Companion diagnostic testing
Drugs of interest to pathologists
Atezolizumab

Editorial Board Member: Gary Tozbikian, M.D.
Editor-in-Chief: Debra L. Zynger, M.D.
Y. Albert Yeh, M.D., Ph.D.

Topic Completed: 23 February 2021

Minor changes: 23 February 2021

Copyright: 2020-2021, PathologyOutlines.com, Inc.

PubMed Search: Atezolizumab[TI] free full text[sb] pathology

Y. Albert Yeh, M.D., Ph.D.
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Cite this page: Yeh YA. Atezolizumab. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/drugsatezolizumab.html. Accessed March 3rd, 2021.
Definition / general
  • A humanized IgG1 monoclonal antibody blocking programmed death ligand 1 (PDL1)
  • Developed by Genentech, Inc.
  • Synonyms: MPDL3280A, RG7446
Trade name
  • Tecentriq®
Indications
  • Urothelial carcinoma locally advanced or metastatic disease fulfilling 1 of the following criteria
    • Not eligible for cisplatin based chemotherapy and tumor expresses PDL1 (PDL1 stained tumor infiltrating immune cells covering ≥ 5% of the tumor area) - FDA approved 2017
    • Not eligible for platinum based chemotherapy with any PDL1 staining status - FDA approved 2017 (Oncologist 2019;24:563)
    • Disease progression with platinum based chemotherapy - FDA approved 2016
  • Non small cell lung cancer (NSCLC) fulfilling one of the following criteria
    • First line treatment for metastatic NSCLC with high PDL1 expression (PDL1 staining ≥ 50% tumor cells or immune cells ≥ 10%) and no EGFR or ALK gene alterations - FDA approved 2020
    • In combination with chemotherapy (paclitaxel protein bound; nab-paclitaxel and carboplatin) for metastatic nonsquamous NSCLC with no EGFR or ALK gene alterations - FDA approved 2019
    • In combination with bevacizumab, paclitaxel and carboplatin for metastatic nonsquamous NSCLC with no EGFR or ALK gene alterations - FDA approved 2018
    • Metastatic NSCLC with EGFR or ALK gene alterations and disease progression when treated with platinum based chemotherapy - FDA approved 2016 (Lancet 2017;389:255)
  • Triple negative breast cancer locally advanced or metastatic with PDL1 expression of immune cells ≥ 1% of tumor area - FDA approved 2019 (N Engl J Med 2018;379:2108)
  • Small cell lung cancer advanced stage in combination with carboplatin and etoposide - FDA approved 2019 (N Engl J Med 2018;379:2220)
  • Hepatocellular carcinoma in combination with bevacizumab - FDA approved 2020 (N Engl J Med 2020;382:1894)
  • Melanoma unresectable or metastatic with BRAF V600 mutation in combination with cobimetinib and vemurafenib - FDA approved 2020 (Nat Med 2019;25:929)
  • Reference: Drugs.com: Tecentriq FDA Approval History [Accessed 18 December 2020]
Pathophysiology
  • PD1 receptor expressed on activated T cells, B cells, macrophages and NK cells (Nat Rev Immunol 2018;18:153)
  • PDL1 expressed on antigen presenting cells and many types of cancer cells (Nature 2016;534:402)
  • Binding of PD1 to PDL1 or B7H1 can suppress T cell proliferation, cytokine production and cytolytic activity
  • Aberrant expression of PDL1 on cancer cells through interaction with PD1 receptor blocks antitumor immunity and escape immune surveillance (Nature 2016;534:402)
  • Atezolizumab, a PDL1 inhibitor, blocks the binding of PD1 with PDL1, resulting in prevention of inhibition of T cell immune response and reactivation of T cell mediated antitumor cytolytic activity (Clin Cancer Res 2017;23:1886)
Diagrams / tables

Images hosted on other servers:
Atezolizumab blocks PDL1 on tumor cells

Atezolizumab blocks PDL1 on tumor cells

PDL1 inhibits T cell dependent cytotoxicity through a STAT3 / caspase-7–dependent signaling pathway in cancer cells

Inhibition of PDL1 through STAT3 / caspase 7 signaling

Crystal structures of the interaction of PDL1 with atezolizumab antigen binding fragment

