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Atezolizumab

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Atezolizumab
Monoclonal antibody
TypeWhole antibody
SourceHumanized
TargetPD-L1
Clinical data
Trade namesTecentriq
Other namesMPDL3280A
AHFS/Drugs.comtecentriq
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

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]

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 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]

In September 2018, it was announced that Tecentriq 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.[5]

In May 2018, Tecentriq was in combination with Avastin and standard chemotherapy for some patients with lung cancer was granted priority review.[6]

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

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.[8]

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.[5]

Aatezolizumab is also used to treat extensive stage small cell lung cancer[9]


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.[10]

Pharmacology

Mechanism of action

Atezolizumab blocks the interaction of PD-L1 with programmed cell death protein 1 (PD-1) and CD80 receptors (B7-1Rs).[11] 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.[11] 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."[11]

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.[11]

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.[12][13]

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.[14]

As of 2019, Atezolizumab is in trial for several types of cancer, such as pancreatic cancer, gastric cancer and ovarian Cancer. [15]

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. ^ a b "FDA approves new treatment for non-small cell lung cancer". FDA. 18 Oct 2016. Retrieved 18 May 2016.
  6. ^ McKee, Selina (2018-05-08). "First-line use of Roche's Tecentriq given priority review". www.pharmatimes.com. Retrieved 2018-05-08.
  7. ^ Schmid, Peter; Adams, Sylvia; Rugo, Hope S.; Schneeweiss, Andreas; Barrios, Carlos H.; Iwata, Hiroji; Diéras, Véronique; Hegg, Roberto; Im, Seock-Ah (2018-10-20). "Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer". New England Journal of Medicine. doi:10.1056/nejmoa1809615. ISSN 0028-4793.
  8. ^ Failed confirmatory trial raises questions about atezolizumab for advanced urothelial cancer. June 2017
  9. ^ 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
  10. ^ FDA Professional Drug Information for Tecentriq.
  11. ^ 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.
  12. ^ "Search of: MPDL3280A - List Results - ClinicalTrials.gov".
  13. ^ 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.
  14. ^ "MPDL3280A Shows Activity in Triple-Negative Breast Cancer".
  15. ^ https://www.roche.com/research_and_development/who_we_are_how_we_work/pipeline.htm
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