Erlotinib

Continuing Education Activity

Erlotinib is a tyrosine kinase receptor inhibitor approved by the US Food and Drug Administration (FDA) for the treatment of non-small cell lung cancer and advanced pancreatic cancer. This drug inhibits the epidermal growth factor receptor (EGFR), affecting both wild-type and mutated EGFRs, which are crucial in cellular differentiation, proliferation, and angiogenesis. Erlotinib’s efficacy is influenced by proper patient selection based on thorough diagnostic evaluation. The drug has a narrow therapeutic index, and its use is associated with adverse effects such as diarrhea and rash.

Proper patient selection based on a thorough diagnostic workup is essential to achieve superior outcomes compared to traditional chemotherapy. This activity provides an overview of erlotinib’s pharmacological features, including its indications, mechanism of action, contraindications, adverse event profile, dosing, and relevant drug interactions. This activity emphasizes interprofessional collaboration among healthcare providers to optimize dosing, manage adverse effects, and ensure safe and effective treatment outcomes through multidisciplinary efforts in monitoring, patient counseling, and overall therapeutic management. In addition, this activity provides clinicians with the knowledge to optimize patient selection through thorough diagnostic evaluation, improving therapeutic outcomes while offering insights into erlotinib’s safety profile, narrow therapeutic index, and potential adverse effects, thereby enhancing overall treatment efficacy.

Objectives:

• Identify the indications and contraindications for erlotinib therapy in patients with non-small cell lung cancer and advanced pancreatic cancer.
• Implement evidence-based dosing strategies for erlotinib, considering patient-specific factors such as smoking status and hepatic impairment.
• Select appropriate interventions to manage common adverse effects of erlotinib, such as diarrhea and rash, to improve patient quality of life.
• Collaborate with a multidisciplinary healthcare team, including oncologists and pharmacists, to provide comprehensive care for patients receiving erlotinib therapy.

Indications

Erlotinib is a first-generation receptor tyrosine kinase inhibitor (TKI) approved by the US Food and Drug Administration (FDA) for the treatment of certain types of non-small cell lung cancer (NSCLC) and advanced pancreatic cancer.

FDA-Approved Indications

Non-small cell lung cancer: The FDA originally approved erlotinib for the treatment of NSCLC in November 2004. According to the American Society of Clinical Oncology (ASCO), erlotinib is recommended as a first-, second-, or third-line therapy for patients with advanced NSCLC. However, erlotinib is recommended as a first-line agent only for patients with a known epidermal growth factor receptor (EGFR) mutation. Erlotinib may be administered as second-line therapy if there is no treatment response after 4 cycles or if disease progression occurs during or after platinum-based therapy. Additionally, erlotinib may be used as a third-line therapy if the disease progresses and the patient is naïve to both erlotinib and gefitinib.[1][2][3] Notably, osimertinib—the third-generation TKI—is associated with improved overall survival compared to erlotinib in patients with EGFR-mutated advanced NSCLC.

Patients with metastatic NSCLC may benefit from oral erlotinib therapy based on confirmed EGFR exon mutations (specifically 19 deletions or exon 21 [L858R] substitutions) in their plasma, as determined by an FDA-approved test or tumor specimens. This treatment can be administered as first-line, maintenance, or second-line therapy following disease progression after at least one prior chemotherapy regimen. Information on FDA-approved tests for detecting EGFR mutations in NSCLC can be found at http://www.fda.gov/CompanionDiagnostics.

Limitations:

• The efficacy and safety of erlotinib have not been established in patients with NSCLC whose tumors have other EGFR mutations.
• Additionally, erlotinib tablets are not recommended for use in combination with platinum-based chemotherapy.

