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Title: | Phase IA/IB study of single-agent tislelizumab, an investigational anti-PD-1 antibody, in solid tumors. | Authors: | Wu C.-Y.;Zhang Y.;Liang L.;Wu J.;Paton V.;Millward M.;Keam B.;Jameson M.;Hou M.-M.;Kang Y.-K.;Markman B.;Lu C.-H.;Rau K.-M.;Lee K.-H.;Horvath L.;Friedlander M.;Hill A.;Sandhu S.;Barlow P.;Desai J.;Deva S.;Lee J.S.;Lin C.-C.;Yen C.-J.;Chao Y. | Institution: | (Desai, Sandhu) Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia (Deva, Barlow) Auckland City Hospital, Auckland, New Zealand (Lee) Seoul National University Bundang Hospital, Seongnam-si, South Korea (Lin) National Taiwan University Hospital, Taipei, Taiwan (Republic of China) (Yen) National Cheng Kung University Hospital, Tainan, Taiwan (Republic of China) (Chao) Taipei Veterans General Hospital, Taipei, Taiwan (Republic of China) (Keam, Lee) Seoul National University Hospital, Seoul, South Korea (Jameson) Waikato Hospital, University of Auckland Waikato Clinical Campus, Hamilton, New Zealand (Hou) Chang Gung Memorial Hospital, Chang Gung University, Linkou, Taiwan (Republic of China) (Kang) Asan Medical Center, Seoul, South Korea (Markman) Monash Health, Monash University, Clayton, VIC, Australia (Lu) Chang Gung Memorial Hospital, Chia-yi, Taiwan (Republic of China) (Rau) Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (Republic of China) (Horvath) Chris o'Brien Lifehouse, Sydney, NSW, Australia (Horvath) Sydney Medical School, University of Sydney, Sydney, NSW, Australia (Friedlander) Department of Medical Oncology, Prince of Wales Hospital and Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia (Hill) Tasman Oncology Research Ltd, Southport, QLD, Australia (Wu, Wu, Paton) BeiGene USA, Inc, San Mateo, California, United States (Zhang, Liang) BeiGene (Beijing) Co., Ltd, Beijing, China (Millward) Linear Clinical Research, Nedlands, WA, Australia | Issue Date: | 4-Jul-2020 | Copyright year: | 2020 | Publisher: | BMJ Publishing Group (E-mail: subscriptions@bmjgroup.com) | Place of publication: | United Kingdom | Publication information: | Journal for ImmunoTherapy of Cancer. 8 (1) (no pagination), 2020. Article Number: e000453. Date of Publication: 14 Jun 2020. | Journal: | Journal for ImmunoTherapy of Cancer | Abstract: | Background The programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) axis plays a central role in suppressing antitumor immunity; axis dysregulation can be used by cancer cells to evade the immune system. Tislelizumab, an investigational monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding to Fc 3R on macrophages to limit antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. The aim of this phase IA/IB study was to investigate the safety/tolerability, antitumor effects and optimal dose and schedule of tislelizumab in patients with advanced solid tumors. Methods Patients (aged >=18 years) enrolled in phase IA received intravenous tislelizumab 0.5, 2, 5 or 10 mg/kg every 2 weeks; 2 or 5 mg/kg administered every 2 weeks or every 3 weeks; or 200 mg every 3 weeks; patients in phase IB received 5 mg/kg every 3 weeks. Primary objectives were to assess tislelizumab's safety/tolerability profile by adverse event (AE) monitoring and antitumor activity using RECIST V.1.1. PD-L1 expression was assessed retrospectively with the VENTANA PD-L1 (SP263) Assay. Results Between May 2015 and October 2017, 451 patients (n=116, IA; n=335, IB) were enrolled. Fatigue (28%), nausea (25%) and decreased appetite (20%) were the most commonly reported AEs. Most AEs were grade 1-2 severity; anemia (4.9%) was the most common grade 3-4 AE. Treatment-related AEs led to discontinuation in 5.3% of patients. Grade 5 AEs were reported in 14 patients; 2 were considered