(a,c) Crystals of PDL1 with atezolizumab

Clinical information
  • Immune mediated diseases associated with treatment with atezolizumab
  • Pneumonitis: withhold or discontinue based on severity (Chest 2017;152:271)
  • Hepatitis: monitor liver function, withhold or discontinue
  • Colitis: withhold or discontinue based on severity (JAMA Oncol 2018;4:1721)
  • Endocrinopathies (JAMA Oncol 2018;4:173):
    • Hypophysitis: withhold based on severity of hypophysitis
    • Hyperthyroidism: monitor thyroid function
    • Adrenal insufficiency: withhold based on severity
    • Type 1 diabetes mellitus: withhold based on severity
  • Infections: withhold for severe infection (Respir Med 2020;161:105853)
  • Infusion related reactions: slow the rate of infusion or discontinue
  • Embryo fetal toxicity: advise females of reproductive potential
  • Pharmacokinetics (Clin Pharmacol Ther 2017;102:305):
    • Dose range: 1 - 20 mg/kg, including a dose of 1,200 mg every 3 weeks
    • Clearance: 0.20 L/day
    • Volume of distribution: 6.91 L
    • Terminal half life: 27 days
    • Steady state: achieved after 6 - 9 weeks (2 - 3 cycles)
  • Tecentriq treatment costs approximately $13,860 per month (Drugs.com: What Is the Cost of Tecentriq? [Accessed 17 December 2020])
Uses by pathologists
  • VENTANA PDL1 SP142 Assay (Roche Diagnostics): FDA approved companion diagnostic to atezolizumab; not substitutable with other PDL1 assays (22C3, SP263) (Appl Immunohistochem Mol Morphol 2019;27:92)
  • Tumor cell (TC) staining: membranous, linear, partial to complete circumferential staining pattern at any intensity (Mod Pathol 2019;32:929, Arch Pathol Lab Med 2018;142:982)
  • Immune cell (IC), including lymphocyte, neutrophil and macrophage staining: punctate, incomplete, membranous staining pattern at any intensity; exclude intravascular immune cells and cells in necrotic area (Mod Pathol 2019;32:929, Arch Pathol Lab Med 2018;142:982)
  • Total tumor area: the area covered by tumor cells with intratumoral and peritumoral stroma
  • Urothelial carcinoma: evaluate immune cells only and disregard tumor cells
    • Positive: presence of staining at any intensity in immune cells ≥ 5% of tumor area
    • Negative: absence of any staining in immune cells < 5% of tumor area (see PDL1 SP142) (Am J Surg Pathol 2018;42:1059)
  • NSCLC: evaluate tumor cells and then evaluate immune cells (if tumor cells negative)
    • Positive: presence of staining at any intensity in tumor cells ≥ 50%
    • Negative: staining at any intensity in tumor cells < 50% (proceed to immune cell count)
    • Positive: presence of staining at any intensity in immune cells ≥ 10% of tumor area
    • Negative: staining at any intensity in immune cells < 10% of tumor area (Histopathology 2018;72:449)
  • Triple negative breast carcinoma: evaluate immune cells only and disregard tumor cells
    • Positive: presence of staining at any intensity in immune cells ≥ 1% of tumor area
    • Negative: staining at any intensity in immune cells < 1% of tumor area (see PDL1 SP142)
Side effects
  • Tecentriq as a single agent (reported in > 20% of patients)
  • Tecentriq in combination with bevacizumab, paclitaxel and carboplatin (reported in > 20% of patients)
    • Arthralgia, asthenia, alopecia, constipation, decreased appetite, diarrhea, hypertension, nausea, peripheral neuropathy (N Engl J Med 2018;378:2288)
  • Tecentriq in combination with paclitaxel protein bound (reported in > 20% of patients)
    • Alopecia, anemia, constipation, cough, decreased appetite, diarrhea, fatigue, headache, nausea, neutropenia, peripheral neuropathies, vomiting (N Engl J Med 2018;379:2108)
  • Others: hyponatremia, pneumonia, hyperkalemia, thrombocytopenia, death
  • Reference: FDA: Tecentriq (atezolizumab) [Accessed 18 December 2020]
Drug administration
  • For metastatic urothelial carcinoma:
    • Tecentriq 1,200 mg IV over 60 min for 3 weeks
  • For treatment of nonsquamous non small cell lung cancer:
    • Tecentriq 1,200 mg IV over 60 minutes, followed by bevacizumab, paclitaxel and carboplatin every 3 weeks for a maximum of 4 - 6 cycles
    • Following completion of chemotherapy, Tecentriq 1,200 mg IV, followed by bevacizumab every 3 weeks
  • For metastatic triple negative breast cancer:
    • Tecentriq 840 mg IV over 60 minutes, followed by 100 mg/m² paclitaxel
    • Every 28 days, Tecentriq is administered on days 1 and 15 and paclitaxel is administered on days 1, 8 and 15
  • Reference: PDR: Atezolizumab - Drug Summary [Accessed 17 December 2020]
Molecular theory
  • PDL1 expressed on tumor cells, through binding to PD1, inhibits T cell immune response
  • PDL1 may suppress IFN mediated cytotoxicity through a STAT3 / caspase 7 dependent signaling pathway (Sci Adv 2020;6:2712)
  • The RMLDVEKC motif of PDL1 is essential to hinder interferon toxicity, while the DTSSK motif blocks this function (Sci Adv 2020;6:2712)
  • PDL1 protects tumor cells from T cell dependent cytotoxicity
  • Crystal structures of interaction of PDL1 with atezolizumab antigen binding fragment through the immunoglobulin superfamily V set domain of PDL1 (Sci Rep 2017;7:5532)
Board review style question #1
Which of the following proteins is blocked by atezolizumab?

  1. PD1
  2. PDL1
  3. PDGF
  4. PDE1
Board review style answer #1
B. PDL1

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Reference: Atezolizumab
Board review style question #2
Which of the following is true about the PDL1 SP142 assay?

  1. Evaluate percentage of tumor cells stained positive for PDL1 in urothelial carcinoma
  2. Evaluate percentage of tumor cells stained positive for PDL1 in triple negative breast carcinoma
  3. Evaluate percentage of tumor cells stained positive for PDL1 and disregard tumor infiltrating immune cells in non small cell lung cancer
  4. Evaluate percentage of tumor cells stained positive for PDL1 and evaluate tumor infiltrating immune cells if tumor cells are negative in non small cell lung cancer
Board review style answer #2
D. Evaluate percentage of tumor cells stained positive for PDL1 and evaluate tumor infiltrating immune cells if tumor cells are negative in non small cell lung cancer

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Reference: Atezolizumab
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