Abdul Rafeh Naqash1,2, Biagio Ricciuti3,4, Dwight H Owen5, Vaia Florou6,7, Yukihiro Toi8, Cynthia Cherry9,10, Maida Hafiz11, Andrea De Giglio3, Mavish Muzaffar10, Sandip H Patel5, Shunichi Sugawara8, Jarred Burkart5, Wungki Park6,12, Rita Chiari3, Jun Sugisaka8, Gregory A Otterson5, Gilberto de Lima Lopes6, Paul R Walker10. 1. Division of Cancer Treatment and Diagnosis, Developmental Therapeutics Clinic, National Cancer Institute, Bldg 31/3A44, 31 Centre Drive, Bethesda, MD, 20892, USA. abdulrafeh.naqash@nih.gov. 2. Division of Hematology/Oncology, Department of Internal Medicine, East Carolina University, Greenville, NC, USA. abdulrafeh.naqash@nih.gov. 3. Thoracic Oncology Unit, Santa Maria Della Misericordia Hospital, University of Perugia, Perugia, Italy. 4. Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. 5. Division of Medical Oncology, Department of Internal Medicine, Ohio State University, Columbus, OH, USA. 6. Division of Oncology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA. 7. Division of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. 8. Department of Pulmonary Medicine, Sendai Kousei Hospital, Hirosemachi, Aoba-Ku, Sendai, Japan. 9. Division of Cancer Treatment and Diagnosis, Developmental Therapeutics Clinic, National Cancer Institute, Bldg 31/3A44, 31 Centre Drive, Bethesda, MD, 20892, USA. 10. Division of Hematology/Oncology, Department of Internal Medicine, East Carolina University, Greenville, NC, USA. 11. Department of Pulmonary Medicine, East Carolina University, Greenville, NC, USA. 12. Memorial Sloan Kettering Cancer Center, New York, USA.
Abstract
BACKGROUND: Immune-related adverse events (irAEs) comprise a distinct spectrum of auto-inflammatory manifestations triggered due to immune checkpoint inhibitors (ICI). Current data on the association of irAEs with outcomes in NSCLC treated with nivolumab are limited. METHODS AND OBJECTIVES: We pooled data from 531 metastatic NSCLC patients from five centers treated with nivolumab after failing platinum-based chemotherapy. The primary objective was to investigate the relationship between irAEs with clinical benefit to nivolumab as well as to elucidate patterns of irAE-related ICI discontinuations and their impact on survival. RESULTS: 33.0% (173/531) of patients treated with nivolumab were noted to have an irAE. Patients with irAEs had a significantly longer median PFS [6.1 vs. 3.1 months, HR 0.68 95% CI (0.55-0.85); p = 0.001] and OS [14.9 vs. 7.4 months, HR 0.66 95% CI (0.52-0.82); p < 0.001)] compared to those without irAEs. In multivariate analysis, the presence of irAEs showed a significantly better PFS [HR 0.69, 95% CI (0.55-0.87); p = 0.002] and a trend for better OS [HR 0.62, 95% CI (0.55-1.03); p = 0.057]. Patients with permanent ICI discontinuation secondary to index irAE had a significantly shorter median PFS [2.3 vs. 6.6 months, HR 1.74 95% CI (1.06-2.80); p = 0.02] and median OS [3.6 vs. 17.6 months; HR 2.61 95% CI (1.61-4.21); p < 0.001] compared to those that did not have permanent ICI discontinuation. CONCLUSIONS: Our pooled exploratory analysis demonstrates improved clinical benefit to nivolumab in NSCLC patients experiencing irAEs. We also observed negative impact of irAE-related treatment discontinuation on survival in this group of patients.
BACKGROUND: Immune-related adverse events (irAEs) comprise a distinct spectrum of auto-inflammatory manifestations triggered due to immune checkpoint inhibitors (ICI). Current data on the association of irAEs with outcomes in NSCLC treated with nivolumab are limited. METHODS AND OBJECTIVES: We pooled data from 531 metastatic NSCLCpatients from five centers treated with nivolumab after failing platinum-based chemotherapy. The primary objective was to investigate the relationship between irAEs with clinical benefit to nivolumab as well as to elucidate patterns of irAE-related ICI discontinuations and their impact on survival. RESULTS: 33.0% (173/531) of patients treated with nivolumab were noted to have an irAE. Patients with irAEs had a significantly longer median PFS [6.1 vs. 3.1 months, HR 0.68 95% CI (0.55-0.85); p = 0.001] and OS [14.9 vs. 7.4 months, HR 0.66 95% CI (0.52-0.82); p < 0.001)] compared to those without irAEs. In multivariate analysis, the presence of irAEs showed a significantly better PFS [HR 0.69, 95% CI (0.55-0.87); p = 0.002] and a trend for better OS [HR 0.62, 95% CI (0.55-1.03); p = 0.057]. Patients with permanent ICI discontinuation secondary to index irAE had a significantly shorter median PFS [2.3 vs. 6.6 months, HR 1.74 95% CI (1.06-2.80); p = 0.02] and median OS [3.6 vs. 17.6 months; HR 2.61 95% CI (1.61-4.21); p < 0.001] compared to those that did not have permanent ICI discontinuation. CONCLUSIONS: Our pooled exploratory analysis demonstrates improved clinical benefit to nivolumab in NSCLCpatients experiencing irAEs. We also observed negative impact of irAE-related treatment discontinuation on survival in this group of patients.
