R L Ferris1, R Haddad2, C Even3, M Tahara4, M Dvorkin5, T E Ciuleanu6, P M Clement7, R Mesia8, S Kutukova9, L Zholudeva10, A Daste11, J Caballero-Daroqui12, B Keam13, I Vynnychenko14, C Lafond15, J Shetty16, H Mann17, J Fan16, S Wildsmith17, N Morsli17, J Fayette18, L Licitra19. 1. Department of Otolaryngology, UPMC Hillman Cancer Center, Pittsburgh, USA. Electronic address: ferrrl@UPMC.EDU. 2. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, USA. 3. Head and Neck Department, Gustave Roussy, Villejuif, France. 4. National Cancer Center Hospital East, Kashiwa, Japan. 5. Omsk Regional Oncology Dispensary, Omsk, Omskaya, Russian Federation. 6. Ion Chiricuta Institute of Oncology, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania. 7. Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium. 8. Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain. 9. Chemotherapy Department, SPb SBIH City Clinical Oncology Dispensary, Saint Petersburg, Russian Federation. 10. Regional Transcarpathian Oncological Dispensary, Uzhgorod, Ukraine. 11. Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France. 12. Department of Oncology, Hospital Universitario La Fe, Valencia, Spain. 13. Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea. 14. Sumy State University, Sumy Regional Oncology Center, Sumy, Ukraine. 15. Department of Oncology, Clinique Victor Hugo/Centre Jean Bernard, Le Mans, France. 16. Late-stage ImmunoOncology, AstraZeneca, Gaithersburg, USA. 17. Research and Development Oncology, AstraZeneca, Cambridge, UK. 18. Department of Medical Oncology, Centre Léon Bérard, Lyon, France. 19. Head & Neck Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori Milano, University of Milan, Milan, Italy. Electronic address: lisa.licitra@istitutotumori.mi.it.
Abstract
BACKGROUND: Targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis has demonstrated clinical benefit in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Combining immunotherapies targeting PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) has shown evidence of additive activity in several tumor types. This phase III study evaluated the efficacy of durvalumab (an anti-PD-L1 monoclonal antibody) or durvalumab plus tremelimumab (an anti-CTLA-4 monoclonal antibody) versus standard of care (SoC) in R/M HNSCC patients. PATIENTS AND METHODS: Patients were randomly assigned to receive 1 : 1 : 1 durvalumab (10 mg/kg every 2 weeks [q2w]), durvalumab plus tremelimumab (durvalumab 20 mg/kg q4w plus tremelimumab 1 mg/kg q4w × 4, then durvalumab 10 mg/kg q2w), or SoC (cetuximab, a taxane, methotrexate, or a fluoropyrimidine). The primary end points were overall survival (OS) for durvalumab versus SoC, and OS for durvalumab plus tremelimumab versus SoC. Secondary end points included progression-free survival (PFS), objective response rate, and duration of response. RESULTS: Patients were randomly assigned to receive durvalumab (n = 240), durvalumab plus tremelimumab (n = 247), or SoC (n = 249). No statistically significant improvements in OS were observed for durvalumab versus SoC [hazard ratio (HR): 0.88; 95% confidence interval (CI): 0.72-1.08; P = 0.20] or durvalumab plus tremelimumab versus SoC (HR: 1.04; 95% CI: 0.85-1.26; P = 0.76). The 12-month survival rates (95% CI) were 37.0% (30.9-43.1), 30.4% (24.7-36.3), and 30.5% (24.7-36.4) for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. Treatment-related adverse events (trAEs) were consistent with previous reports. The most common trAEs (any grade) were hypothyroidism for durvalumab and durvalumab plus tremelimumab (11.4% and 12.2%, respectively), and anemia (17.5%) for SoC. Grade ≥3 trAE rates were 10.1%, 16.3%, and 24.2% for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. CONCLUSION: There were no statistically significant differences in OS for durvalumab or durvalumab plus tremelimumab versus SoC. However, higher survival rates at 12 to 24 months and response rates demonstrate clinical activity for durvalumab. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02369874.
