Dataset Information

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors.

ABSTRACT: Introduction:The prominent immune checkpoint molecule, programmed cell death ligand-1 (PD-L1), is the object of increasing attention. Here, we report a meta-analysis investigating the safety and efficacy of durvalumab (MEDI4736), an inhibitor of PD-L1, in various solid tumors. Methods:A systematic search of PubMed, Embase, and related articles was performed. Safety data were analyzed using Comprehensive Meta-Analysis software program version 2. Ultimately, 17 studies with 1,529 patients were included in our analysis. Results:The major adverse events associated with durvalumab were pruritus and fatigue, while pruritus, increased alanine transaminase, and increased aspartate aminotransferase were common among patients treated with a combination of durvalumab and tremelimumab. Higher PD-L1 expression was associated with a superior objective response rate. Conclusion:Durvalumab is safe in patients with many solid cancers and, in combination with tremelimumab, it has a tolerable safety profile and is associated with improved prognosis. PD-L1 expression is a biomarker of the efficacy of durvalumab.

SUBMITTER: Yang H

PROVIDER: S-EPMC6038862 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Safety and efficacy of durvalumab (MEDI4736) in various solid tumors.

Yang Hui H Shen Kai K Zhu Chenjing C Li Qingfang Q Zhao Yunuo Y Ma Xuelei X

Drug design, development and therapy 20180706

<h4>Introduction</h4>The prominent immune checkpoint molecule, programmed cell death ligand-1 (PD-L1), is the object of increasing attention. Here, we report a meta-analysis investigating the safety and efficacy of durvalumab (MEDI4736), an inhibitor of PD-L1, in various solid tumors.<h4>Methods</h4>A systematic search of PubMed, Embase, and related articles was performed. Safety data were analyzed using Comprehensive Meta-Analysis software program version 2. Ultimately, 17 studies with 1,529 pa ...[more]

PMID: 30013326

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Project description:Background: Camrelizumab (SHR1210) is a high-affinity, humanized immunoglobulin programmed cell death 1 (PD-1) monoclonal antibody. It was developed by Jiangsu Hengrui Medicine Co. Ltd. and has been approved for relapsed or refractory classical Hodgkin lymphoma patients and hepatocellular carcinoma patients in China. Apatinib is an orally administered vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor and has been approved for advanced gastric adenocarcinoma or gastroesophageal junction adenocarcinoma in China. Camrelizumab alone and its combination with apatinib have been used in the treatment of various solid cancers. Methods: We searched Embase, PubMed, and other databases with the keyword “camrelizumab” or “SHR1210,” and evaluated the safety and efficacy data of the involved studies. Adverse events (AEs) mentioned in at least two studies were summarized, including any grade and grade ≥3 treatment-related AEs. Meanwhile, efficacy data were collected, such as overall response rate (ORR), disease control rate (DCR), duration of response, 6-month progression-free survival (PFS) rate, median PFS time, 12-month overall survival rate, and median overall survival time. Results: The major AEs of camrelizumab alone were reactive cutaneous capillary endothelial proliferation, fatigue, aspartate aminotransferase increase, proteinuria, pruritus, and alanine transaminase increase. The ORR and DCR were 20.2% (95% CI: 15.1–26.6%, p = 0.000, I2 = 70.360) and 45.8% (95% CI: 39.0–52.7%, p = 0.256, I2 = 58.661), respectively. In the three studies of combination therapy, two studies were combined with apatinib and one combined with chemotherapy. For these studies, common AEs were hypertension, platelet count decrease, nausea, proteinuria, aspartate aminotransferase increase, and white blood cell count decrease. The pooled ORR, DCR, and 6-month PFS rate were 41.8% (95% CI: 29.7–54.9%, p = 0.220, I2 = 86.265), 82.4% (95% CI: 75.9–87.4%, p = 0.000, I2 = 55.207), and 56.2% (95% CI: 35.8–74.6%, p = 0.559, I2 = 79.739), respectively. Conclusion: Camrelizumab and its combination are tolerable and appear to be efficient in treating numerous solid cancers. The combination therapy appears to have better efficacy with durable toxicity. However, these remain to be shown in future studies. Besides, baseline lactate dehydrogenase, programmed cell death ligand 1 (PD-L1) expression, tumor mutation burden, and the incidence of reactive cutaneous capillary endothelial proliferation may be efficacy predictors and need to be clarified in further studies.

