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Ref Type Journal Article
PMID (31812554)
Authors Geoerger B, Kang HJ, Yalon-Oren M, Marshall LV, Vezina C, Pappo A, Laetsch TW, Petrilli AS, Ebinger M, Toporski J, Glade-Bender J, Nicholls W, Fox E, DuBois SG, Macy ME, Cohn SL, Pathiraja K, Diede SJ, Ebbinghaus S, Pinto N
Title Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.
Journal Vol Issue Date Pages Journal Short Title
The Lancet. Oncology 21 1 2020 Jan 121-133 Lancet Oncol
URL
Abstract Text Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8·6 months (IQR 2·5-16·4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60·0%; 95% CI 32·3-83·7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5·9% (95% CI 2·6-11·3).Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.Merck Sharp & Dohme, a subsidiary of Merck & Co.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CD274 positive high grade ependymoma predicted - sensitive Pembrolizumab Case Reports/Case Series Actionable In a Phase I/II trial (KEYNOTE-051), Keytruda (pembrolizumab) treatment resulted in size reduction of target lesion in a pediatric patient with CD274 (PD-L1)-positive ependymoma (PMID: 31812554; NCT02332668). 31812554
CD274 positive Advanced Solid Tumor predicted - sensitive Pembrolizumab Phase Ib/II Actionable In a Phase I/II trial (KEYNOTE-051), Keytruda (pembrolizumab) treatment resulted in an objective response rate of 5.9% (8/136, 8 partial response) and a disease control rate of 26.5% in pediatric patients with CD274 (PD-L1)-positive advanced solid tumors, with a median progression-free survival of 1.9 months and a median overall survival of 9.0 months (PMID: 31812554; NCT02332668). 31812554
CD274 positive glioblastoma conflicting Pembrolizumab Case Reports/Case Series Actionable In a Phase I/II trial (KEYNOTE-051), Keytruda (pembrolizumab) treatment resulted in size reduction of target lesion in a pediatric patient with CD274 (PD-L1)-positive glioblastoma (PMID: 31812554; NCT02332668). 31812554
CD274 positive lymphoepithelioma-like carcinoma predicted - sensitive Pembrolizumab Case Reports/Case Series Actionable In a Phase I/II trial (KEYNOTE-051), Keytruda (pembrolizumab) treatment resulted in a partial response in a pediatric patient with CD274 (PD-L1)-positive lymphoepithelial carcinoma (PMID: 31812554; NCT02332668). 31812554
CD274 positive ganglioglioma predicted - sensitive Pembrolizumab Case Reports/Case Series Actionable In a Phase I/II trial (KEYNOTE-051), Keytruda (pembrolizumab) treatment resulted in a partial response in a pediatric patient with CD274 (PD-L1)-positive ganglioglioma (PMID: 31812554; NCT02332668). 31812554
CD274 positive sarcoma predicted - sensitive Pembrolizumab Case Reports/Case Series Actionable In a Phase I/II trial (KEYNOTE-051), Keytruda (pembrolizumab) treatment resulted in size reduction of target lesion in 2 pediatric patients with CD274 (PD-L1)-positive soft tissue sarcoma (PMID: 31812554; NCT02332668). 31812554
CD274 positive neuroblastoma predicted - sensitive Pembrolizumab Case Reports/Case Series Actionable In a Phase I/II trial (KEYNOTE-051), Keytruda (pembrolizumab) treatment resulted in size reduction of target lesion in a pediatric patient with CD274 (PD-L1)-positive neuroblastoma (PMID: 31812554; NCT02332668). 31812554
CD274 positive adrenocortical carcinoma predicted - sensitive Pembrolizumab Case Reports/Case Series Actionable In a Phase I/II trial (KEYNOTE-051), Keytruda (pembrolizumab) treatment resulted in a partial response in 2 pediatric patients with CD274 (PD-L1)-positive adrenocortical carcinoma (PMID: 31812554; NCT02332668). 31812554
CD274 positive fibrosarcoma of bone predicted - sensitive Pembrolizumab Case Reports/Case Series Actionable In a Phase I/II trial (KEYNOTE-051), Keytruda (pembrolizumab) treatment resulted in size reduction of target lesion in a pediatric patient with CD274 (PD-L1)-positive malignant histiocytosis (PMID: 31812554; NCT02332668). 31812554