related to tislelizumab. Pneumonitis (2%) and colitis (1%) were the most common serious tislelizumab-related AEs. As of May 2019, 18% of patients achieved a confirmed objective response in phase IA and 12% in phase IB; median follow-up duration was 13.6 and 7.6 months, respectively. Pharmacokinetics, safety and antitumor activity obtained from both phase IA and IB determined the tislelizumab recommended dose; ultimately, tislelizumab 200 mg intravenous every 3 weeks was the dose and schedule recommended to be taken into subsequent clinical trials. Conclusions Tislelizumab monotherapy demonstrated an acceptable safety/tolerability profile. Durable responses were observed in heavily pretreated patients with advanced solid tumors, supporting the evaluation of tislelizumab 200 mg every 3 weeks, as monotherapy and in combination therapy, for the treatment of solid tumors and hematological malignancies. Trial registration number NCT02407990.Copyright © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1136/jitc-2019-000453 | PubMed URL: | 32540858 [http://www.ncbi.nlm.nih.gov/pubmed/?term=32540858] | ISSN: | 2051-1426 (electronic) | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/29145 | Type: | Article | Subjects: | hypercalcemia/si [Side Effect] hyperglycemia/si [Side Effect] hypertransaminasemia/si [Side Effect] hypokalemia/si [Side Effect] hyponatremia/si [Side Effect] liver cell carcinoma/dt [Drug Therapy] loss of appetite/si [Side Effect] lower respiratory tract infection/si [Side Effect] lung embolism/si [Side Effect] major clinical study male maximum tolerated dose melanoma/dt [Drug Therapy] merkel cell carcinoma/dt [Drug Therapy] microsatellite instability *monotherapy multiple cycle treatment nausea and vomiting/si [Side Effect] non small cell lung cancer/dt [Drug Therapy] optimal drug dose ovary carcinoma/dt [Drug Therapy] pancreas cancer/dt [Drug Therapy] phase 1 clinical trial pleura effusion/si [Side Effect] pneumonia/si [Side Effect] priority journal rash/si [Side Effect] recommended drug dose renal cell carcinoma/dt [Drug Therapy] retrospective study sepsis/si [Side Effect] skin carcinoma/dt [Drug Therapy] small intestine obstruction/si [Side Effect] *solid malignant neoplasm/dt [Drug Therapy] stomach cancer/dt [Drug Therapy] time to maximum plasma concentration treatment response time triple negative breast cancer/dt [Drug Therapy] upper gastrointestinal bleeding/si [Side Effect] bilirubin/ec [Endogenous Compound] *new drug/ct [Clinical Trial] *new drug/do [Drug Dose] *new drug/dt [Drug Therapy] *new drug/to [Drug Toxicity] *new drug/iv [Intravenous Drug Administration] *new drug/pk [Pharmacokinetics] *new drug/pv [Special Situation for Pharmacovigilance] programmed death 1 ligand 1/ec [Endogenous Compound] *tislelizumab/ae [Adverse Drug Reaction] *tislelizumab/ct [Clinical Trial] *tislelizumab/cr [Drug Concentration] *tislelizumab/do [Drug Dose] *tislelizumab/dt [Drug Therapy] *tislelizumab/to [Drug Toxicity] *tislelizumab/iv [Intravenous Drug Administration] *tislelizumab/pk [Pharmacokinetics] *tislelizumab/pv [Special Situation for Pharmacovigilance] *tislelizumab/tm [Unexpected Outcome of Drug Treatment] immunohistochemical test kit VENTANA PD-L1 (SP263) maximum concentration adult aged anemia/si [Side Effect] antineoplastic activity area under the curve article ascites/si [Side Effect] backache/si [Side Effect] bile duct carcinoma/dt [Drug Therapy] body weight disorder/si [Side Effect] clinical outcome cohort analysis colitis/si [Side Effect] colorectal cancer/dt [Drug Therapy] constipation/si [Side Effect] controlled study coughing/si [Side Effect] diarrhea/si [Side Effect] drug dosage form comparison drug dose escalation drug dose regimen drug efficacy drug half life drug safety