Atezolizumab

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]

Atezolizumab
Monoclonal antibody
TypeWhole antibody
SourceHumanized
TargetPD-L1
Clinical data
Trade namesTecentriq
Other namesMPDL3280A
AHFS/Drugs.comMonograph
MedlinePlusa616035
License data
Pregnancy
category
  • AU: D
  • US: N (Not classified yet)
    Drug classAntineoplastic agent
    ATC code
    Legal status
    Legal status
    Identifiers
    CAS Number
    DrugBank
    ChemSpider
    • none
    UNII
    KEGG
    Chemical and physical data
    FormulaC6446H9902N1706O1998S42
    Molar mass144612.59 g·mol−1

    History

    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 U.S. Food and Drug Administration (FDA).[2]

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

    In May 2018, atezolizumab was in combination with Avastin and standard chemotherapy for some patients with lung cancer was granted priority review.[5]

    In September 2018, it was announced that atezolizumab prolongs survival in extensive stage small cell lung cancer treatment, according to study results presented at the 19th World Conference on Lung Cancer (WCLC) in Toronto, Canada.[6]

    In October 2018, a combined clinical trial of the drug with nab-paclitaxel on patients with advanced triple negative breast cancer concluded.[7]

    In March 2019, it was approved in the United States, in combination with paclitaxel protein-bound, for adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] of any intensity covering ≥ 1% of the tumor area), as determined by an FDA-approved test.[8] The FDA also approved the VENTANA PD-L1 (SP142) Assay as a companion diagnostic device for selecting TNBC patients for atezolizumab.[9]

    Approval was based on IMpassion130 (NCT02425891), a multicenter, international, double-blinded, placebo-controlled, randomized trial that included 902 patients with unresectable locally advanced or metastatic TNBC who had not received prior chemotherapy for metastatic disease.[9] Patients were randomized (1:1) to receive either atezolizumab (840 mg) or placebo intravenous infusions on days 1 and 15 of every 28-day cycle, plus paclitaxel protein-bound (100 mg/m2) administered via intravenous infusion on days 1, 8, and 15 of every 28-day cycle.[9]

    Tumor specimens (archival or fresh) were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at a central laboratory and the results were used as a stratification factor for randomization and to define the PD-L1 positive population for pre-specified analyses.[9]

    In patients whose tumors express PD-L1, median progression-free survival (PFS) was 7.4 months (6.6, 9.2) for patients receiving atezolizumab with paclitaxel protein-bound and 4.8 months (3.8, 5.5) for those receiving placebo with paclitaxel protein-bound.[9] The stratified hazard ratio for PFS was 0.60 (95% CI: 0.48, 0.77; p<0.0001) in favor of the atezolizumab plus paclitaxel protein-bound arm.[9] Objective response rate (ORR) in patients with confirmed responses was 53% compared to 33% for the atezolizumab and the placebo-containing arms, respectively.[9] Overall survival data were immature with 43% deaths in the intent to treat (ITT) population.[9]

    In March 2019, it was approved in the United States, in combination with carboplatin and etoposide, for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC).[10]

    Approval was based on IMpower133 (NCT02763579), a randomized (1:1), multicenter, double-blind, placebo-controlled trial in 403 patients with ES-SCLC who received no prior chemotherapy for extensive stage disease and had ECOG performance status 0 or 1.[10] Patients were randomized to one of the following:

    • atezolizumab 1200 mg and carboplatin AUC 5 mg/mL/min on day 1 and etoposide 100 mg/m2 intravenously on days 1, 2 and 3 of each 21-day cycle for a maximum of 4 cycles, followed by atezolizumab 1200 mg once every 3 weeks until disease progression or unacceptable toxicity,[10] or
    • placebo and carboplatin AUC 5 mg/mL/min on day 1 and etoposide 100 mg/m2 intravenously on days 1, 2, and 3 of each 21-day cycle for a maximum of 4 cycles, followed by placebo once every 3 weeks until disease progression or unacceptable toxicity.[10]

    Major efficacy outcome measures were overall survival (OS) and progression-free survival (PFS) as assessed by investigator per RECIST 1.1 in the intent-to-treat population.[10] Median OS was 12.3 months (10.8, 15.9) for patients receiving atezolizumab with chemotherapy and 10.3 months (9.3, 11.3) for those receiving placebo with chemotherapy (hazard ratio 0.70; 95% CI: 0.54, 0.91; p=0.0069).[10] Median PFS was 5.2 months (4.4, 5.6) compared with 4.3 months (4.2, 4.5) in the atezolizumab and placebo arms, respectively (HR 0.77; 0.62, 0.96; p=0.0170).[10]

    Medical uses

    In May 2016, the FDA granted accelerated approval to atezolizumab for locally advanced or metastatic urothelial carcinoma treatment after failure of cisplatin-based chemotherapy.[3][11] The confirmatory trial (to convert the accelerated approval into a full approval) failed to achieve its primary endpoint of overall survival.[12] In 2018, FDA altered the use of atezolizumab as a first-line treatment for metastatic bladder cancer in patients who can't receive cisplatin-based chemotherapy and have high levels of PD-L1.[13]

    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]

    Atezolizumab is also used to treat extensive stage small cell lung cancer.[14]

    In March 2019, the FDA approved Atezolizumab for the treatment of patients with triple-negative breast cancer.

