Ralf Gutzmer1, Daniil Stroyakovskiy2, Helen Gogas3, Caroline Robert4, Karl Lewis5, Svetlana Protsenko6, Rodrigo P Pereira7, Thomas Eigentler8, Piotr Rutkowski9, Lev Demidov10, Georgy Moiseevich Manikhas11, Yibing Yan12, Kuan-Chieh Huang12, Anne Uyei12, Virginia McNally13, Grant A McArthur14, Paolo A Ascierto15. 1. Haut-Tumor-Zentrum Hannover, Klinik für Dermatologie, Allergologie und Venerologie, Medizinische Hochschule Hannover, Hannover, Germany. Electronic address: gutzmer.ralf@mh-hannover.de. 2. Moscow City Oncology Hospital Number 62 of Moscow Healthcare Department, Moscow, Russia. 3. First Department of Medicine, Laiko General Hospital, National and Kapodistrian University of Athens, Greece. 4. Gustave Roussy and Université Paris-Saclay, Villejuif-Paris, France. 5. University of Colorado Comprehensive Cancer Center, Aurora, CO, USA. 6. Department of Chemotherapy and Innovative Technologies, NN Petrov National Medical Research Center of Oncology, St Petersburg, Russia. 7. Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. 8. University Hospital Tübingen, Tübingen, Germany. 9. Department of Soft Tissue-Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland. 10. NN Blokhin Russian Cancer Research Center, Ministry of Health, Moscow, Russia. 11. St Petersburg Oncology Hospital, St Petersburg, Russia. 12. Genentech, South San Francisco, CA, USA. 13. Roche Products, Welwyn Garden City, UK. 14. Melanoma and Skin Service and Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. 15. Istituto Nazionale Tumori IRCCS Fondazione G Pascale, Naples, Italy.
Abstract
BACKGROUND: IMspire150 aimed to evaluate first-line combination treatment with BRAF plus MEK inhibitors and immune checkpoint therapy in BRAFV600 mutation-positive advanced or metastatic melanoma. METHODS: IMspire150 was a randomised, double-blind, placebo-controlled phase 3 study done at 112 institutes in 20 countries. Patients with unresectable stage IIIc-IV, BRAFV600 mutation-positive melanoma were randomly assigned 1:1 to 28-day cycles of atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) or atezolizumab placebo, vemurafenib, and cobimetinib (control group). In cycle 1, all patients received vemurafenib and cobimetinib only; atezolizumab placebo was added from cycle 2 onward. Randomisation was stratified by lactate dehydrogenase concentration and geographical region. Blinding for atezolizumab was achieved by means of an identical intravenous placebo, and blinding for vemurafenib was achieved by means of a placebo tablet. The primary outcome was investigator-assessed progression-free survival. This trial (ClinicalTrials.gov, NCT02908672) is ongoing but no longer recruiting patients. FINDINGS:Between Jan 13, 2017, and April 26, 2018, 777 patients were screened and 514 were enrolled and randomly assigned to the atezolizumabgroup (n=256) or control group (n=258). At a median follow-up of 18·9 months (IQR 10·4-23·8), progression-free survival as assessed by the study investigator was significantly prolonged with atezolizumab versus control (15·1 vs 10·6 months; hazard ratio [HR] 0·78; 95% CI 0·63-0·97; p=0·025). Common treatment-related adverse events (>30%) in the atezolizumab and control groups were blood creatinine phosphokinase increased (51·3% vs 44·8%), diarrhoea (42·2% vs 46·6%), rash (40·9%, both groups), arthralgia (39·1% vs 28·1%), pyrexia (38·7% vs 26·0%), alanine aminotransferase increased (33·9% vs 22·8%), and lipase increased (32·2% vs 27·4%); 13% of patients in the atezolizumab group and 16% in the control group stopped all treatment because of adverse events. INTERPRETATION: The addition of atezolizumab to targeted therapy with vemurafenib and cobimetinib was safe and tolerable and significantly increased progression-free survival in patients with BRAFV600 mutation-positive advanced melanoma. FUNDING: F Hoffmann-La Roche and Genentech.
RCT Entities:
BACKGROUND: IMspire150 aimed to evaluate first-line combination treatment with BRAF plus MEK inhibitors and immune checkpoint therapy in BRAFV600 mutation-positive advanced or metastatic melanoma. METHODS: IMspire150 was a randomised, double-blind, placebo-controlled phase 3 study done at 112 institutes in 20 countries. Patients with unresectable stage IIIc-IV, BRAFV600 mutation-positive melanoma were randomly assigned 1:1 to 28-day cycles of atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) or atezolizumab placebo, vemurafenib, and cobimetinib (control group). In cycle 1, all patients received vemurafenib and cobimetinib only; atezolizumab placebo was added from cycle 2 onward. Randomisation was stratified by lactate dehydrogenase concentration and geographical region. Blinding for atezolizumab was achieved by means of an identical intravenous placebo, and blinding for vemurafenib was achieved by means of a placebo tablet. The primary outcome was investigator-assessed progression-free survival. This trial (ClinicalTrials.gov, NCT02908672) is ongoing but no longer recruiting patients. FINDINGS: Between Jan 13, 2017, and April 26, 2018, 777 patients were screened and 514 were enrolled and randomly assigned to the atezolizumab group (n=256) or control group (n=258). At a median follow-up of 18·9 months (IQR 10·4-23·8), progression-free survival as assessed by the study investigator was significantly prolonged with atezolizumab versus control (15·1 vs 10·6 months; hazard ratio [HR] 0·78; 95% CI 0·63-0·97; p=0·025). Common treatment-related adverse events (>30%) in the atezolizumab and control groups were blood creatinine phosphokinase increased (51·3% vs 44·8%), diarrhoea (42·2% vs 46·6%), rash (40·9%, both groups), arthralgia (39·1% vs 28·1%), pyrexia (38·7% vs 26·0%), alanine aminotransferase increased (33·9% vs 22·8%), and lipase increased (32·2% vs 27·4%); 13% of patients in the atezolizumab group and 16% in the control group stopped all treatment because of adverse events. INTERPRETATION: The addition of atezolizumab to targeted therapy with vemurafenib and cobimetinib was safe and tolerable and significantly increased progression-free survival in patients with BRAFV600 mutation-positive advanced melanoma. FUNDING: F Hoffmann-La Roche and Genentech.
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