Naiyer A Rizvi1, Julien Mazières2, David Planchard3, Thomas E Stinchcombe4, Grace K Dy5, Scott J Antonia6, Leora Horn7, Hervé Lena8, Elisa Minenza9, Bertrand Mennecier10, Gregory A Otterson11, Luis T Campos12, David R Gandara13, Benjamin P Levy14, Suresh G Nair15, Gérard Zalcman16, Jürgen Wolf17, Pierre-Jean Souquet18, Editta Baldini19, Federico Cappuzzo20, Christos Chouaid21, Afshin Dowlati22, Rachel Sanborn23, Ariel Lopez-Chavez24, Christian Grohe25, Rudolf M Huber26, Christopher T Harbison27, Christine Baudelet27, Brian J Lestini27, Suresh S Ramalingam28. 1. Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Electronic address: nar2144@cumc.columbia.edu. 2. Hôpital Larrey, Centre Hospitalier Universitaire de Toulouse, Toulouse, France. 3. L'Institut Gustave Roussy, Villejuif, France. 4. University of North Carolina School of Medicine, Chapel Hill, NC, USA. 5. Roswell Park Cancer Institute, Buffalo, NY, USA. 6. H Lee Moffitt Cancer Center, Tampa, FL, USA. 7. Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. 8. Centre Hospitalier Universitaire de Rennes, Rennes, France. 9. Ospedale S Maria, Terni, Italy. 10. Nouvel Hôpital Civil Chru de Strasbourg, Strasbourg, France. 11. The Ohio State University Medical Center, Columbus, OH, USA. 12. Oncology Consultants, PA, Houston, TX, USA. 13. University of California Davis Cancer Center, Sacramento, CA, USA. 14. Mount Sinai Beth Israel Comprehensive Cancer Center, New York, NY, USA. 15. Lehigh Valley Hospital, Allentown, PA, USA. 16. Centre Hospitalier Universitaire de Caen, Caen, France. 17. Universitaetsklinik Koeln, Koeln, Germany. 18. Hospices Civils de Lyon, Ch Lyon Sud, Pierre Benite, France. 19. Ospedale Campo Di Marte, Lucca, Italy. 20. Istituto Toscano Tumori, Livorno, Italy. 21. Chi De Creteil, Creteil, France. 22. University Hospitals of Cleveland, Cleveland, OH, USA. 23. Providence Portland Medical Center, Portland, OR, USA. 24. University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL, USA. 25. Evangelische Lungenklinik Berlin, Berlin, Germany. 26. Klinikum der Universitaet Muenchen-Innenstadt, German Center for Lung Research, Munich, Germany. 27. Bristol-Myers Squibb, Princeton, NJ, USA. 28. Winship Cancer Institute, Emory University, Atlanta, GA, USA.
Abstract
BACKGROUND: Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. METHODS: We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov, number NCT01721759. FINDINGS: Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7-22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2-4·8), and median duration of response was not reached (95% CI 8·31-not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7-10·9). 20 (17%) of 117 patients reported grade 3-4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. INTERPRETATION: Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. FUNDING: Bristol-Myers Squibb.
BACKGROUND:Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. METHODS: We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov, number NCT01721759. FINDINGS: Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7-22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2-4·8), and median duration of response was not reached (95% CI 8·31-not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7-10·9). 20 (17%) of 117 patients reported grade 3-4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. INTERPRETATION:Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. FUNDING: Bristol-Myers Squibb.