Pancreatic cancer: The FDA approved erlotinib as a treatment for pancreatic cancer in 2005. Many human pancreatic cancers exhibit the EGFR mutation, and patients with this mutation often have a poor prognosis. Historically, gemcitabine monotherapy was the standard treatment for advanced pancreatic cancer. However, recent studies have shown promising results with combinations of gemcitabine and other anti-cancer agents, including erlotinib. The combination of erlotinib and gemcitabine has demonstrated superior benefits compared to gemcitabine monotherapy for patients with locally advanced or metastatic pancreatic cancer. Consequently, erlotinib, in combination with gemcitabine, is indicated as the first-line treatment for patients with locally advanced, unresectable, or metastatic pancreatic cancer. Erlotinib has not been studied as a monotherapy for pancreatic cancer.[4]

Off-Label Use

Advanced renal cell carcinoma (papillary): Erlotinib is administered at a dosage of 150 mg orally once daily, with or without bevacizumab, until disease progression occurs or unacceptable toxicity is observed.[5]

Mechanism of Action

Erlotinib is a reversible first-generation receptor TKI that primarily targets the EGFR, which belongs to the ErbB receptor family. The drug interacts with both wild-type and mutated forms of EGFR. Members of the ErbB family can form homodimers or heterodimers, which are often involved in the downstream effects and pathogenesis of various carcinomas studied in humans. Receptor TKIs inhibit the phosphorylation of their substrates within the cell signaling pathway. EGFR has a critical role in numerous cellular functions, including differentiation, proliferation, and angiogenesis, all of which are hallmarks of cancer.[6][7]

EGFR mutation in NSCLC is typically an activating mutation. Patient risk factors that increase the likelihood of an EGFR mutation include a lack of smoking history, adenocarcinoma confirmed by histological analysis, Asian ethnicity, and female sex.[8] Secondary mutations in EGFR commonly occur and are discussed below. Erlotinib induces the cytochrome P450 (CYP) isoenzymes CYP1A1 and 1A2, strongly inhibits CYP1A1, and moderately inhibits CYP3A4 and 2C8.[9]

Pharmacokinetics

Absorption: Erlotinib's oral absorption is about 60% when taken on an empty stomach but increases to nearly 100% when consumed with food.

Distribution: Erlotinib has a distribution volume of 232 L, with approximately 93% of the drug binding to albumin and α1-acid glycoprotein in the blood.

Metabolism: Erlotinib is primarily metabolized in the liver by the enzyme CYP3A4, with lesser contributions from CYP1A1, CYP1A2, and CYP2C. The bioavailability of the drug is approximately 100% when taken with food and 60% without. The drug has an elimination half-life of 36.2 hours and reaches peak plasma concentration within 4 hours of administration.

Elimination: Erlotinib is primarily excreted as metabolites, with 83% eliminated through feces and 8% through urine.

Administration

Available Dosage Forms and Strengths

Erlotinib is available in oral tablet form with strengths of 25 mg, 100 mg, and 150 mg.

Adult Dosage

The recommended starting dose for NSCLC is 150 mg daily, while for pancreatic cancer, the standard starting dose is 100 mg daily when used in combination with gemcitabine.

The updated ASCO guidelines for metastatic pancreatic cancer recommend gemcitabine monotherapy as the first-line treatment for patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or those with comorbid conditions that make more aggressive therapies unsuitable. In these cases, erlotinib may be added to gemcitabine therapy, with dosing adjustments made to minimize toxicity.[10]

Erlotinib has a narrow therapeutic index and is recommended to be taken on an empty stomach, as studies have shown that its bioavailability significantly increases when taken with food.

Specific Patient Populations

Hepatic impairment: Erlotinib should be withheld and possibly discontinued if bilirubin levels double or transaminase levels triple compared to baseline in patients with preexisting liver conditions or biliary obstruction. Erlotinib should also be withheld in patients without preexisting hepatic impairment who have total bilirubin levels greater than 3 times the upper limit of normal or transaminase levels exceeding 5 times the upper limit of normal.

Renal impairment: Erlotinib should be withheld in patients with severe renal toxicity, and discontinuation should be considered.

Pregnancy considerations: Animal studies and the drug's mechanisms of action suggest that erlotinib may cause fetal harm if administered to a pregnant woman. Limited data on erlotinib use during pregnancy is insufficient to determine the risk of major congenital disabilities or miscarriage; however, it is known to cross the placenta.[11][12] Clinicians should inform pregnant women about the potential risks to the fetus.

Breastfeeding considerations: Patients should be advised against breastfeeding during treatment with erlotinib and for 2 weeks after the last dose.

