Clinical Trial

. 2022 Apr 30;399(10336):1718-1729.

doi: 10.1016/S0140-6736(22)00562-1. Epub 2022 Apr 1.

Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial

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; KEYNOTE-716 Investigators

Affiliations

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.

PMID: 35367007
DOI: 10.1016/S0140-6736(22)00562-1

Clinical Trial

Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial

Jason J Luke et al. Lancet. 2022.

. 2022 Apr 30;399(10336):1718-1729.

doi: 10.1016/S0140-6736(22)00562-1. Epub 2022 Apr 1.

Authors

Affiliations

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.

PMID: 35367007
DOI: 10.1016/S0140-6736(22)00562-1

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.

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Conflict of interest statement

Declaration of interests JJL reports research funding to their institution for clinical studies from Merck Sharp & Dohme (MSD), AbbVie, Agios, Array, Astellas, AstraZeneca, Bristol-Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, and Xencor; membership on data safety monitoring boards for AbbVie and Immutep; membership on scientific advisory boards with no stock ownership or stock options for 7 Hills, Bright Peak, Fstar, Inzen, RefleXion, Xilioo, and with stock for Actym, Alphamab Oncology, Arch Oncology, Kanaph, Mavu, NeoTx, Onc.AI, Pyxis, and Tempest; compensation for consultancy with AbbVie, Alnylam, Bayer, Bristol-Myers Squibb, CheckMate, Codiak, Crown, Cstone, Day One, Eisai, EMD Serono, Flame, Genentech, Gilead, HotSpot, Kadmon, KQS, Janssen Ikena, Immunocore, Incyte, Macrogenics, Merck, Mersana, Nektar, Novartis, Pfizer, Regeneron, Ribon, Rublus, Silicon, Synlogic, Synthekine, TRex, Werewold, and Xencor; and a provisional patent for cancer immunotherapy (PCT/US18/36052: Microbiome Biomarkers for anti-PD-1/PD-L1 responsiveness: diagnostic, prognostic and therapeutic uses thereof). PR reports research funding to their institution from MSD and Pfizer and honoraria for lectures and advisory board participation from MSD, Bristol Myers Squibb, Novartis, Pierre Fabre, Sanofi, Merck, Philogen, and Blueprint Medicines. PQ reports research finding to their institution for clinical studies from MSD, and honoraria as consultant or advisor role from Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Sun Pharma, Sanofi-Regeneron, and Roche. MDV reports research finding to their institution for clinical studies from MSD and honoraria as consultant or advisor for Novartis, Bristol Myers Squibb, MSD, and Pierre Fabre. JM reports research funding to their institution for clinical studies from MSD; honoraria from Bristol Myers Squibb, MSD, Roche, Novartis, and Pierre Fabre; and consultant or advisor roles for Bristol Myers Squibb and MSD. VC-S reports research funding to their institution for clinical studies from MSD; reimbursement for travel and accommodation for medical congress from Bristol Myers Squibb and Pierre Fabre; and honoraria for advisory board participation from Novartis and Pierre Fabre. LdlCM reports research funding to their institution for clinical studies from Celgene, MSD, and Roche; reimbursement for travel expenses from Roche; and consultant or advisor roles for Bristol Myers Squibb, MSD, Novartis, and Roche. MAK reports research funding to their institution for clinical studies from MSD and MSD Australia; fees as speaker from Bristol Myers Squibb, Novartis, Merck Serono, and MSD Australia; and reimbursement for travel from Bristol Myers Squibb and Roche. DS reports research funding to their institution for clinical studies from Bristol Myers Squibb, MSD, Novartis, Amgen, and Array; grants paid to their institution from Bristol Myers Squibb, MSD, Novartis, Merck-EMD, Philogen, Pfizer, Array, InflarX, OncoSec, Replimune, Neracare, Nektar, SunPharma, Sandoz, and UltimoVacs; reimbursement for travel from Bristol Myers Squibb, Merck, Novartis, Merck-EMD, Pfizer, Pierre Fabre, InflarX, NeraCare, and Nektar; and non-financial support from Bristol Myers Squibb, MSD, Novartis, Merck-EMD, Pierre-Fabre, InFlarX, Neracare, Nektar, SunPharma, and Sandoz. GVL reports research funding to their institution for clinical studies from MSD and fees as a consultant or advisor from Aduro Biotech, Amgen, Arrary Biopharma, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG, Highlight Therapeutics S L, MSD, Novartis Pharma AG, OncoSec, Pierre Fabre, QBiotics Group, Regeneron Pharmaceuticals, SkylineDX BV, and Specialised Therapeutics Australia. PAA reports research funding to their institution for clinical studies from MSD, Bristol Myers Squibb, Roche-Genentech, Sanofi, and Pfizer and fees as a consultant or advisor from Bristol Myers Squibb, Roche-Genentech, MSD, Novartis, Merck