H Gogas1, B Dréno2, J Larkin3, L Demidov4, D Stroyakovskiy5, Z Eroglu6, P Francesco Ferrucci7, J Pigozzo8, P Rutkowski9, J Mackiewicz10, I Rooney11, A Voulgari12, S Troutman11, B Pitcher13, Y Guo11, Y Yan11, M Castro11, S Mulla13, K Flaherty14, A Arance15. 1. First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece. Electronic address: helgogas@gmail.com. 2. Dermatology Department, CHU Nantes, CIC 1413, CRCINA, University Nantes, Nantes, France. 3. Royal Marsden NHS Foundation Trust, London, United Kingdom. 4. N.N.Blokhin Russian Cancer Research Center, Ministry of Health, Moscow, Russia. 5. Moscow City Oncology Hospital #62 of Moscow Healthcare Department, Moscow Oblast, Russia. 6. Department of Cutaneous Oncology, H.Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. 7. European Institute of Oncology - IRCCS, Milan, Italy. 8. Veneto Institute of Oncology IOV - IRCCS, Padua, Italy. 9. Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland. 10. Department of Medical and Experimental Oncology, Heliodor Święcicki Clinical Hospital, Department of Biology and Environmental Studies, University of Medical Sciences, and Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Center, Poznań, Poland. 11. Genentech, Inc., South San Francisco, CA, USA. 12. Roche Products Ltd, Welwyn Garden City, UK. 13. Hoffmann-La Roche Ltd., Mississauga, ON, Canada. 14. Massachusetts General Hospital Cancer Center, Boston, MA, USA. 15. Department of Medical Oncology and IDIBAPS, Hospital Clínic Barcelona, Barcelona, Spain.
Abstract
BACKGROUND: Emerging data suggest that the combination of MEK inhibitors with immunotherapeutic agents may result in improved efficacy in melanoma. We evaluated whether combining MEK inhibition and immune checkpoint inhibition was more efficacious than immune checkpoint inhibition alone in patients with previously untreated BRAFV600 wild-type advanced melanoma. PATIENTS AND METHODS: IMspire170 was an international, randomized, open-label, phase 3 study.Patients were randomized 1:1 to receive cobimetinib (60 mg, days 1-21) plus anti-programmed death-ligand 1 atezolizumab (840 mg every 2 weeks) in 28-day cycles or anti-programmed death-1 pembrolizumab (200 mg every 3 weeks) alone until loss of clinical benefit, unacceptable toxicity, or consent withdrawal.The primary outcome was progression-free survival (PFS), assessed by an independent review committee in the intention-to-treat population. RESULTS:Between December 11, 2017, and January 29, 2019, 446 patients were randomized to receive cobimetinib plus atezolizumab (n = 222) or pembrolizumab (n = 224).Median follow-up was 7.1 months (interquartile range [IQR] 4.8-9.9) for cobimetinib plus atezolizumab and 7.2 months (IQR 4.9-10.1) for pembrolizumab.Median PFS was 5.5 months (95% CI 3.8-7.2) with cobimetinib plus atezolizumab versus 5.7 months (95% CI 3.7-9.6) with pembrolizumab (stratified hazard ratio 1.15 [95% CI 0.88-1.50]; P = 0.30).Hazard ratios for PFS were consistent across prespecified subgroups.In exploratory biomarker analyses, higher tumor mutational burden was associated with improved clinical outcomes in both treatment arms.The most common grade 3-5 adverse events were increased blood creatine phosphokinase (10.0% with cobimetinib plus atezolizumab vs 0.9% with pembrolizumab), diarrhea (7.7% vs 1.9%), rash (6.8% vs 0.9%), hypertension (6.4% vs 3.7%), and dermatitis acneiform (5.0% vs 0).Serious adverse events occurred in 44.1% of patients with cobimetinib plus atezolizumab and 20.8% with pembrolizumab. CONCLUSION:Cobimetinib plus atezolizumab did not improve PFS compared with pembrolizumab monotherapy in patients with BRAFV600 wild-type advanced melanoma.
RCT Entities:
BACKGROUND: Emerging data suggest that the combination of MEK inhibitors with immunotherapeutic agents may result in improved efficacy in melanoma. We evaluated whether combining MEK inhibition and immune checkpoint inhibition was more efficacious than immune checkpoint inhibition alone in patients with previously untreated BRAFV600 wild-type advanced melanoma. PATIENTS AND METHODS: IMspire170 was an international, randomized, open-label, phase 3 study.Patients were randomized 1:1 to receive cobimetinib (60 mg, days 1-21) plus anti-programmed death-ligand 1 atezolizumab (840 mg every 2 weeks) in 28-day cycles or anti-programmed death-1 pembrolizumab (200 mg every 3 weeks) alone until loss of clinical benefit, unacceptable toxicity, or consent withdrawal.The primary outcome was progression-free survival (PFS), assessed by an independent review committee in the intention-to-treat population. RESULTS: Between December 11, 2017, and January 29, 2019, 446 patients were randomized to receive cobimetinib plus atezolizumab (n = 222) or pembrolizumab (n = 224).Median follow-up was 7.1 months (interquartile range [IQR] 4.8-9.9) for cobimetinib plus atezolizumab and 7.2 months (IQR 4.9-10.1) for pembrolizumab.Median PFS was 5.5 months (95% CI 3.8-7.2) with cobimetinib plus atezolizumab versus 5.7 months (95% CI 3.7-9.6) with pembrolizumab (stratified hazard ratio 1.15 [95% CI 0.88-1.50]; P = 0.30).Hazard ratios for PFS were consistent across prespecified subgroups.In exploratory biomarker analyses, higher tumor mutational burden was associated with improved clinical outcomes in both treatment arms.The most common grade 3-5 adverse events were increased blood creatine phosphokinase (10.0% with cobimetinib plus atezolizumab vs 0.9% with pembrolizumab), diarrhea (7.7% vs 1.9%), rash (6.8% vs 0.9%), hypertension (6.4% vs 3.7%), and dermatitis acneiform (5.0% vs 0).Serious adverse events occurred in 44.1% of patients with cobimetinib plus atezolizumab and 20.8% with pembrolizumab. CONCLUSION:Cobimetinib plus atezolizumab did not improve PFS compared with pembrolizumab monotherapy in patients with BRAFV600 wild-type advanced melanoma.
Authors: Jeffrey Zhao; Carlos Galvez; Kathryn Eby Beckermann; Douglas B Johnson; Jeffrey A Sosman Journal: Expert Rev Precis Med Drug Dev Date: 2021-08-11
Authors: Li Zhou; Xuan Wang; Zhihong Chi; Xinan Sheng; Yan Kong; Lili Mao; Bin Lian; Bixia Tang; Xieqiao Yan; Xue Bai; Siming Li; Jun Guo; Chuanliang Cui; Lu Si Journal: Front Immunol Date: 2021-07-05 Impact factor: 7.561