Authors: Roy S Herbst; Jean-Charles Soria; Marcin Kowanetz; Gregg D Fine; Omid Hamid; Michael S Gordon; Jeffery A Sosman; David F McDermott; John D Powderly; Scott N Gettinger; Holbrook E K Kohrt; Leora Horn; Donald P Lawrence; Sandra Rost; Maya Leabman; Yuanyuan Xiao; Ahmad Mokatrin; Hartmut Koeppen; Priti S Hegde; Ira Mellman; Daniel S Chen; F Stephen Hodi Journal: Nature Date: 2014-11-27 Impact factor: 49.962
Authors: Julie R Brahmer; Charles G Drake; Ira Wollner; John D Powderly; Joel Picus; William H Sharfman; Elizabeth Stankevich; Alice Pons; Theresa M Salay; Tracee L McMiller; Marta M Gilson; Changyu Wang; Mark Selby; Janis M Taube; Robert Anders; Lieping Chen; Alan J Korman; Drew M Pardoll; Israel Lowy; Suzanne L Topalian Journal: J Clin Oncol Date: 2010-06-01 Impact factor: 44.544
Authors: Suzanne L Topalian; F Stephen Hodi; Julie R Brahmer; Scott N Gettinger; David C Smith; David F McDermott; John D Powderly; Richard D Carvajal; Jeffrey A Sosman; Michael B Atkins; Philip D Leming; David R Spigel; Scott J Antonia; Leora Horn; Charles G Drake; Drew M Pardoll; Lieping Chen; William H Sharfman; Robert A Anders; Janis M Taube; Tracee L McMiller; Haiying Xu; Alan J Korman; Maria Jure-Kunkel; Shruti Agrawal; Daniel McDonald; Georgia D Kollia; Ashok Gupta; Jon M Wigginton; Mario Sznol Journal: N Engl J Med Date: 2012-06-02 Impact factor: 91.245
Authors: Duarte Domingues; Alice Turner; Maria Dília Silva; Dânia Sofia Marques; Juan Carlos Mellidez; Luciano Wannesson; Giannis Mountzios; Ramon Andrade de Mello Journal: Immunotherapy Date: 2014 Impact factor: 4.196
Authors: Jedd D Wolchok; Axel Hoos; Steven O'Day; Jeffrey S Weber; Omid Hamid; Celeste Lebbé; Michele Maio; Michael Binder; Oliver Bohnsack; Geoffrey Nichol; Rachel Humphrey; F Stephen Hodi Journal: Clin Cancer Res Date: 2009-11-24 Impact factor: 12.531
Authors: Paul C Tumeh; Christina L Harview; Jennifer H Yearley; I Peter Shintaku; Emma J M Taylor; Lidia Robert; Bartosz Chmielowski; Marko Spasic; Gina Henry; Voicu Ciobanu; Alisha N West; Manuel Carmona; Christine Kivork; Elizabeth Seja; Grace Cherry; Antonio J Gutierrez; Tristan R Grogan; Christine Mateus; Gorana Tomasic; John A Glaspy; Ryan O Emerson; Harlan Robins; Robert H Pierce; David A Elashoff; Caroline Robert; Antoni Ribas Journal: Nature Date: 2014-11-27 Impact factor: 49.962
Authors: Shona Hendry; Roberto Salgado; Thomas Gevaert; Prudence A Russell; Tom John; Bibhusal Thapa; Michael Christie; Koen van de Vijver; M V Estrada; Paula I Gonzalez-Ericsson; Melinda Sanders; Benjamin Solomon; Cinzia Solinas; Gert G G M Van den Eynden; Yves Allory; Matthias Preusser; Johannes Hainfellner; Giancarlo Pruneri; Andrea Vingiani; Sandra Demaria; Fraser Symmans; Paolo Nuciforo; Laura Comerma; E A Thompson; Sunil Lakhani; Seong-Rim Kim; Stuart Schnitt; Cecile Colpaert; Christos Sotiriou; Stefan J Scherer; Michail Ignatiadis; Sunil Badve; Robert H Pierce; Giuseppe