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      Pembrolizumab Plus Concurrent Chemoradiation Therapy in Patients With Unresectable, Locally Advanced, Stage III Non–Small Cell Lung Cancer : The Phase 2 KEYNOTE-799 Nonrandomized Trial

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          Abstract

          This nonrandomized trial evaluates the treatment outcomes and safety of pembrolizumab plus concurrent chemoradiation therapy in stage III non–small cell lung cancer.

          Key Points

          Question

          Is administration of pembrolizumab plus concurrent chemoradiation therapy (cCRT) effective and safe in patients with locally advanced, stage III non–small cell lung cancer (NSCLC)?

          Findings

          In this nonrandomized 2-cohort trial, pembrolizumab plus cCRT demonstrated objective response rates of 70.5% in cohort A (n = 112; squamous/nonsquamous) and 70.6% in cohort B (n = 102; nonsquamous). The incidence of grade 3 or higher pneumonitis was 8.0% in cohort A and 6.9% in cohort B.

          Meaning

          The findings of this 2-cohort trial suggest robust antitumor activity of pembrolizumab plus cCRT with manageable safety that may represent a promising therapy in patients with previously untreated, locally advanced, stage III NSCLC.

          Abstract

          Importance

          Administration of pembrolizumab plus concurrent chemoradiation therapy (cCRT) may provide treatment benefit to patients with locally advanced, stage III non–small cell lung cancer (NSCLC).

          Objective

          To evaluate treatment outcomes and safety of pembrolizumab plus cCRT in stage III NSCLC.

          Design, Setting, and Participants

          The phase 2, nonrandomized, 2-cohort, open-label KEYNOTE-799 study enrolled patients between November 5, 2018, and July 31, 2020, from 52 academic facilities and community-based institutions across 10 countries. As of October 28, 2020, median (range) follow-up was 18.5 (13.6-23.8) months in cohort A and 13.7 (2.9-23.5) months in cohort B. Of 301 patients screened, 216 eligible patients with previously untreated, unresectable, and pathologically/radiologically confirmed stage IIIA/IIIB/IIIC NSCLC with measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) were enrolled.

          Interventions

          Patients in cohort A (squamous/nonsquamous) received 1 cycle (3 weeks) of carboplatin (area under the curve [AUC] 6 mg/mL/min), paclitaxel (200 mg/m 2), and pembrolizumab (200 mg), followed by carboplatin (AUC 2 mg/mL/min) and paclitaxel (45 mg/m 2) once weekly for 6 weeks and 2 cycles of pembrolizumab plus standard thoracic radiotherapy. Patients in cohort B (nonsquamous) received 3 cycles of cisplatin (75 mg/m 2), pemetrexed (500 mg/m 2), and pembrolizumab (200 mg) every 3 weeks and thoracic radiotherapy in cycles 2 and 3. Patients received 14 additional cycles of pembrolizumab.

          Main Outcomes and Measures

          Coprimary end points were objective response rate per RECIST v1.1 by blinded independent central review and incidence of grade 3 to 5 pneumonitis.

          Results

          A total of 112 patients received treatment in cohort A (76 men [67.9%]; median [range] age, 66.0 [46-90] years; 66 patients [58.9%] with programmed cell death ligand 1 [PD-L1] tumor proportion score ≥1%) and 102 patients received treatment in cohort B (62 men [60.8%]; median [range] age, 64.0 [35-81] years; 40 patients [39.2%] with PD-L1 tumor proportion score ≥1%). Objective response rate was 70.5% (79 of 112; 95% CI, 61.2%-78.8%) in cohort A and 70.6% (72 of 102; 95% CI, 60.7%-79.2%) in cohort B. Median duration of response was not reached, but 79.7% and 75.6%, respectively, had response duration of 12 months or longer. Grade 3 or higher pneumonitis occurred in 9 of 112 patients (8.0%) in cohort A and 7 of 102 (6.9%) in cohort B. Grade 3 to 5 treatment-related adverse events occurred in 72 of 112 (64.3%) and 51 of 102 (50.0%) patients, respectively.

          Conclusions and Relevance

          The findings of this phase 2, nonrandomized, 2-cohort study suggest promising antitumor activity of pembrolizumab plus cCRT and manageable safety in patients with previously untreated, locally advanced, stage III NSCLC.