Project description:BACKGROUND:MEDI9197 is an intratumorally administered toll-like receptor 7 and 8 agonist. In mice, MEDI9197 modulated antitumor immune responses, inhibited tumor growth and increased survival. This first-time-in-human, phase 1 study evaluated MEDI9197 with or without the programmed cell death ligand-1 (PD-L1) inhibitor durvalumab and/or palliative radiation therapy (RT) for advanced solid tumors. PATIENTS AND METHODS:Eligible patients had at least one cutaneous, subcutaneous, or deep-seated lesion suitable for intratumoral (IT) injection. Dose escalation used a standard 3+3 design. Patients received IT MEDI9197 0.005-0.055?mg with or without RT (part 1), or IT MEDI9197 0.005 or 0.012?mg plus durvalumab 1500?mg intravenous with or without RT (part 3), in 4-week cycles. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics, pharmacodynamics, and objective response based on Response Evaluation Criteria for Solid Tumors version 1.1. Exploratory endpoints included tumor and peripheral biomarkers that correlate with biological activity or predict response. RESULTS:From November 2015 to March 2018, part 1 enrolled 35 patients and part 3 enrolled 17 patients; five in part 1 and 2 in part 3 received RT. The maximum tolerated dose of MEDI9197 monotherapy was 0.037?mg, with dose-limiting toxicity (DLT) of cytokine release syndrome in two patients (one grade 3, one grade 4) and 0.012?mg in combination with durvalumab 1500?mg with DLT of MEDI9197-related hemorrhagic shock in one patient (grade 5) following liver metastasis rupture after two cycles of MEDI9197. Across parts 1 and 3, the most frequent MEDI9197-related adverse events (AEs) of any grade were fever (56%), fatigue (31%), and nausea (21%). The most frequent MEDI9197-related grade ?3 events were decreased lymphocytes (15%), neutrophils (10%), and white cell counts (10%). MEDI9197 increased tumoral CD8+ and PD-L1+ cells, inducing type 1 and 2 interferons and Th1 response. There were no objective clinical responses; 10 patients in part 1 and 3 patients in part 3 had stable disease ?8 weeks. CONCLUSION:IT MEDI9197 was feasible for subcutaneous/cutaneous lesions but AEs precluded its use in deep-seated lesions. Although no patients responded, MEDI9197 induced systemic and intratumoral immune activation, indicating potential value in combination regimens in other patient populations. TRIAL REGISTRATION NUMBER:NCT02556463.

Project description:ImportanceTherapies targeting the programmed cell death 1 (PD-1) receptor or its ligand (PD-L1), such as the humanized monoclonal antibody durvalumab, have shown durable clinical responses in several tumor types. However, concerns about the safety and feasibility of PD-1/PD-L1 blockade in HIV-1-infected individuals have led to the exclusion of these patients from clinical trials on cancer immunotherapies.ObjectiveTo evaluate the feasibility and safety of durvalumab treatment in patients with advanced cancer and virologically controlled HIV-1 infection.Design, setting, and participantsThe DURVAST study was a nonrandomized, open-label, phase 2 clinical trial in patients with any solid tumor type in which anti-PD-1 or anti-PD-L1 antibodies have approved indications or for which there are data of antitumoral activity with no other available curative therapy. All patients had basal undetectable plasma viremia while undergoing combination antiretroviral therapy.InterventionsTreatment consisted of intravenous infusion of durvalumab (1500 mg every 4 weeks) until disease progression or unacceptable toxic effects.Main outcomes and measuresAdverse events were graded with the use of the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. Tumor response was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1.ResultsA total of 20 HIV-1-infected patients with advanced cancer were enrolled; 16 (80%) were male, the median (range) age was 54 (30-73) years, and 12 (60%) had progressed with previous cancer treatment lines. A median (range) of 4 (1-16) cycles of durvalumab were administered. Drug-related adverse events were observed in 50% of patients, and all were grade 1 and 2 (mainly diarrhea, asthenia, and arthromyalgia). Four of 16 response-evaluable patients (25%) had a partial response. Five patients (31%) had stable disease, including 4 with durable stable disease (disease control rate of 50%). CD4+ and CD8+ T-cell counts and plasma HIV-1 viremia remained stable throughout the study.Conclusions and relevanceDurvalumab treatment was feasible and safe in HIV-1-infected patients with cancer receiving combination antiretroviral therapy. HIV-1-infected patients on suppressive antiretroviral therapy with advanced cancer should have access to cancer immunotherapy treatments.Trial registrationClinicalTrials.gov Identifier: NCT03094286.

Dataset Information

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors.

Publications

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors.

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