    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.[15]

    Pharmacology

    Mechanism of action

    Atezolizumab blocks the interaction of PD-L1 with programmed cell death protein 1 (PD-1) and CD80 receptors (B7-1Rs).[16] 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.[16] 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."[16]

    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.[16]

    Research

    As of 2016, it is currently in clinical trials for colorectal cancer, melanoma, breast cancer, non-small-cell lung carcinoma, bladder cancer, renal cell carcinoma.[17][18]

    Promising results have been observed for melanoma and non-small-cell lung cancer,[19] and bladder cancer.[1]

    A phase 1 trial reported a 19% objective response rate in metastatic triple-negative breast cancer.[20]

    As of 2019, atezolizumab is in trial for several types of cancer, such as pancreatic cancer, gastric cancer and ovarian Cancer. [21]

    References
    1. "Genentech Presents Positive Results of Atezolizumab in Advanced Bladder Cancer". 2 October 2015.
    2. Shields, Michael (11 April 2016). "Roche says FDA fast tracks atezolizumab in specific type of lung cancer". Reuters. Retrieved 11 April 2016.
    3. "FDA approves new, targeted treatment for bladder cancer" (Press release). U.S. Food and Drug Administration (FDA). 18 May 2016. Retrieved 20 May 2016. This article incorporates text from this source, which is in the public domain.
    4. "Roche's shocking Tecentriq fail raises red flag for bladder cancer rivals". FiercePharma. Retrieved 11 May 2017.
    5. McKee, Selina (8 May 2018). "First-line use of Roche's Tecentriq given priority review". www.pharmatimes.com. Retrieved 8 May 2018.
    6. "FDA approves new treatment for non-small cell lung cancer". U.S. Food and Drug Administration (FDA). 18 October 2016. Retrieved 18 May 2016. This article incorporates text from this source, which is in the public domain.
    7. Schmid, Peter; Adams, Sylvia; Rugo, Hope S.; Schneeweiss, Andreas; Barrios, Carlos H.; Iwata, Hiroji; Diéras, Véronique; Hegg, Roberto; Im, Seock-Ah (20 October 2018). "Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer". New England Journal of Medicine. 379 (22): 2108–2121. doi:10.1056/nejmoa1809615. ISSN 0028-4793. PMID 30345906.
    8. "Roche scores first U.S. approval of immunotherapy for breast cancer". STAT. Retrieved 9 March 2019.
    9. "FDA approves atezolizumab for PD-L1 positive unresectable locally advanced or metastatic triple-negative breast cancer". U.S. Food and Drug Administration (FDA) (Press release). 18 March 2019. Archived from the original on 5 December 2019. Retrieved 4 December 2019.
    10. "FDA approves atezolizumab for extensive-stage small cell lung cancer". U.S. Food and Drug Administration (FDA). 19 March 2019. Archived from the original on 5 December 2019. Retrieved 5 December 2019. This article incorporates text from this source, which is in the public domain.
    11. "Tecentriq (atezolizumab) Injection". U.S. Food and Drug Administration (FDA). 21 June 2016. Archived from the original on 5 December 2019. Retrieved 4 December 2019.
    12. Today, HemOnc; June 25; 2017. "Failed confirmatory trial raises questions about atezolizumab for advanced urothelial cancer". www.healio.com.
    13. "Checkpoint Inhibitor Use Changed for Bladder Cancer". National Cancer Institute. 26 July 2018.
    14. Concurrent Tecentriq Adds First Survival Benefit Seen in Small Cell Lung Cancer in 20 Years | https://www.curetoday.com/articles/concurrent-tecentriq-adds-first-survival-benefit-seen-in-small-cell-lung-cancer-in-20-years
    15. FDA Professional Drug Information for Tecentriq.
    16. Syn, Nicholas L; Teng, Michele W L; Mok, Tony S K; Soo, Ross A (2017). "De-novo and acquired resistance to immune checkpoint targeting". The Lancet Oncology. 18 (12): e731–e741. doi:10.1016/s1470-2045(17)30607-1. PMID 29208439.
    17. "Search of: MPDL3280A - List Results - ClinicalTrials.gov".
    18. 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.
    19. Facchinetti, Francesco. [Profile of atezolizumab in the treatment of metastatic non-small-cell lung cancer: patient selection and perspectives: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137949/ "Profile of atezolizumab in the treatment of metastatic non-small-cell lung cancer: patient selection and perspectives"] Check |url= value (help). US National Library of Medicine National Institutes of Health Search database Search term Clear input. Drug Design, Development and therapy. Retrieved 4 November 2019.
    20. "MPDL3280A Shows Activity in Triple-Negative Breast Cancer".
    21. "Pipeline". www.roche.com.
    • "Atezolizumab". Drug Information Portal. U.S. National Library of Medicine.
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