Atezolizumab

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    Atezolizumab (also known as MPDL3280A; anti-PDL1) is an investigational monoclonal antibody designed to interfere with a protein called PD-L1. Atezolizumab is designed to target PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, preventing it from binding to PD-1 and B7.1 on the surface of T cells. By inhibiting PD-L1, atezolizumab may enable the activation of T cells.

    All studies of atezolizumab include the evaluation of an investigational IHC test that uses the antibody SP142 to measure PD-L1 expression on both tumor cells and infiltrating immune cells. The goal of PD-L1 as a biomarker is to identify those people most likely to benefit when treated with atezolizumab alone, and to determine which people may benefit most from a combination of atezolizumab and another medicine. There are 11 ongoing or planned Phase III studies of atezolizumab across certain kinds of lung, kidney, breast and bladder cancer.

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    Genentech

    Atezolizumab meets endpoint

    SOUTH SAN FRANCISCO, Calif.–(BUSINESS WIRE)– Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that in the IMvigor 210 study, the investigational cancer immunotherapy atezolizumab (MPDL3280A; anti-PDL1) shrank tumors (objective response rate; ORR; the primary endpoint of this Phase II study) in people with locally advanced or metastatic urothelial bladder […]

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    [/td_text_with_title][td_text_with_title custom_title=”From Wikipedia”]
    Atezolizumab
    Monoclonal antibody
    Type Whole antibody
    Source Humanized
    Target PD-L1
    Clinical data
    Trade names Tecentriq
    Synonyms MPDL3280A
    AHFS/Drugs.com tecentriq
    Legal status
    Legal status
    Identifiers
    CAS Number
    DrugBank
    ChemSpider
    • none
    UNII
    KEGG
    Chemical and physical data
    Formula C6446H9902N1706O1998S42
    Molar mass 144,612.59 g·mol−1

    Atezolizumab (trade name Tecentriq) is a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death-ligand 1 (PD-L1).[1]

    In 2015, it was in clinical trials as an immunotherapy for several types of solid tumors.[1] It was under investigation by Genentech/Roche.[1]

    In April 2016, Roche announced that atezolizumab had been granted fast track status for lung cancer by the FDA.[2]

    In May 2016, it was approved by the FDA for bladder cancer treatment.[3], but in May 2017 it failed phase 3 trial for second line bladder cancer.[4]

    Medical uses

    In May 2016 FDA granted accelerated approval to atezolizumab for locally advanced or metastatic urothelial carcinoma treatment after failure of cisplatin-based chemotherapy.[3] The confirmatory trial (to convert the accelerated approval into a full approval) failed to achieve its primary endpoint of overall survival.[5]

    In October 2016, FDA approved atezolizumab for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose disease progressed during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving atezolizumab.[6]

    Adverse effects

    The most common adverse effects in studies were fatigue, decreased appetite, nausea, and infections. Urinary tract infection was the most common severe adverse effect.[7]

    Pharmacology

    Mechanism of action

    Atezolizumab blocks the interaction of PD-L1 with programmed cell death protein 1 (PD-1) and CD80 receptors (B7-1Rs).[8] PD-L1 can be highly expressed on certain tumors, which is thought to lead to reduced activation of immune cells (cytotoxic T-cells in particular) that might otherwise recognize and attack the cancer.[8] Inhibition of PD-L1 by atezolizumab can remove this inhibitor effect and thereby engender an anti-tumor response. It is one of several ways to block inhibitory signals related to T-cell activation, a more general strategy known as "immune checkpoint inhibition."[8]

    For some cancers (notably bladder) the probability of benefit is related to PD-L1 expression, but most cancers with PD-L1 expression still do not respond, and many (about 15%) without PD-L1 expression do respond.[8]

    Research

    As of 2016[update], it is currently in clinical trials for colorectal cancer, melanoma, breast cancer, non-small-cell lung carcinoma, bladder cancer, renal cell carcinoma.[9][10]

    Promising results have been observed for melanoma and non-small-cell lung cancer,[citation needed] and bladder cancer.[1]

    A phase 1 trial reported a 19% objective response rate in metastatic triple-negative breast cancer.[11]

    References

    1. ^ a b c d "Genentech Presents Positive Results of Atezolizumab in Advanced Bladder Cancer". Oct 2, 2015. 
    2. ^ Shields, Michael (11 Apr 2016). "Roche says FDA fast tracks atezolizumab in specific type of lung cancer". Reuters. Retrieved 11 Apr 2016. 
    3. ^ a b "FDA approves new, targeted treatment for bladder cancer". FDA. 18 May 2016. Retrieved 20 May 2016. 
    4. ^ "Roche's shocking Tecentriq fail raises red flag for bladder cancer rivals | FiercePharma". www.fiercepharma.com. Retrieved 2017-05-11. 
    5. ^ Failed confirmatory trial raises questions about atezolizumab for advanced urothelial cancer. June 2017
    6. ^ "FDA approves new treatment for non-small cell lung cancer". FDA. 18 Oct 2016. Retrieved 18 May 2016. 
    7. ^ FDA Professional Drug Information for Tecentriq.
    8. ^ a b c d Syn, Nicholas L; Teng, Michele W L; Mok, Tony S K; Soo, Ross A. "De-novo and acquired resistance to immune checkpoint targeting". The Lancet Oncology. 18 (12): e731–e741. doi:10.1016/s1470-2045(17)30607-1. 
    9. ^ "Search of: MPDL3280A - List Results - ClinicalTrials.gov". 
    10. ^ Bendell, Johanna C.; Kim, Tae Won; Goh, Boon C.; Wallin, Jeffrey; Oh, Do-Youn; Han, Sae-Won; Lee, Carrie B.; Hellmann, Matthew David; Desai, Jayesh; Lewin, Jeremy Howard; Solomon, Benjamin J.; Chow, Laura Quan Man; Miller, Wilson H.; Gainor, Justin F.; Flaherty, Keith; Infante, Jeffrey R.; Das-Thakur, Meghna; Foster, Paul; Cha, Edward; Bang, Yung-Jue. "Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC). - 2016 ASCO Annual Meeting Abstracts". Meeting Abstracts. 
    11. ^ "MPDL3280A Shows Activity in Triple-Negative Breast Cancer". 
    source: https://en.wikipedia.org/wiki/Atezolizumab[/td_text_with_title]