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          Most cited references35

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          Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer

          First-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial.
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            Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer

            We assessed the efficacy and safety of programmed cell death 1 (PD-1) inhibition with pembrolizumab in patients with advanced non-small-cell lung cancer enrolled in a phase 1 study. We also sought to define and validate an expression level of the PD-1 ligand 1 (PD-L1) that is associated with the likelihood of clinical benefit. We assigned 495 patients receiving pembrolizumab (at a dose of either 2 mg or 10 mg per kilogram of body weight every 3 weeks or 10 mg per kilogram every 2 weeks) to either a training group (182 patients) or a validation group (313 patients). We assessed PD-L1 expression in tumor samples using immunohistochemical analysis, with results reported as the percentage of neoplastic cells with staining for membranous PD-L1 (proportion score). Response was assessed every 9 weeks by central review. Common side effects that were attributed to pembrolizumab were fatigue, pruritus, and decreased appetite, with no clear difference according to dose or schedule. Among all the patients, the objective response rate was 19.4%, and the median duration of response was 12.5 months. The median duration of progression-free survival was 3.7 months, and the median duration of overall survival was 12.0 months. PD-L1 expression in at least 50% of tumor cells was selected as the cutoff from the training group. Among patients with a proportion score of at least 50% in the validation group, the response rate was 45.2%. Among all the patients with a proportion score of at least 50%, median progression-free survival was 6.3 months; median overall survival was not reached. Pembrolizumab had an acceptable side-effect profile and showed antitumor activity in patients with advanced non-small-cell lung cancer. PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy of pembrolizumab. (Funded by Merck; KEYNOTE-001 ClinicalTrials.gov number, NCT01295827.).
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              Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial

              First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater.
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                Author and article information