Serono, Pierre Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Nektar, Italfarmaco, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, and ITeos. MM reports research funding to their institution for clinical studies from MSD and personal fees from MSD, Pierre Fabre, Novartis, Bristol Myers Squibb, and Sanofi. FDG and J-JG report research funding to their institutions for clinical studies from MSD. AH reports research funding to their institution for clinical studies from MSD and fees for advisory board membership from Novartis, Bristol Myers Squibb, and MSD. RD reports research funding to their institution for clinical studies from MSD and consulting or advisory roles with MSD, Novartis, Roche, Bristol Myers Squibb, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, and touchIME. CR reports research funding to their institution for clinical studies from MSD and fees as a consultant or advisor for Amgen, AstraZeneca, Bristol Myers Squibb, MSD, Novartis, Pfizer, Pierre Fabre, Roche, and Sanofi. MSC reports research funding to their institution for clinical studies for MSD and honoraria for consulting from Bristol Myers Squibb, Eisia, IDEAYA Biosciences, Merck Serono, MSD, Novartis, Oncosec, Pierre Fabre, Qbiotics, Roche, and Sanofi. PM reports research funding to their institution for clinical studies from MSD, Amgen, Johnson & Johnson, Merck Serono, Novartis, Pfizer, Sanofi, and Sun Pharma; honoraria from Amgen, Bristol Myers Squibb, Merck, MSD, Novartis, Pierre Fabre, Roche/Genentech, and Sanofi; consulting or advisory roles for Amgen, Bristol Myers Squibb, Merck, MSD, Novartis, Pierre Fabre, Roche, and Sanofi; fees for speakers bureau from Amgen, Bristol Myers Squibb, MSD, Novartis, Roche, and Sanofi; and reimbursement for travel, accommodation, and expenses from Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche, Sanofi, and Sun Pharma. AP reports research funding to their institution for clinical studies from MSD; fees for consulting or advisory roles from Novartis; and fees for speakers bureau from Bristol Myers Squibb. VKS reports research funding to their institution for clinical studies from MSD and Neogene Therapeutic and fees for participation in independent data safety monitoring committees and participation in advisory boards from Bristol Myers Squibb, Eisai, Novartis, Merck, Regeneron, and Replimune. RAS reports research funding to their institution from MSD and fees for professional services from F Hoffmann-La Roche, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, MSD, NeraCare, AMGEN, Bristol Myers Squibb, Myriad Genetics, and GSK. RAS is supported by an Australian National Health and Medical Research Council Practitioner Fellowship (APP1141295). JMK reports research funding to their institution from MSD, Amgen, Bristol Myers Squibb, Checkmate Pharmaceuticals, Immunocore, Iovance Biotherapies, Novartis Pharmaceuticals, Castle Biosciences, and Merck; personal fees from Amgen, Ankyra Therapeutics, Axio Research/Instil Bio, Bristol Myers Squibb, Checkmate Pharmaceuticals, DermTech, Elsevier, Harbour BioMed, Immunocore, Iovance Biotherapies, Istari Oncology, Millenium Pharm/Takeda Pharm, Natera, Novartis Pharmaceutical, OncoCyte Corporation, OncoSec Medical, Pfizer, Scopus BioPharma, Merck, Becker Pharmaceutical Consulting, Fenix Group International, Intellisphere LLC/Cancer Network, IQVIA, Replimune, and SR One Capital Managment. KC, SJD, SA, and NI are employees of and own stock in MSD. AMME reports research funding to their institution for clinical studies from MSD; fees for advisory board membership for Merck, Agenus, Biocad, BioInvent, BioNTech, Bristol Myers Squibb, CatalYm, Ellipses, Galecto, GSK, IO Biotech, ISA Pharmaceuticals, Merck, MSD, Nektar, Novartis, Pfizer, Sellas, SkylineDX, TigaTx, and TxDiscovery; personal fees for independent data monitoring committee for Biocad, GSK, Pfizer, and Novartis; fees for participation in speakers bureau from Biocad, Bristol Myers Squibb, and Merck; and equity in IO Biotech, SkylineDX.

Comment in

Pembrolizumab reduces recurrence risk in stage II melanoma.
Killock D. Killock D. Nat Rev Clin Oncol. 2022 Jun;19(6):359. doi: 10.1038/s41571-022-00638-w. Nat Rev Clin Oncol. 2022. PMID: 35440772 No abstract available.
Adjuvant therapy in stage IIB and IIC melanoma: is sentinel biopsy needed?
Hindié E. Hindié E. Lancet. 2022 Aug 20;400(10352):559. doi: 10.1016/S0140-6736(22)01388-5. Lancet. 2022. PMID: 35988562 No abstract available.

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Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial

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Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial

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