drug tolerability drug withdrawal dysphagia/si [Side Effect] dyspnea/si [Side Effect] esophagus cancer/dt [Drug Therapy] esophagus carcinoma/dt [Drug Therapy] fatigue/si [Side Effect] female follow up gastrointestinal stromal tumor/dt [Drug Therapy] head and neck squamous cell carcinoma/dt [Drug Therapy] human hyperbilirubinemia/si [Side Effect] hypercalcemia hyperglycemia hypertransaminasemia hypokalemia hyponatremia liver cell carcinoma loss of appetite lower respiratory tract infection lung embolism maximum tolerated dose melanoma merkel cell carcinoma microsatellite instability monotherapy multiple cycle treatment nausea and vomiting non small cell lung cancer optimal drug dose ovary carcinoma pancreas cancer phase 1 pleura effusion pneumonia rash recommended drug dose renal cell carcinoma sepsis skin carcinoma small intestine obstruction solid malignant neoplasm stomach cancer time to maximum plasma concentration triple negative breast cancer upper gastrointestinal bilirubin new drug/ct new drug programmed 1 ligand 1 tislelizumab [Adverse Drug Reaction] tislelizumab/ct tislelizumab immunohistochemical test kit VENTANA PD-L1 (SP263) maximum concentration aged anemia antineoplastic activity ascites backache bile duct carcinoma body weight disorder colitis colorectal cancer constipation coughing diarrhea drug dosage form comparison drug dose escalation drug dose regimen drug efficacy drug half life drug safety drug tolerability drug withdrawal dysphagia dyspnea esophagus cancer esophagus carcinoma fatigue gastrointestinal stromal tumor head and neck squamous cell carcinoma hyperbilirubinemia clinical outcome cohort analysis colitis / side effect colorectal cancer / drug therapy constipation / side effect controlled study coughing / side effect diarrhea / side effect drug dosage form comparison drug dose escalation drug dose regimen drug efficacy drug half life drug safety drug tolerability drug withdrawal dysphagia / side effect dyspnea / side effect esophagus cancer / drug therapy esophagus carcinoma / drug therapy fatigue / side effect female follow up gastrointestinal stromal tumor / drug therapy head and neck squamous cell carcinoma / drug therapy human hyperbilirubinemia / side effect hypercalcemia / side effect hyperglycemia / side effect hypertransaminasemia / side effect hypokalemia / side effect hyponatremia / side effect liver cell carcinoma / drug therapy loss of appetite / side effect lower respiratory tract infection / side effect lung embolism / side effect major clinical study male maximum concentration maximum tolerated dose melanoma / drug therapy merkel cell carcinoma / drug therapy microsatellite instability *monotherapy multiple cycle treatment nausea and vomiting / side effect non small cell lung cancer / drug therapy aged ovary carcinoma / drug therapy pancreas cancer / drug therapy phase 1 clinical trial pleura effusion / side effect pneumonia / side effect priority journal rash / side effect recommended drug dose renal cell carcinoma / drug therapy retrospective study sepsis / side effect skin carcinoma / drug therapy small intestine obstruction / side effect *solid malignant neoplasm / *drug therapy stomach cancer / drug therapy time to maximum plasma concentration treatment response time triple negative breast cancer / drug therapy upper gastrointestinal bleeding / side effect adult optimal drug dose anemia / side effect antineoplastic activity area under the curve Article ascites / side effect backache / side effect bile duct carcinoma / drug therapy body weight disorder / side effect |
Type of Clinical Study or Trial: | Observational study (cohort, case-control, cross sectional or survey) |
Appears in Collections: | Articles |
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