Jason J Luke1, Piotr Rutkowski2, Paola Queirolo3, Michele Del Vecchio4, Jacek Mackiewicz5, Vanna Chiarion-Sileni6, Luis de la Cruz Merino7, Muhammad A Khattak8, Dirk Schadendorf9, Georgina V Long10, Paolo A Ascierto11, Mario Mandala12, Federica De Galitiis13, Andrew Haydon14, Reinhard Dummer15, Jean-Jacques Grob16, Caroline Robert17, Matteo S Carlino18, Peter Mohr19, Andrew Poklepovic20, Vernon K Sondak21, Richard A Scolyer22, John M Kirkwood23, Ke Chen24, Scott J Diede24, Sama Ahsan24, Nageatte Ibrahim24, Alexander M M Eggermont25. 1. UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Electronic address: lukejj@upmc.edu. 2. Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland. 3. Istituto Europeo di Oncologia - IRCCS, Milano; Ospedale San Martino IRCCS, Genova, Italy. 4. Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. 5. Poznan University of Medical Sciences, Poznan, Poland; Greater Poland Cancer Center, Poznan, Poland. 6. Istituto Oncologico Veneto, IOV-IRCCS, Padova, Italy. 7. Clinical Oncology Department, Hospital Universitario Virgen Macarena, Sevilla, Spain; Medicine Department, Universidad de Sevilla, Sevilla, Spain. 8. Fiona Stanley Hospital & Edith Cowan University, Perth, WA, Australia. 9. University Hospital Essen and German Cancer Consortium Partner Site, Essen, Germany. 10. Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Charles Perkins Center, The University of Sydney, Sydney, NSW, Australia; Royal North Shore and Mater Hospitals, Sydney, NSW, Australia. 11. Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy. 12. University of Perugia, Perugia, Italy; Ospedale Papa Giovanni XXIII, Bergamo, Italy. 13. Dermopathic Institute of the Immaculate IDI-IRCCS, Rome, Italy. 14. Alfred Hospital, Monash University, Melbourne, VIC, Australia. 15. University Hospital Zürich, University of Zurich, Skin Cancer Center, Zurich, Switzerland. 16. AP-HM Hospital, Aix-Marseille University, Marseille, France. 17. Institut Gustave Roussy, Villejuif, France; Paris-Saclay University, Villejuif, France. 18. Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Westmead and Blacktown Hospitals, Sydney, NSW, Australia. 19. Elbe Kliniken Buxtehude, Buxtehude, Germany. 20. VCU Massey Cancer Center, Richmond, VA, USA. 21. H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. 22. Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Charles Perkins Center, The University of Sydney, Sydney, NSW, Australia; Royal Prince Alfred Hospital Sydney, NSW, Australia; NSW Health Pathology, Sydney, NSW, Australia. 23. UPMC Hillman Cancer Center, Pittsburgh, PA, USA. 24. Merck & Co, Inc., Kenilworth, NJ, USA. 25. University Medical Center Utrecht, Utrecht, Netherlands; Princess Máxima Center, Utrecht, Netherlands; Comprehensive Cancer Center Munich, Munich, Germany.
Abstract
BACKGROUND: Pembrolizumab prolongs progression-free and overall survival among patients with advanced melanoma and recurrence-free survival in resected stage III disease. KEYNOTE-716 assessed pembrolizumab as adjuvant therapy in patients with completely resected, high-risk, stage II melanoma. We report results from the planned first and second interim analyses for recurrence-free survival. METHODS: In this double-blind, randomised, placebo-controlled phase 3 study, involving 160 academic medical centres and hospitals in 16 countries (Australia, Belgium, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Poland, South Africa, Spain, Switzerland, the UK, and the USA), patients aged 12 years or older with newly diagnosed, completely resected stage IIB or IIC melanoma (TNM stage T3b or T4 with a negative sentinel lymph node biopsy) were recruited. Eligible patients were randomly assigned (1:1), in blocks of four and stratified by T-category (3b, 4a, and 4b) and paediatric status (age 12-17 years vs ≥18 years), using an interactive response technology system to intravenous pembrolizumab 200 mg (2 mg/kg in paediatric patients) or placebo every 3 weeks for 17 cycles or until disease recurrence or unacceptable toxicity. All patients, clinical investigators, and analysts were masked to treatment assignment. The primary endpoint was investigator-assessed recurrence-free survival (defined as time from randomisation to recurrence or death) in the intention-to-treat (ITT) population (ie, all patients randomly assigned to treatment). The primary endpoint was met if recurrence-free survival was significantly improved for pembrolizumab versus placebo at either the first interim analysis (after approximately 128 patients had events) or second interim analysis (after 179 patients had events) under multiplicity control. Safety was assessed in all patients randomly assigned to treatment who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03553836, and is closed to accrual. FINDINGS: Between Sept 23, 2018, and Nov 4, 2020, 1182 patients were screened, of whom 976 were randomly assigned to pembrolizumab (n=487) or placebo (n=489; ITT population). The median age was 61 years (IQR 52-69) and 387 (40%) patients were female and 589 (60%) were male. 874 (90%) of 976 patients were White and 799 (82%) were not Hispanic or Latino. 483 (99%) of 487 patients in the pembrolizumab group and 486 (99%) of 489 in the placebo group received assigned treatment. At the first interim analysis (data cutoff on Dec 4, 2020; median follow-up of 14·4 months [IQR 10·2-18·7] in the pembrolizumab group and 14·3 months [10·1-18·7] in the placebo group), 54 (11%) of 487 patients in the pembrolizumab group and 82 (17%) of 489 in the placebo group had a first recurrence of disease or died (hazard ratio [HR] 0·65 [95% CI 0·46-0·92]; p=0·0066). At the second interim analysis (data cutoff on June 21, 2021; median follow-up of 20·9 months [16·7-25·3] in the pembrolizumab group and 20·9 months [16·6-25·3] in the placebo group), 72 (15%) patients in the pembrolizumab group and 115 (24%) in the placebo group had a first recurrence or died (HR 0·61 [95% CI 0·45-0·82]). Median recurrence-free survival was not reached in either group at either assessment timepoint. At the first interim analysis, grade 3-4 treatment-related adverse events occurred in 78 (16%) of 483 patients in the pembrolizumab groups versus 21 (4%) of 486 in the placebo group. At the first interim analysis, four patients died from an adverse event, all in the placebo group (one each due to pneumonia, COVID-19-related pneumonia, suicide, and recurrent cancer), and at the second interim analysis, one additional patient, who was in the pembrolizumab group, died from an adverse event (COVID-19-related pneumonia). No deaths due to study treatment occurred. INTERPRETATION: Pembrolizumab as adjuvant therapy for up to approximately 1 year for stage IIB or IIC melanoma resulted in a significant reduction in the risk of disease recurrence or death versus placebo, with a manageable safety profile. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA.