Viale; Nicolas Sirtaine; Frederique Penault-Llorca; Tomohagu Sugie; Susan Fineberg; Soonmyung Paik; Ashok Srinivasan; Andrea Richardson; Yihong Wang; Ewa Chmielik; Jane Brock; Douglas B Johnson; Justin Balko; Stephan Wienert; Veerle Bossuyt; Stefan Michiels; Nils Ternes; Nicole Burchardi; Stephen J Luen; Peter Savas; Frederick Klauschen; Peter H Watson; Brad H Nelson; Carmen Criscitiello; Sandra O'Toole; Denis Larsimont; Roland de Wind; Giuseppe Curigliano; Fabrice André; Magali Lacroix-Triki; Mark van de Vijver; Federico Rojo; Giuseppe Floris; Shahinaz Bedri; Joseph Sparano; David Rimm; Torsten Nielsen; Zuzana Kos; Stephen Hewitt; Baljit Singh; Gelareh Farshid; Sibylle Loibl; Kimberly H Allison; Nadine Tung; Sylvia Adams; Karen Willard-Gallo; Hugo M Horlings; Leena Gandhi; Andre Moreira; Fred Hirsch; Maria V Dieci; Maria Urbanowicz; Iva Brcic; Konstanty Korski; Fabien Gaire; Hartmut Koeppen; Amy Lo; Jennifer Giltnane; Marlon C Rebelatto; Keith E Steele; Jiping Zha; Kenneth Emancipator; Jonathan W Juco; Carsten Denkert; Jorge Reis-Filho; Sherene Loi; Stephen B Fox Journal: Adv Anat Pathol Date: 2017-11 Impact factor: 3.875
Authors: Farhad Fakhrejahani; Yusuke Tomita; Agnes Maj-Hes; Jane B Trepel; Maria De Santis; Andrea B Apolo Journal: Curr Opin Urol Date: 2015-11 Impact factor: 2.309
Authors: Kimberly Loo; Katy K Tsai; Kelly Mahuron; Jacqueline Liu; Mariela L Pauli; Priscila M Sandoval; Adi Nosrati; James Lee; Lawrence Chen; Jimmy Hwang; Lauren S Levine; Matthew F Krummel; Alain P Algazi; Miguel Pampaloni; Michael D Alvarado; Michael D Rosenblum; Adil I Daud Journal: JCI Insight Date: 2017-07-20
Authors: Jaydira Del Rivero; Lisa M Cordes; Joanna Klubo-Gwiezdzinska; Ravi A Madan; Lynnette K Nieman; James L Gulley Journal: Oncologist Date: 2019-10-10
Authors: Howard Y Li; Maria McSharry; Deandra Walker; Amber Johnson; Jeff Kwak; Bonnie Bullock; Alexander Neuwelt; Joanna M Poczobutt; Trisha R Sippel; Robert L Keith; Mary C M Weiser-Evans; Eric Clambey; Raphael A Nemenoff Journal: Oncoimmunology Date: 2018-02-13 Impact factor: 8.110
Authors: Patrick H Lizotte; Elena V Ivanova; Mark M Awad; Robert E Jones; Lauren Keogh; Hongye Liu; Ruben Dries; Christina Almonte; Grit S Herter-Sprie; Abigail Santos; Nora B Feeney; Cloud P Paweletz; Meghana M Kulkarni; Adam J Bass; Anil K Rustgi; Guo-Cheng Yuan; Donald W Kufe; Pasi A Jänne; Peter S Hammerman; Lynette M Sholl; F Stephen Hodi; William G Richards; Raphael Bueno; Jessie M English; Mark A Bittinger; Kwok-Kin Wong Journal: JCI Insight Date: 2016-09-08
Authors: Adil I Daud; Kimberly Loo; Mariela L Pauli; Robert Sanchez-Rodriguez; Priscila Munoz Sandoval; Keyon Taravati; Katy Tsai; Adi Nosrati; Lorenzo Nardo; Michael D Alvarado; Alain P Algazi; Miguel H Pampaloni; Iryna V Lobach; Jimmy Hwang; Robert H Pierce; Iris K Gratz; Matthew F Krummel; Michael D Rosenblum Journal: J Clin Invest Date: 2016-08-15 Impact factor: 14.808