Authors: E E Vokes; N Ready; E Felip; L Horn; M A Burgio; S J Antonia; O Arén Frontera; S Gettinger; E Holgado; D Spigel; D Waterhouse; M Domine; M Garassino; L Q M Chow; G Blumenschein; F Barlesi; B Coudert; J Gainor; O Arrieta; J Brahmer; C Butts; M Steins; W J Geese; A Li; D Healey; L Crinò Journal: Ann Oncol Date: 2018-04-01 Impact factor: 32.976
Authors: Dirk Schadendorf; Jedd D Wolchok; F Stephen Hodi; Vanna Chiarion-Sileni; Rene Gonzalez; Piotr Rutkowski; Jean-Jacques Grob; C Lance Cowey; Christopher D Lao; Jason Chesney; Caroline Robert; Kenneth Grossmann; David McDermott; Dana Walker; Rafia Bhore; James Larkin; Michael A Postow Journal: J Clin Oncol Date: 2017-08-25 Impact factor: 44.544
Authors: Julie R Brahmer; Christina Lacchetti; Bryan J Schneider; Michael B Atkins; Kelly J Brassil; Jeffrey M Caterino; Ian Chau; Marc S Ernstoff; Jennifer M Gardner; Pamela Ginex; Sigrun Hallmeyer; Jennifer Holter Chakrabarty; Natasha B Leighl; Jennifer S Mammen; David F McDermott; Aung Naing; Loretta J Nastoupil; Tanyanika Phillips; Laura D Porter; Igor Puzanov; Cristina A Reichner; Bianca D Santomasso; Carole Seigel; Alexander Spira; Maria E Suarez-Almazor; Yinghong Wang; Jeffrey S Weber; Jedd D Wolchok; John A Thompson Journal: J Clin Oncol Date: 2018-02-14 Impact factor: 44.544
Authors: Deborah B Doroshow; Miguel F Sanmamed; Katherine Hastings; Katerina Politi; David L Rimm; Lieping Chen; Ignacio Melero; Kurt A Schalper; Roy S Herbst Journal: Clin Cancer Res Date: 2019-03-01 Impact factor: 12.531
Authors: Douglas B Johnson; Justin M Balko; Margaret L Compton; Spyridon Chalkias; Joshua Gorham; Yaomin Xu; Mellissa Hicks; Igor Puzanov; Matthew R Alexander; Tyler L Bloomer; Jason R Becker; David A Slosky; Elizabeth J Phillips; Mark A Pilkinton; Laura Craig-Owens; Nina Kola; Gregory Plautz; Daniel S Reshef; Jonathan S Deutsch; Raquel P Deering; Benjamin A Olenchock; Andrew H Lichtman; Dan M Roden; Christine E Seidman; Igor J Koralnik; Jonathan G Seidman; Robert D Hoffman; Janis M Taube; Luis A Diaz; Robert A Anders; Jeffrey A Sosman; Javid J Moslehi Journal: N Engl J Med Date: 2016-11-03 Impact factor: 91.245
Authors: Fiamma Berner; David Bomze; Stefan Diem; Omar Hasan Ali; Mirjam Fässler; Sandra Ring; Rebekka Niederer; Christoph J Ackermann; Petra Baumgaertner; Natalia Pikor; Cristina Gil Cruz; Willem van de Veen; Mübeccel Akdis; Sergey Nikolaev; Heinz Läubli; Alfred Zippelius; Fabienne Hartmann; Hung-Wei Cheng; Gideon Hönger; Mike Recher; Jonathan Goldman; Antonio Cozzio; Martin Früh; Jacques Neefjes; Christoph Driessen; Burkhard Ludewig; Ahmed N Hegazy; Wolfram Jochum; Daniel E Speiser; Lukas Flatz Journal: JAMA Oncol Date: 2019-07-01 Impact factor: 31.777
Authors: Andrew Nashed; Shijun Zhang; Chien-Wei Chiang; M Zitu; Gregory A Otterson; Carolyn J Presley; Kari Kendra; Sandip H Patel; Andrew Johns; Mingjia Li; Madison Grogan; Gabrielle Lopez; Dwight H Owen; Lang Li Journal: Cancer Immunol Immunother Date: 2021-02-24 Impact factor: 6.968
Authors: Abdul Rafeh Naqash; Alba J Kihn-Alarcón; Chara Stavraka; Kathleen Kerrigan; Saman Maleki Vareki; David James Pinato; Sonam Puri Journal: Ann Transl Med Date: 2021-06