CD274 positive inflammatory myofibroblastic tumor predicted - sensitive Pembrolizumab Case Reports/Case Series Actionable In a Phase I/II trial (KEYNOTE-051), Keytruda (pembrolizumab) treatment resulted in size reduction of target lesion in a pediatric patient with CD274 (PD-L1)-positive inflammatory myofibroblastic tumor (PMID: 31812554; NCT02332668). 31812554
CD274 positive Hodgkin's lymphoma predicted - sensitive Pembrolizumab Phase Ib/II Actionable In a Phase I/II trial (KEYNOTE-051), Keytruda (pembrolizumab) treatment resulted in an objective response rate of 60.0% (9/15, 2 complete response, 7 partial response) and a disease control rate of 80.0% in pediatric patients with CD274 (PD-L1)-positive Hodgkin's lymphoma, with a median progression-free survival of 12.2 months (PMID: 31812554; NCT02332668). 31812554
CD274 positive chordoma predicted - sensitive Pembrolizumab Case Reports/Case Series Actionable In a Phase I/II trial (KEYNOTE-051), Keytruda (pembrolizumab) treatment resulted in size reduction of target lesion in a pediatric patient with CD274 (PD-L1)-positive chordoma (PMID: 31812554; NCT02332668). 31812554
CD274 positive hepatoblastoma predicted - sensitive Pembrolizumab Case Reports/Case Series Actionable In a Phase I/II trial (KEYNOTE-051), Keytruda (pembrolizumab) treatment resulted in size reduction of target lesion in a pediatric patient with CD274 (PD-L1)-positive hepatoblastoma (PMID: 31812554; NCT02332668). 31812554
CD274 positive rhabdoid cancer predicted - sensitive Pembrolizumab Case Reports/Case Series Actionable In a Phase I/II trial (KEYNOTE-051), Keytruda (pembrolizumab) treatment resulted in a partial response in a pediatric patient with CD274 (PD-L1)-positive rhabdoid cancer (PMID: 31812554; NCT02332668). 31812554
CD274 positive congenital mesoblastic nephroma predicted - sensitive Pembrolizumab Case Reports/Case Series Actionable In a Phase I/II trial (KEYNOTE-051), Keytruda (pembrolizumab) treatment resulted in size reduction of target lesion in a pediatric patient with CD274 (PD-L1)-positive mesoblastic nephroma (PMID: 31812554; NCT02332668). 31812554
CD274 positive embryonal rhabdomyosarcoma predicted - sensitive Pembrolizumab Case Reports/Case Series Actionable In a Phase I/II trial (KEYNOTE-051), Keytruda (pembrolizumab) treatment resulted in size reduction of target lesion in 2 pediatric patients with CD274 (PD-L1)-positive embryonal rhabdomyosarcoma (PMID: 31812554; NCT02332668). 31812554
CD274 positive high grade glioma predicted - sensitive Pembrolizumab Case Reports/Case Series Actionable In a Phase I/II trial (KEYNOTE-051), Keytruda (pembrolizumab) treatment resulted in size reduction of target lesion in 2 pediatric patients with CD274 (PD-L1)-positive high-grade glioma (PMID: 31812554; NCT02332668). 31812554
CD274 positive ganglioneuroblastoma predicted - sensitive Pembrolizumab Case Reports/Case Series Actionable In a Phase I/II trial (KEYNOTE-051), Keytruda (pembrolizumab) treatment resulted in size reduction of target lesion in a pediatric patient with CD274 (PD-L1)-positive ganglioneuroblastoma (PMID: 31812554; NCT02332668). 31812554
CD274 positive malignant mesothelioma predicted - sensitive Pembrolizumab Case Reports/Case Series Actionable In a Phase I/II trial (KEYNOTE-051), Keytruda (pembrolizumab) treatment resulted in a partial response in 2 pediatric patients with CD274 (PD-L1)-positive mesothelioma (PMID: 31812554; NCT02332668). 31812554
CD274 positive epithelioid sarcoma predicted - sensitive Pembrolizumab Case Reports/Case Series Actionable In a Phase I/II trial (KEYNOTE-051), Keytruda (pembrolizumab) treatment resulted in a partial response in a pediatric patient with CD274 (PD-L1)-positive epithelioid sarcoma (PMID: 31812554; NCT02332668). 31812554