Smoking: Cigarette smoking decreases the area under the curve of erlotinib by 64% compared to former or never smokers, necessitating higher doses for these patients. For patients who smoke, erlotinib doses should be increased by 50 mg every 2 weeks, up to a maximum of 300 mg. If the patient quits smoking, the erlotinib dose should be promptly reduced to the recommended level of 150 mg or 100 mg daily.

Adverse Effects

According to the manufacturer’s labeling, reported adverse reactions occur more frequently during erlotinib monotherapy than with placebo. Adverse reactions occurring in less than 3% of patients are not included here.

General Adverse Effects

• Fatigue: 9.0%

Gastrointestinal Adverse Effects

• Diarrhea: 20.3%
• Anorexia: 9.2%
• Weight loss: 3.9%

Dermatological Adverse Effects

• Rash: 49%
• Pruritis: 7.4%
• Acne: 6.2%
• Dermatitis acneiform: 4.6%
• Xerosis: 4.4%
• Paronychia: 3.9%

Adverse effects of erlotinib are similar to those seen with other EGFR-TKIs, with diarrhea and rash being the most notable. Chest pain is also frequently reported. A multicenter, open-label, phase 3 clinical trial found that 13% of patients receiving erlotinib developed a rash during treatment, compared to 0% in the standard chemotherapy group. Another phase 3 open-label study revealed that 50% of patients in the erlotinib group reported a rash, while only 5% in the chemotherapy group did. Additionally, 18% of patients in the erlotinib group experienced diarrhea, compared to 2% in the chemotherapy group. Severe adverse events are less common in patients treated with erlotinib compared to the treatment groups receiving standard chemotherapy.[13]

Severe Adverse Effects

According to the manufacturer’s package insert, the following severe adverse events have been reported in patients receiving erlotinib:

• Acute renal failure and renal insufficiency, particularly in dehydrated patients.
• Cardiac arrhythmias in patients coadministered gemcitabine.
• Hepatotoxicity and hepatorenal syndrome, which can be fatal.
• International normalized ratio (INR) elevations in patients coadministered warfarin.
• Exfoliative skin disorders.
• Gastrointestinal perforations, which can be fatal.
• Corneal perforation.
• Myocardial infarction, myocardial ischemia, cerebrovascular accident (CVA), and microangiopathic hemolytic anemia with thrombocytopenia, especially in patients with comorbid pancreatic cancer.

Drug-Drug Interactions

• Patients should avoid using proton pump inhibitors while taking erlotinib, as increased stomach pH can reduce erlotinib concentrations.
• H2 antagonists and antacids should be administered several hours before erlotinib to prevent absorption interference.[14]
• For patients taking potent CYP3A4 inhibitors, the erlotinib dose should be reduced in 50 mg increments or concomitant use should be avoided if possible. 
• When used with CYP3A4 inducers, erlotinib doses should be increased by 50 mg every 2 weeks, up to a maximum of 450 mg, as tolerated. Avoid concomitant use if possible.

Contraindications

According to the US manufacturer's label, there are no formal contraindications to erlotinib. However, while data on its use during pregnancy is limited, animal studies suggest that erlotinib may cause harm to the fetus. Despite this, there have been documented cases of women receiving erlotinib during pregnancy and giving birth without complications. Notably, it is recommended that women of childbearing potential use contraception during treatment with erlotinib and for at least one month after discontinuation of the drug.[11][15][16]

Monitoring

Due to reports of hepatotoxicity and hepatic failure, close monitoring of patients on erlotinib is essential. Discontinuation is recommended if total bilirubin rises to 3 times above baseline or transaminase levels increase to 5 times above baseline. While all patients need regular monitoring, those with preexisting hepatic impairment are at a higher risk for hepatotoxicity when taking erlotinib.[14]

Tumors may develop resistance to EGFR-TKIs, often requiring changes to the treatment regimen. The most common resistance mechanism is a secondary EGFR mutation, known as the T790M mutation, which occurs in exon 20 of the gene. This mutation has been identified in up to half of the patients treated with erlotinib or gefitinib. Other mechanisms of EGFR-TKI resistance include the upregulation of MET, insulin-like growth factor 1 (IGF-1), and hepatocyte growth factor.[17] If TKI resistance arises from a secondary mutation, second- and third-generation TKIs may be effective. The FDA has granted breakthrough approval for the third-generation TKI osimertinib as a first-line treatment for patients with NSCLC harboring the T790M mutation.[2]

