Erlotinib (trade name name Tarceva), is a medication used to treat non-small cell lung cancer (NSCLC) and pancreatic cancer. Specifically it is used for NSCLC with mutations in the epidermal growth factor receptor (EGFR) — either an exon 19 deletion (del19) or exon 21 (L858R) substitution mutation — which has spread to other parts of the body.

Erlotinib is a receptor tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor (EGFR). It was approved for medical use in the United States in 2004, and is on the World Health Organization’s List of Essential Medicines.

Clinical Uses of Erlotinib

Erlotinib is not a substrate for either of hepatic OATPs (OATP1B1 or OATP1B3). Also, erlotinib is not an inhibitor of OATP-1B1 or OATP-1B3 transporter.

Lung Cancer

Erlotinib in unresectable non-small cell lung cancer when added to chemotherapy has been shown to improve overall survival by 19%, and improved progression-free survival (PFS) by 29%, compared to chemotherapy alone1. The U.S. Food and Drug Administration (FDA) has approved erlotinib for the treatment of locally advanced or metastatic non-small cell lung cancer that has failed at least one prior chemotherapy regimen2.

In lung cancer, erlotinib has been shown to be effective in patients with or without EGFR mutations, but appears to be more effective in patients with EGFR mutations3. Overall survival, progression-free survival and one-year survival are similar to standard second-line therapy (docetaxel or pemetrexed).

Overall response rate is about 50% better than standard second-line chemotherapy. Patients who are non-smokers, and light former smokers, with adenocarcinoma or subtypes like BAC are more likely to have EGFR mutations, but mutations can occur in all types of patients.

Pancreatic Cancer

In November 2005, the FDA approved erlotinib in combination with gemcitabine for treatment of locally advanced, unresectable, or metastatic pancreatic cancer.

Resistance To Erlotinib

As with other ATP competitive small molecule tyrosine kinase inhibitors, such as imatinib in CML, patients rapidly develop resistance. In the case of erlotinib this typically occurs 8–12 months from the start of treatment. Over 50% of resistance is caused by a mutation in the ATP binding pocket of the EGFR kinase domain involving substitution of a small polar threonine residue with a large nonpolar methionine residue (T790M).

Approximately 20% of drug resistance is caused by amplification of the hepatocyte growth factor receptor, which drives ERBB3 dependent activation of PI3K4.

Common Side Effects

  • Rash occurs in the majority of patients. This resembles acne and primarily involves the face and neck. It is self-limited and resolves in the majority of cases, even with continued use. Some clinical studies have indicated a correlation between the severity of the skin reactions and increased survival though this has not been quantitatively assessed.
  • Diarrhea
  • Loss of appetite
  • Fatigue
  • Partial hair loss (by strands, not typically in clumps)

More rarely seen side effects include ingrown hairs, such as eyelashes, corneal lesions, pulmonary fibrosis, and interstitial pneumonitis. Use in pregnancy may harm the baby.

Mechanism of Action

Erlotinib is an epidermal growth factor receptor inhibitor (EGFR inhibitor). The drug follows Iressa (gefitinib), which was the first drug of this type.

Erlotinib specifically targets the epidermal growth factor receptor(EGFR) tyrosine kinase, which is highly expressed and occasionally mutated in various forms of cancer. It binds in a reversible fashion to the adenosine triphosphate (ATP) binding site of the receptor.

For the signal to be transmitted, two EGFR molecules need to come together to form a homodimer. These then use the molecule of ATP to trans-phosphorylate each other on tyrosine residues, which generates phosphotyrosine residues, recruiting the phosphotyrosine-binding proteins to EGFR to assemble protein complexes that transduce signal cascades to the nucleus or activate other cellular biochemical processes.

When erlotinib binds to EGFR, formation of phosphotyrosine residues in EGFR is not possible and the signal cascades are not initiated.

  1. Joel W Neal. The SATURN trial: the value of maintenance erlotinib in patients with non-small-cell lung cancer. Future Oncology 2010 6:12, 1827-1832 ↩︎

  2. Cohen, Martin H.; Johnson, John R.; Chen, Yeh-Fong; Sridhara, Rajeshwari; Pazdur, Richard (August 2005). FDA drug approval summary: erlotinib (Tarceva) tablets. The Oncologist. 10 (7): 461–466. ↩︎

  3. Qi WX, Shen Z, Lin F, et al. (2012). Comparison of the efficacy and safety of EFGR tyrosine kinase inhibitor monotherapy with standard second-line chemotherapy in previously treated advanced non-small-cell lung cancer: A systematic review and meta-analysis. Asian Pacific Journal of Cancer Prevention. 13 (10): 5177–5182. ↩︎

  4. Engelman JA, Zejnullahu K, Mitsudomi T, et al. (2007). MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling. Science. 316 (5827): 1039–43. ↩︎

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