BACKGROUND: Targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis has demonstrated clinical benefit in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Combining immunotherapies targeting PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) has shown evidence of additive activity in several tumor types. This phase III study evaluated the efficacy of durvalumab (an anti-PD-L1 monoclonal antibody) or durvalumab plus tremelimumab (an anti-CTLA-4 monoclonal antibody) versus standard of care (SoC) in R/M HNSCC patients. PATIENTS AND METHODS: Patients were randomly assigned to receive 1 : 1 : 1 durvalumab (10 mg/kg every 2 weeks [q2w]), durvalumab plus tremelimumab (durvalumab 20 mg/kg q4w plus tremelimumab 1 mg/kg q4w × 4, then durvalumab 10 mg/kg q2w), or SoC (cetuximab, a taxane, methotrexate, or a fluoropyrimidine). The primary end points were overall survival (OS) for durvalumab versus SoC, and OS for durvalumab plus tremelimumab versus SoC. Secondary end points included progression-free survival (PFS), objective response rate, and duration of response. RESULTS: Patients were randomly assigned to receive durvalumab (n = 240), durvalumab plus tremelimumab (n = 247), or SoC (n = 249). No statistically significant improvements in OS were observed for durvalumab versus SoC [hazard ratio (HR): 0.88; 95% confidence interval (CI): 0.72-1.08; P = 0.20] or durvalumab plus tremelimumab versus SoC (HR: 1.04; 95% CI: 0.85-1.26; P = 0.76). The 12-month survival rates (95% CI) were 37.0% (30.9-43.1), 30.4% (24.7-36.3), and 30.5% (24.7-36.4) for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. Treatment-related adverse events (trAEs) were consistent with previous reports. The most common trAEs (any grade) were hypothyroidism for durvalumab and durvalumab plus tremelimumab (11.4% and 12.2%, respectively), and anemia (17.5%) for SoC. Grade ≥3 trAE rates were 10.1%, 16.3%, and 24.2% for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. CONCLUSION: There were no statistically significant differences in OS for durvalumab or durvalumab plus tremelimumab versus SoC. However, higher survival rates at 12 to 24 months and response rates demonstrate clinical activity for durvalumab. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02369874.
Authors: Chen Huang; Lijun Chen; Sara R Savage; Rodrigo Vargas Eguez; Yongchao Dou; Yize Li; Felipe da Veiga Leprevost; Eric J Jaehnig; Jonathan T Lei; Bo Wen; Michael Schnaubelt; Karsten Krug; Xiaoyu Song; Marcin Cieślik; Hui-Yin Chang; Matthew A Wyczalkowski; Kai Li; Antonio Colaprico; Qing Kay Li; David J Clark; Yingwei Hu; Liwei Cao; Jianbo Pan; Yuefan Wang; Kyung-Cho Cho; Zhiao Shi; Yuxing Liao; Wen Jiang; Meenakshi Anurag; Jiayi Ji; Seungyeul Yoo; Daniel Cui Zhou; Wen-Wei Liang; Michael Wendl; Pankaj Vats; Steven A Carr; D R Mani; Zhen Zhang; Jiang Qian; Xi S Chen; Alexander R Pico; Pei Wang; Arul M Chinnaiyan; Karen A Ketchum; Christopher R Kinsinger; Ana I Robles; Eunkyung An; Tara Hiltke; Mehdi Mesri; Mathangi Thiagarajan; Alissa M Weaver; Andrew G Sikora; Jan Lubiński; Małgorzata Wierzbicka; Maciej Wiznerowicz; Shankha Satpathy; Michael A Gillette; George Miles; Matthew J Ellis; Gilbert S Omenn; Henry Rodriguez; Emily S Boja; Saravana M Dhanasekaran; Li Ding; Alexey I Nesvizhskii; Adel K El-Naggar; Daniel W Chan; Hui Zhang; Bing Zhang Journal: Cancer Cell Date: 2021-01-07 Impact factor: 31.743
Authors: Robert L Ferris; William C Spanos; Rom Leidner; Anthony Gonçalves; Uwe M Martens; Chrisann Kyi; William Sharfman; Christine H Chung; Lot A Devriese; Helene Gauthier; Simon I Chiosea; Lazar Vujanovic; Janis M Taube; Julie E Stein; Jun Li; Bin Li; Tian Chen; Adam Barrows; Suzanne L Topalian Journal: J Immunother Cancer Date: 2021-06 Impact factor: 12.469