Toxicity

According to the manufacturer, cancer patients can tolerate weekly doses of up to 1600 mg before toxicity occurs. If an overdose of erlotinib is suspected, symptomatic treatment and discontinuation of the medication are recommended. Therapy should be withheld if the patient experiences persistent severe diarrhea unresponsive to medical management (eg, loperamide), severe rash unresponsive to treatment, or keratitis of grade 3 or 4 (NCI-CTC version 4.0), or grade 2 keratitis lasting longer than 2 weeks.

Erlotinib tablets should be discontinued if a patient experiences any of the following adverse events:

• Interstitial lung disease
• Severe hepatic toxicity that does not improve significantly or resolve within 3 weeks
• Gastrointestinal perforation
• Corneal perforation or severe ulceration [18]

Enhancing Healthcare Team Outcomes

Effective communication among healthcare team members is essential for the successful administration of erlotinib, which has a narrow therapeutic index and is typically prescribed by oncology specialists. Clinicians must handle the drug with care, as it is classified as a hazardous agent by the National Institute for Occupational Safety and Health (NIOSH). All healthcare team members, including primary care providers, nursing staff, and pharmacists, should be aware of the risks of diarrhea, rash, and severe adverse events. Clinicians should be aware of the CYP enzyme interactions that can affect blood levels of erlotinib, either elevating or decreasing them. Consequently, it is essential to frequently monitor patients' medication lists to prevent these interactions. This is where the expertise of a board-certified oncology pharmacist is invaluable, as they collaborate with the prescriber on optimal dosing, assess potential interactions, and provide counseling to patients about adverse events.

Nursing staff should also be aware of these adverse effects during their monitoring, as they typically have more patient contact than other healthcare team members. The entire healthcare team must guide the patient on the correct administration of the medication, which should occur either before or 2 hours after meals. Additionally, the primary care team should be informed of the recommendation that women taking this medication should avoid becoming pregnant, and discussions about ongoing contraception should be encouraged. These strategies and interprofessional actions contribute to optimizing therapeutic outcomes and enhancing patient safety with erlotinib.

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Azzoli CG, Temin S, Giaccone G. 2011 Focused Update of 2009 American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non-Small-Cell Lung Cancer. J Oncol Pract. 2012 Jan;8(1):63-6. [PMC free article: PMC3266319] [PubMed: 22548014]

2.

Bulbul A, Husain H. First-Line Treatment in EGFR Mutant Non-Small Cell Lung Cancer: Is There a Best Option? Front Oncol. 2018;8:94. [PMC free article: PMC5932412] [PubMed: 29755953]

3.

Saito H, Fukuhara T, Furuya N, Watanabe K, Sugawara S, Iwasawa S, Tsunezuka Y, Yamaguchi O, Okada M, Yoshimori K, Nakachi I, Gemma A, Azuma K, Kurimoto F, Tsubata Y, Fujita Y, Nagashima H, Asai G, Watanabe S, Miyazaki M, Hagiwara K, Nukiwa T, Morita S, Kobayashi K, Maemondo M. Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol. 2019 May;20(5):625-635. [PubMed: 30975627]

4.

Wang Y, Hu GF, Zhang QQ, Tang N, Guo J, Liu LY, Han X, Wang X, Wang ZH. Efficacy and safety of gemcitabine plus erlotinib for locally advanced or metastatic pancreatic cancer: a systematic review and meta-analysis. Drug Des Devel Ther. 2016;10:1961-72. [PMC free article: PMC4912328] [PubMed: 27358556]

5.

Gordon MS, Hussey M, Nagle RB, Lara PN, Mack PC, Dutcher J, Samlowski W, Clark JI, Quinn DI, Pan CX, Crawford D. Phase II study of erlotinib in patients with locally advanced or metastatic papillary histology renal cell cancer: SWOG S0317. J Clin Oncol. 2009 Dec 01;27(34):5788-93. [PMC free article: PMC2793000] [PubMed: 19884559]

6.

Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M, Maiello MR, Carotenuto A, De Feo G, Caponigro F, Salomon DS. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene. 2006 Jan 17;366(1):2-16. [PubMed: 16377102]

7.

Normanno N, Maiello MR, De Luca A. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs): simple drugs with a complex mechanism of action? J Cell Physiol. 2003 Jan;194(1):13-9. [PubMed: 12447985]

8.

Roengvoraphoj M, Tsongalis GJ, Dragnev KH, Rigas JR. Epidermal growth factor receptor tyrosine kinase inhibitors as initial therapy for non-small cell lung cancer: focus on epidermal growth factor receptor mutation testing and mutation-positive patients. Cancer Treat Rev. 2013 Dec;39(8):839-50. [PubMed: 23768755]

9.

Luong TT, Powers CN, Reinhardt BJ, McAnulty MJ, Weina PJ, Shou KJ, Ambar CB. Retrospective Evaluation of Drug-Drug Interactions With Erlotinib and Gefitinib Use in the Military Health System. Fed Pract. 2023 Aug;40(Suppl 3):S24-S34. [PMC free article: PMC10681012] [PubMed: 38021095]

10.

Sohal DPS, Kennedy EB, Cinar P, Conroy T, Copur MS, Crane CH, Garrido-Laguna I, Lau MW, Johnson T, Krishnamurthi S, Moravek C, O'Reilly EM, Philip PA, Pant S, Shah MA, Sahai V, Uronis HE, Zaidi N, Laheru D. Metastatic Pancreatic Cancer: ASCO Guideline Update. J Clin Oncol. 2020 Sep 20;38(27):3217-3230. [PubMed: 32755482]

11.

Ji Y, Schwartz J, Hartford A, Ramsey J, Phillips J, Verschraegen C. Successful Treatment of Non-Small Cell Lung Cancer With Erlotinib Throughout Pregnancy. JAMA Oncol. 2015 Sep;1(6):838-40. [PubMed: 26181671]

12.

Jovelet C, Seck A, Mir O, Simasotchi C, Broutin S, Goffinet F, Bidart JM, Paci A, Gil S. Variation in transplacental transfer of tyrosine kinase inhibitors in the human perfused cotyledon model. Ann Oncol. 2015 Jul;26(7):1500-4. [PubMed: 25851627]

13.

Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Muñoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L., Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 Mar;13(3):239-46. [PubMed: 22285168]

14.

Kucharczuk CR, Ganetsky A, Vozniak JM. Drug-Drug Interactions, Safety, and Pharmacokinetics of EGFR Tyrosine Kinase Inhibitors for the Treatment of Non-Small Cell Lung Cancer. J Adv Pract Oncol. 2018 Mar;9(2):189-200. [PMC free article: PMC6302998] [PubMed: 30588353]

15.

Rivas G, Llinás N, Bonilla C, Rubiano J, Cuello J, Arango N. Use of erlotinib throughout pregnancy: a case-report of a patient with metastatic lung adenocarcinoma. Lung Cancer. 2012 Aug;77(2):469-72. [PubMed: 22534670]

16.

Zambelli A, Prada GA, Fregoni V, Ponchio L, Sagrada P, Pavesi L. Erlotinib administration for advanced non-small cell lung cancer during the first 2 months of unrecognized pregnancy. Lung Cancer. 2008 Jun;60(3):455-7. [PubMed: 18063195]

17.

Takeda M, Nakagawa K. First- and Second-Generation EGFR-TKIs Are All Replaced to Osimertinib in Chemo-Naive EGFR Mutation-Positive Non-Small Cell Lung Cancer? Int J Mol Sci. 2019 Jan 03;20(1) [PMC free article: PMC6337322] [PubMed: 30609789]

18.

Tamura M, Takai Y, Nakamura S, Ohira A. A case report of pseudo-exfoliation syndrome with prolonged corneal epithelial regeneration because of erlotinib-induced unilateral corneal ulcer and anterior uveitis. Acta Ophthalmol. 2020 Dec;98(8):e1055-e1056. [PubMed: 32483873]

Disclosure: Jake Carter declares no relevant financial relationships with ineligible companies.

Disclosure: Prasanna Tadi declares no relevant financial relationships with ineligible companies.