                Journal
                JAMA Oncol
                JAMA Oncol
                JAMA Oncology
                American Medical Association
                2374-2437
                2374-2445
                4 June 2021
                September 2021
                4 June 2021
                : 7
                : 9
                : 1-9
                Affiliations
                [1 ]Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick
                [2 ]Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, South Korea
                [3 ]Department of Infectious Diseases and Respiratory Medicine, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
                [4 ]N.N. Blokhin Russian Cancer Research Center, Moscow, Russia
                [5 ]The Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
                [6 ]Northeastern Health System, Tahlequah, Oklahoma
                [7 ]N.N. Petrov National Medical Research Center of Oncology, St Petersburg, Russia
                [8 ]Thoracic Oncology Unit, Department of Medical Oncology, IDIBAPS, Hospital Clínic, Barcelona, Spain
                [9 ]Vall d’Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d’Hebron, Barcelona, Spain
                [10 ]Mid North Coast Cancer Institute, Port Macquarie Base Hospital, Port Macquarie, New South Wales, Australia
                [11 ]Radiotherapie, Clinique Clairval, Marseille, France
                [12 ]Medical Oncology, Republican Dispensary of Tatarstan Ministry of Healthcare, Kazan, Russia
                [13 ]Division of Hematology/Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
                [14 ]Hematology/Medical Oncology, Parkview Cancer Institute, Fort Wayne, Indiana
                [15 ]Sanford Health, Sioux Falls, South Dakota
                [16 ]Ballarat Health Services, Ballarat, Victoria, Australia
                [17 ]Merck & Co, Inc, Kenilworth, New Jersey
                [18 ]LungenClinic, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany
                Author notes
                Article Information
                Accepted for Publication: May 3, 2021.
                Published Online: June 4, 2021. doi:10.1001/jamaoncol.2021.2301
                Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2021 Jabbour SK et al. JAMA Oncology.
                Corresponding Author: Salma K. Jabbour, MD, Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, 195 Little Albany St, New Brunswick, NJ 08903 ( jabbousk@ 123456cinj.rutgers.edu ).
                Author Contributions: Dr Jabbour had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
                Concept and design: Jabbour, Park, Reck.
                Acquisition, analysis, or interpretation of data: All authors.
                Drafting of the manuscript: Jabbour, Martinez-Marti, Park, Samkari.
                Critical revision of the manuscript for important intellectual content: All authors.
                Statistical analysis: Liu, Samkari.
                Administrative, technical, or material support: Lee, Houghton, Park, Komiya, Keller, Reck.
                Supervision: Jabbour, Lee, Frost, Pollock, Levchenko, Martinez-Marti, Houghton, Paoli, Park, Sanford, Samkari, Keller, Reck.
                Other—patient recruitment: Reguart.
                Conflict of Interest Disclosures: Dr Jabbour reported receiving grants, personal fees, and nonfinancial support from Merck & Co during the conduct of the study; and receiving grants from the National Cancer Institute and grants to institution from Merck & Co outside the submitted work. Dr Lee reported receiving personal fees for advisory board meetings from Bristol Myers Squibb, Merck Sharp & Dohme, AstraZeneca, Pfizer, and Eli Lilly outside the submitted work. Dr Frost reported receiving personal fees and nonfinancial support from Merck Sharp & Dohme during the conduct of the study; and receiving personal fees from Boehringer Ingelheim, Bristol Myers Squibb, Roche, Pfizer, Takeda, Novartis, and AbbVie, Berlin-Chemie, Sanofi, and BeiGene; travel grants from Takeda, AstraZeneca, Bristol Myers Squibb, AbbVie, and Eli Lilly; and nonfinancial support from Bristol Myers Squibb outside the submitted work. Dr Kowalski reported serving on advisory boards for Bristol Myers Squibb, AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Takeda, and Roche outside the submitted work. Dr Reguart reported receiving grants from Novartis and Pfizer, personal fees (advisory panels, invited speaker, congress registration) from Merck Sharp & Dohme, Eli Lilly, Roche, Takeda, Novartis, Pfizer, and Janssen, and personal fees (advisory panels, invited speaker) from Bristol Myers Squibb outside the submitted work. Dr Martinez-Marti reported receiving personal fees and travel expenses from Bristol Myers Squibb, F. Hoffmann-La Roche, Merck Sharp & Dohme, Pfizer, Boehringer Ingelheim, Merck Sharp & Dohme Oncology, and AstraZeneca outside the submitted work. Dr Houghton reported receiving personal fees (trial funding) from Merck during the conduct of the study; and receiving personal fees (advisory board) from Merck outside the submitted work. Dr Paoli reported receiving nonfinancial support from Merck Sharp & Dohme during the conduct of the study; and receiving personal fees from Bristol Myers Squibb and AstraZeneca and nonfinancial support from Merck Sharp & Dohme France, Fresenius Kabi France, Ipsen Pharma, Boehringer Ingelheim France, Pierre Fabre Medicament, Eisai SAS, Janssen-Cilag, Pfizer SAS, Roche SAS, Isis Méditerranée, Novartis Pharma SAS, Mundipharma, Vifor France SA, Sandoz, Kyowa Kirin, Bristol Myers Squibb, and AstraZeneca outside the submitted work. Dr Park reported receiving grants (research funding) from Merck Sharp & Dohme outside the submitted work; and serving as an advisor for Merck Sharp & Dohme outside the submitted work. Dr Sanford reported receiving grants to institution from Merck during the conduct of the study; and receiving grants from Eli Lilly, NantWorks, and QuantumLeap Health outside the submitted work. Drs Liu, Samkari, and Keller reported being an employee of Merck. Dr Reck reported receiving personal fees (honoraria for lectures and consultancy) from Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Mirati, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Samsung Bioepis outside the submitted work. No other disclosures were reported.
                Funding/Support: Funding for this research was provided by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, New Jersey.
                Role of the Funder/Sponsor: The sponsor was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
                Meeting Presentation: A portion of the results from this analysis was presented virtually at the 2021 American Society of Clinical Oncology Annual Meeting; June 4, 2021.
                Data Sharing Statement: See Supplement 3.
                Additional Contributions: Medical writing assistance was provided by Christabel Wilson, MSc, and Shilpa Kamboj, PhD, of ICON plc (North Wales, Pennsylvania). This assistance was funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, New Jersey. We thank the patients and their families and caregivers for participating in this study, along with all investigators and site personnel.
                Article
                coi210037
                10.1001/jamaoncol.2021.2301
                8446818
                34086039
                38eea911-2f1e-4ac7-b169-cd32c6d44d30
                Copyright 2021 Jabbour SK et al. JAMA Oncology.

                This is an open access article distributed under the terms of the CC-BY-NC-ND License.

                History
                : 5 April 2021
                : 3 May 2021
                Funding
                Funded by: Merck Sharp & Dohme Corp
                Categories
                Research
                Research
                Original Investigation
                Online First
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