Erlotinib

Mechanism of Action

Erlotinib is a reversible first-generation receptor tyrosine kinase inhibitor (along with gefitinib) acting primarily on the epidermal growth factor receptor (EGFR), a member of the ErbB receptor family. The drug interacts with both wild-type and mutation EGFR. The ErbB family can form homodimers or heterodimers, often implicated in downstream effects and pathogenesis of many types of carcinomas studied in humans. Receptor tyrosine kinase inhibitors (TKI) prevent the phosphorylation of their substrate in the cell signaling pathway. EGFR normally plays a role in many cellular functions, including differentiation, proliferation, and angiogenesis, all of which are hallmarks of cancer.[4][5]

EGFR mutation in NSCLC is typically an activating mutation. Some patient characteristics that make the presence of EGFR mutation more likely include no history of smoking confirmed adenocarcinoma by histologic analysis, Asian ethnicity, and female sex.[6] Secondary mutations in the EGFR commonly occur, which this topic describes below. 

Administration

Erlotinib is available in 25 mg, 100 mg, and 150 mg of oral tablets. The recommended starting dose for NSCLC is 150 mg daily, while the standard starting dose for pancreatic cancer is 100 mg daily. The recommendation is that patients take erlotinib on an empty stomach, as studies have shown that bioavailability increases when taken with food. Patients should avoid concomitant use of proton pump inhibitors (PPIs) while taking erlotinib, as a higher stomach pH can alter erlotinib concentrations. H2 blockers and antacids should be given several hours before the administration of erlotinib.[7]

To avoid adverse interactions, reduce the dose of erlotinib when used with potent CYP3A4 inhibitors. Increase the dose when used with CYP3A4 inducers. 

Adverse Effects

According to the manufacturer’s labeling, the reported adverse reactions occur more frequently in single-agent erlotinib therapy compared to placebo. Adverse reactions in less than 3% of patients do not appear here.

General

• Fatigue (9.0% any grade)

Gastrointestinal

• Diarrhea (20.3% any grade)
• Anorexia (9.2% any grade)
• Weight loss (3.9% any grade)

Dermatologic

• Rash (49% any grade)
• Pruritis (7.4% any grade)
• Acne (6.2% any grade)
• Dermatitis acneiform (4.6% any grade)
• Xerosis (4.4% any grade)
• Paronychia (3.9% any grade)

Adverse effects of erlotinib are similar to those of the rest of the EGFR TKI family, the most notable being diarrhea and rash. Chest pain is also commonly seen. One multicenter, open-label, phase 3 clinical trial demonstrated that 13% of erlotinib vs. 0% on standard chemotherapy developed a rash during treatment. Another phase 3 open-label study found that 50% of the erlotinib treatment group reported rash vs. 5% in the chemotherapy group. This study also observed that 18% of patients in the erlotinib treatment group reported diarrhea vs. 2% in the chemotherapy group. One must note that serious adverse events are less common in erlotinib treatment groups compared to standard chemotherapy treatment groups.[8] 

Serious Adverse Effects

According to the manufacturer’s package insert, the following are the serious adverse events reported in patients taking erlotinib:

• Acute renal failure and renal insufficiency (recommendations are to withhold erlotinib if a patient becomes dehydrated)
• Cardiac arrhythmias in patients taking erlotinib with gemcitabine
• Hepatotoxicity and hepatorenal syndrome, including fatalities
• INR elevations in patients taking erlotinib and Warfarin concomitantly
• Exfoliative skin disorders.
• GI perforations, including fatalities
• Corneal perforation
• In patients with comorbid pancreatic cancer, myocardial infarction, myocardial ischemia, CVA, and microangiopathic hemolytic anemia with thrombocytopenia

Contraindications

The US manufacturer’s label indicates that there are no contraindications to erlotinib. While data on erlotinib in pregnancy is limited, animal studies indicate that erlotinib could potentially cause harm in pregnancy. Case reports of women taking erlotinib giving birth without complications are available. Contraception is recommended in women with childbearing potential throughout treatment with erlotinib, continuing for at least 1 month after discontinuation of the drug.[9][10][11]

Monitoring

Due to reports of hepatotoxicity and hepatic failure, patients require close monitoring. The recommendation is to discontinue erlotinib if total bilirubin increases to levels 3 times higher than the patient’s baseline or if transaminase levels increase to 5 times higher than the patient’s baseline. While all patients require monitoring, it is important to note that patients with baseline hepatic impairment are at increased risk for hepatoxicity when taking erlotinib.[7]

It is important to note that tumors may develop resistance to EGFR-TKIs, which can necessitate altering the treatment regimen. The most common mode of resistance comes through a secondary mutation in EGFR known as T790M mutation, which occurs in exon 20 of EGFR. Research has found the T790M mutation in up to half of the patients treated with erlotinib or gefitinib. Other mechanisms of EGFR-TKI resistance are the upregulation of MET, insulin-like growth factor 1, and hepatocyte growth factor.[12] If TKI resistance occurs due to a secondary mutation, using second and third-generation TKIs can be beneficial. The FDA has granted breakthrough approval for third-generation TKI osimertinib as a first-line treatment in NSCLC with a positive T790M mutation.[2]

Toxicity

According to the manufacturer, cancer patients tolerate weekly dosing totaling 1600 mg without toxicity. If a clinician believes that a patient has had an overdose of erlotinib, then the recommendation is for symptomatic treatment, as well as the discontinuation of the medication.

Enhancing Healthcare Team Outcomes

Communication between all interprofessional healthcare team members is requisite for the successful use of erlotinib. Erlotinib has a narrow therapeutic index and is typically only prescribed by oncology specialists. However, all healthcare team members, including primary care physicians, nursing staff, and pharmacy, should be aware of the potential for diarrhea, rash, and erlotinib's other adverse effects. All healthcare team members should be mindful of the CYP enzyme interactions that can elevate or decrease blood levels of erlotinib; the patient's medication list should be frequently monitored to ensure these interactions are not occurring. This is where the services of a board-certified oncology pharmacist can be crucial; they can work with the prescriber on optimal dosing, checking for potential interactions, and counseling the patient regarding adverse events. Nursing staff must also be aware of these side effects as part of their monitoring, as they likely have more patient contact than other team members. It is also essential that the entire healthcare team monitors and counsels the patient on the correct administration of this medication either before or 2 hours after meals. The patient's primary care team should also be aware of the recommendation that women taking this medication should not become pregnant; discussion about ongoing contraception should be encouraged. All these interprofessional team actions can help optimize therapeutic results with erlotinib.