BACKGROUND: Pembrolizumab prolongs progression-free and overall survival among patients with advanced melanoma and recurrence-free survival in resected stage III disease. KEYNOTE-716 assessed pembrolizumab as adjuvant therapy in patients with completely resected, high-risk, stage II melanoma. We report results from the planned first and second interim analyses for recurrence-free survival. METHODS: In this double-blind, randomised, placebo-controlled phase 3 study, involving 160 academic medical centres and hospitals in 16 countries (Australia, Belgium, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Poland, South Africa, Spain, Switzerland, the UK, and the USA), patients aged 12 years or older with newly diagnosed, completely resected stage IIB or IIC melanoma (TNM stage T3b or T4 with a negative sentinel lymph node biopsy) were recruited. Eligible patients were randomly assigned (1:1), in blocks of four and stratified by T-category (3b, 4a, and 4b) and paediatric status (age 12-17 years vs ≥18 years), using an interactive response technology system to intravenous pembrolizumab 200 mg (2 mg/kg in paediatric patients) or placebo every 3 weeks for 17 cycles or until disease recurrence or unacceptable toxicity. All patients, clinical investigators, and analysts were masked to treatment assignment. The primary endpoint was investigator-assessed recurrence-free survival (defined as time from randomisation to recurrence or death) in the intention-to-treat (ITT) population (ie, all patients randomly assigned to treatment). The primary endpoint was met if recurrence-free survival was significantly improved for pembrolizumab versus placebo at either the first interim analysis (after approximately 128 patients had events) or second interim analysis (after 179 patients had events) under multiplicity control. Safety was assessed in all patients randomly assigned to treatment who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03553836, and is closed to accrual. FINDINGS: Between Sept 23, 2018, and Nov 4, 2020, 1182 patients were screened, of whom 976 were randomly assigned to pembrolizumab (n=487) or placebo (n=489; ITT population). The median age was 61 years (IQR 52-69) and 387 (40%) patients were female and 589 (60%) were male. 874 (90%) of 976 patients were White and 799 (82%) were not Hispanic or Latino. 483 (99%) of 487 patients in the pembrolizumab group and 486 (99%) of 489 in the placebo group received assigned treatment. At the first interim analysis (data cutoff on Dec 4, 2020; median follow-up of 14·4 months [IQR 10·2-18·7] in the pembrolizumab group and 14·3 months [10·1-18·7] in the placebo group), 54 (11%) of 487 patients in the pembrolizumab group and 82 (17%) of 489 in the placebo group had a first recurrence of disease or died (hazard ratio [HR] 0·65 [95% CI 0·46-0·92]; p=0·0066). At the second interim analysis (data cutoff on June 21, 2021; median follow-up of 20·9 months [16·7-25·3] in the pembrolizumab group and 20·9 months [16·6-25·3] in the placebo group), 72 (15%) patients in the pembrolizumab group and 115 (24%) in the placebo group had a first recurrence or died (HR 0·61 [95% CI 0·45-0·82]). Median recurrence-free survival was not reached in either group at either assessment timepoint. At the first interim analysis, grade 3-4 treatment-related adverse events occurred in 78 (16%) of 483 patients in the pembrolizumab groups versus 21 (4%) of 486 in the placebo group. At the first interim analysis, four patients died from an adverse event, all in the placebo group (one each due to pneumonia, COVID-19-related pneumonia, suicide, and recurrent cancer), and at the second interim analysis, one additional patient, who was in the pembrolizumab group, died from an adverse event (COVID-19-related pneumonia). No deaths due to study treatment occurred. INTERPRETATION: Pembrolizumab as adjuvant therapy for up to approximately 1 year for stage IIB or IIC melanoma resulted in a significant reduction in the risk of disease recurrence or death versus placebo, with a manageable safety profile. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA.
Authors: James E Han; Alicia Lozano; Shaakir Hasan; J Isabelle Choi; Arpit M Chhabra; Henry Tsai; Nasiruddin Mohammed; Samir Patel; Sanford Katz; John H Chang; Charles B Simone; Robert H Press Journal: Int J Part Ther Date: 2022-07-06
Authors: Grace H Attrill; Hansol Lee; Annie T Tasker; Nurudeen A Adegoke; Angela L Ferguson; Ines Pires da Silva; Robyn P M Saw; John F Thompson; Umaimainthan Palendira; Georgina V Long; Peter M Ferguson; Richard A Scolyer; James S Wilmott Journal: Front Immunol Date: 2022-08-08 Impact factor: 8.786