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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
At the time of writing, Phase III studies are also underway evaluating the use of durvalumab in a number of other solid tumor types including biliary, bladder, cervical, endometrial, fallopian tube, head and neck, liver, ovarian, peritoneal, and renal cancers.
BRCA Mutation and PARP Inhibitors
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Arjun Mittra, James H. Doroshow, Alice P. Chen
Recently, a phase 1/2 trial combining olaparib with the programmed death-ligand 1 (PD-L1) inhibitor durvalumab was found to be active in women with advanced solid tumors. This combination was driven by the hypothesis that DNA damage results in neoantigen exposure that might improve the activity of immunotherapy [37]. Twenty-six women were enrolled and received either durvalumab with olaparib or durvalumab with cediranib in a 3+3 dose escalation format. No dose limiting toxicities were recorded in the durvalumab and olaparib combination group, and the ORR was 17% (2 of 12 patients). Eight patients had stable disease > 4 months, yielding a disease control rate (DCR) of 83% (10 of 12) [67].
Uterine Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Claudia von Arx, Hani Gabra, Christina Fotopoulou
These findings have led to further testing of immunotherapy in MMRd and POLE subtype EC. The results obtained so far are encouraging. In particular, two Phase II trials testing the activity of durvalumab alone or in combination with tremelimumab have been presented at the ASCO meeting 2019. In the first trial, durvalumab was tested as monotherapy in advanced endometrial cancer according to mismatch repair, and it has shown an ORR of 40% in patients with MMR-D tumors and 3% in patients with a proficiency MMR.134 In the second trial, the activity of durvalumab was tested with or without tremelimumab in persistent or recurrent EC and endometrial carcinosarcoma. A modest activity was documented for both regimens; however, a second stage accrual is ongoing (NCT03015129).
Next-generation immunotherapy for solid tumors: combination immunotherapy with crosstalk blockade of TGFβ and PD-1/PD-L1
Published in Expert Opinion on Investigational Drugs, 2022
Hue Tu Quach, Zhaohua Hou, Rebecca Y. Bellis, Jasmeen K. Saini, Alfredo Amador-Molina, Prasad S. Adusumilli, Yuquan Xiong
Durvalumab is a human IgG1 monoclonal PD-L1 antibody developed by Medimmune/AstraZeneca that is administered intravenously. The first report of durvalumab for the treatment of patients with solid tumors was in a study of patients with stage III non-small cell lung cancer (NSCLC) [60]. Durvalumab was also investigated for the treatment of patients with other solid tumors, including head and neck squamous carcinoma [61], pleural mesothelioma [62], hepatocellular carcinoma [63], triple-negative breast cancer [61], and urothelial carcinoma [64]. Following the PACIFIC trial results, durvalumab was approved as an adjuvant therapy for patients with stage III, unresectable NSCLC after standard chemoradiotherapy [60]. In combination with either cisplatin or carboplatin and etoposide, durvalumab has been used as a first-line treatment for adults with extensive-stage NSCLC [65].
Durvalumab: an investigational agent for unresectable hepatocellular carcinoma
Published in Expert Opinion on Investigational Drugs, 2022
Marta Maestri, Maria Pallozzi, Francesco Santopaolo, Lucia Cerrito, Maurizio Pompili, Antonio Gasbarrini, Francesca Romana Ponziani
The binding interface of Durvalumab with PD-L1 is composed of heavy and light chains [63,64]. It highly overlaps with the PD-1 binding interface with PD-L1, thus realizing a competitive inhibitory mechanism. Although Durvalumab shows a higher affinity for PD-L1 than PD-1, a possible limitation for its efficacy is its large size, which could determine a poor penetrance in the TME [64]. Pharmacokinetics of Durvalumab shows a dose-related behavior. Plasmatic levels increase in a linear way if drug dosage is ≥3 mg/kg, with a steady state obtained after 16 weeks, and a median half-life of 18 days. Durvalumab is removed by protein catabolism and reticuloendothelial system, so its half-life and clearance are not influenced by renal or hepatic impairment. No adjustment for age is required; moreover, exposure seems independent on the weight-based dose or on the flat-dosing regimen of 1500 mg q4w i.v., the latter being the main one currently experimented in clinical trials [65].
Targeting Aggressive Fibroblasts to Enhance the Treatment of Pancreatic Cancer
Published in Expert Opinion on Therapeutic Targets, 2021
Yuanyuan Yu, Kathleen Schuck, Helmut Friess, Bo Kong
Under physiological circumstances, immune checkpoint proteins act to prevent the overreaction of immune response, which otherwise would attack healthy cells. Overexpression of immune checkpoint proteins by cancer cells plays an essential role in evading immune response [54]. Immune checkpoint inhibitors applied in cancer therapy restore the ability of cytotoxic T cells to eliminate cancer cells. Two immune checkpoints most commonly targeted are cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and the programmed cell death 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) receptor/ligand pair [55]. Durvalumab is a selective, high affinity, human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD81, allowing T cells to recognize and to kill cancer cells [55]. Clinical trials of Durvalumab in several advanced, unresectable malignant tumors including PDAC have achieved significant progress [56]. However, the highly immunosuppressive microenvironment of PDAC limits the efficiency of immunotherapy [57–59]. Considering that inactivated PSCs/CAFs could promote T cell-infiltration in PDAC, a combination of anti-PSCs/CAFs or anti-stroma treatment with immune checkpoint inhibitors is conceivable. In indeed, targeting chemokine (C-X-C motif) ligand 12 (CXCL12) specifically expressed by FAP+ CAFs, promotes T-cell accumulation and synergizes with anti-PD-L1 immunotherapy to cause cancer regression [60]. Besides, blocking IL-6 combined with a PD-L1 antibody reduces murine PDAC progression in preclinical studies [61].