with lower systemic toxicity and fewer side effects.
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Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study
Georgina V. Long,Reinhard Dummer,Omid Hamid,Thomas F. Gajewski,Christian Caglevic,Stéphane Dalle,Ana Arance,Matteo S. Carlino,Jean-Jacques Grob,Tae Min Kim,Lev V. Demidov,Caroline Robert,James Larkin,James R. Anderson,Janet Maleski,Mark M. Jones,Scott J. Diede,Tara C. Mitchell +17 more
TL;DR: Epacadostat 100 mg twice daily plus pembrolizumab did not improve progression-free survival or overall survival compared with placebo plus pEmbrolizumsab in patients with unresectable or metastatic melanoma.
References
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Journal ArticleDOI
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
Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma
Jedd D. Wolchok,Vanna Chiarion-Sileni,Rene Gonzalez,Piotr Rutkowski,Jean-Jacques Grob,C. Lance Cowey,Christopher D. Lao,John Wagstaff,Dirk Schadendorf,Pier Francesco Ferrucci,Michael Smylie,Reinhard Dummer,Andrew F. Hill,David Hogg,John B. A. G. Haanen,Matteo S. Carlino,Oliver Bechter,Michele Maio,Ivan Marquez-Rodas,Massimo Guidoboni,Grant A. McArthur,Céleste Lebbé,Paolo A. Ascierto,Georgina V. Long,Jonathan Cebon,Jeffrey A. Sosman,Michael A. Postow,Margaret K. Callahan,Dana Walker,Linda Rollin,Rafia Bhore,F. Stephen Hodi,James Larkin,James Larkin +33 more
TL;DR: Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with n ivolumAB alone than with ipil optimumab alone.
Journal ArticleDOI
Time-Dependent ROC Curves for Censored Survival Data and a Diagnostic Marker
TL;DR: This work proposes summarizing the discrimination potential of a marker X, measured at baseline (t = 0), by calculating ROC curves for cumulative disease or death incidence by time t, which is presented as ROC(t), and presents an example where ROC (t) is used to compare a standard and a modified flow cytometry measurement for predicting survival after detection of breast cancer.
Journal ArticleDOI
Immune Checkpoint Blockade in Cancer Therapy
TL;DR: Concluding remarks are made that principles learned during the development of CTLA-4 and PD-1/PD-L1 approaches will likely be used as new immunologic checkpoint blocking antibodies begin clinical investigation, and whether they enhance the efficacy of either approach alone is investigated.
Journal ArticleDOI
Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma
Dirk Schadendorf,F. Stephen Hodi,Caroline Robert,Jeffrey S. Weber,Kim Margolin,Omid Hamid,Debra A. Patt,Tai-Tsang Chen,David Berman,Jedd D. Wolchok +9 more
TL;DR: A plateau in the survival curve was observed, beginning at approximately 3 years, which was independent of prior therapy or ipilimumab dose, and added to the evidence supporting the durability of long-term survival in ipILimumab-treated patients with advanced melanoma.
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