Atezolizumab

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]

In May 2018, Tecentriq was in combination with Avastin and standard chemotherapy for some patients with lung cancer was granted priority review.[5] A decision by the U.S. Food and Drug Administration is expected by 5 September 2018.[6]

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.[7]

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.[8]

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.[9]

Pharmacology

Mechanism of action

Atezolizumab blocks the interaction of PD-L1 with programmed cell death protein 1 (PD-1) and CD80 receptors (B7-1Rs).[10] 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.[10] 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."[10]

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.[10]

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.[11][12]

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

A phase 1 trial reported a 19% objective response rate in metastatic triple-negative breast cancer.[13]

References

  1. 1 2 3 4 "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. 1 2 "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. ↑ McKee, Selina (2018-05-08). "First-line use of Roche's Tecentriq given priority review". www.pharmatimes.com. Retrieved 2018-05-08.
  6. ↑ Editorial, Reuters. "Roche's Tecentriq combo wins fast FDA review in race to catch rivals". U.S. Retrieved 2018-05-08.
  7. ↑ Failed confirmatory trial raises questions about atezolizumab for advanced urothelial cancer. June 2017
  8. ↑ "FDA approves new treatment for non-small cell lung cancer". FDA. 18 Oct 2016. Retrieved 18 May 2016.
  9. ↑ FDA Professional Drug Information for Tecentriq.
  10. 1 2 3 4 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.
  11. ↑ "Search of: MPDL3280A - List Results - ClinicalTrials.gov".
  12. ↑ 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.
  13. ↑ "MPDL3280A Shows Activity in Triple-Negative Breast Cancer".
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