Afatinib Vs Gefitinib​ For Lung Cancer Treatment

Lung cancer, particularly non-small cell lung cancer (NSCLC), ranks among the most common causes of cancer-related deaths around the world. The advent of targeted therapies in the treatment of NSCLC has changed the way clinicians interact with the condition, specifically in patients with epidermal growth factor receptor (EGFR) mutations. Two medications have more or less emerged as front-runners in this category: Afatinib and Gefitinib. Both are tyrosine kinase inhibitors (TKIs) that target the EGFR, but are different drugs with differing mechanisms of action. This blog will delineate the differences, similarities, and clinical implications of Afatinib vs Gefitinib for EGFR-mutated NSCLC.

Key Differences between Afatinib and Gefitinib

Define Afatinib and Gefitinib

Afatinib and Gefitinib are both oral prescription medications used for lung cancer patients with specific EGFR gene mutations. These mutations lead to irregular activation of EGFR and, therefore, abnormal increase of malignant and other cancer cells. 

Afatinib (Gilotrif) is a second-generation EGFR inhibitor that irreversibly attaches to EGFR. This irreversible binding leads to a longer duration of action for Afatinib, with prolonged tumor suppression. Pretreatment with Afatinib resulted in a median of 10.9 months of progression-free survival after first-line treatment or after chemotherapy.

Gefitinib (Iressa) is a first-generation EGFR inhibitor. Gefitinib works by reversibly binding to EGFR and blocking the signalling pathways that promote cancer cell proliferation.

Both drugs have received approval from the FDA and other regulatory bodies for the treatment of advanced NSCLC with EGFR mutation and for patients who are treatment naive or unresponsive to chemotherapy.

Mechanism of Action

The key difference between Afatinib and Gefitinib is their mechanism of action and their effects on the EGFR pathway:
 

• Afatinib: An irreversible TKI, Afatinib binds covalently to the tyrosine kinase domain of EGFR, HER2, and HER4. This mechanism of action has shown that Afatinib effectively blocks all EGFR-driven signaling pathways regardless of mutations in other related receptors. Because of this broad action, Afatinib is effective for many different mutations, including the most common - L858R, Exon 19 deletion mutations, and the less common T790M resistance mutation.

• Gefitinib: A reversible TKI that binds to the tyrosine kinase domain of EGFR, blocking the ability to transmit the signals that lead to cancer cell growth. Gefitinib is less potent than Afatinib in general and particularly in certain mutations and resistance mechanisms, even if both drugs are effective for EGFR-mutant tumors.

Efficacy: Afatinib and Gefitinib

The information gained from clinical trials comparing Afatinib and Gefitinib could demonstrate efficacy in tumor shrinkage, as well as progression-free survival (PFS). 

• Afatinib: In the LUX-Lung studies, Afatinib was shown to enhance PFS compared to traditional chemotherapy in patients with EGFR-mutant NSCLC. In the LUX-Lung 3 trial, Afatinib was demonstrated to improve median PFS by 11.0 months compared to standard chemotherapy/chemoradiation, although it was not superior in T790M mutation in resistance to first-generation EGFR TKIs such as Gefitinib. 

• Gefitinib: The IPASS trial, as an important piece of evidence for failure of the therapy, showed that Gefitinib improved PFS compared to chemotherapy in patients with EGFR mutations. The median PFS in this test was 9.5 months. In addition, it has been indicated that resistance develops relatively rapidly against Gefitinib (T790M mutation), whereas Afatinib has been shown to demonstrate efficacy.

Side Effects of Afatinib vs Gefitinib

Afatinib and gefitinib have common side effects, but the severity and frequency of side effects may differ. 

• Afatinib: The common side effects of afatinib include diarrhea, skin rash, mouth sores, and nail changes. One of the most challenging side effects can be diarrhea that may require dose changes and hydration management. However, there are some cases when afatinib side effects can be more manageable than gefitinib due to better patient support and interventions.

• Gefitinib: Similarly, gefitinib patients will have gastrointestinal side effects, such as diarrhea, but are also more likely to experience mild liver enzyme elevation. Growing areas of skin rash are common and may be painful for patients. Most of these side effects are treatable with symptomatic approaches.

Generic Options

One of the factors that affects treatment choices is the cost of the medications involved. Afatinib and Gefitinib have generic versions available, so they are cheaper alternatives for patients.

• Generic Afatinib: Afatinib has a generic version available as the chemical name Afatinib (the branded drug). The generic version is typically less expensive (than the branded version), so it could be a preferred option for patients with insurance or out-of-pocket costs are a barrier.

• Generic Gefitinib: The same can be said for the generic versions of Gefitinib in many countries. The cost in each region may differ, which may or may not affect the availability of the drug.

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Conclusion

Afatinib and Gefitinib play vital roles in the treatment of EGFR-mutant NSCLC, though each drug has its benefits or considerations. Afatinib's wider, more potent mechanism of action is favorable to some patients, especially to patients with resistance mutations like T790M. Gefitinib, however, continues to have a place among the standard options for many patients with EGFR mutations, with an overall favorable side effect profile. Therefore, the choice between Afatinib and Gefitinib is predicated on a patient’s mutation status, general health, and risk for resistance. Consultation with an oncologist is recommended to identify the most appropriate treatment based on the patient's clinical scenario.

It is essential that disease providers better understand the complexities of different options, as this will allow them to select the options that are best for each individual patient and inform the therapeutic process for patients suffering from lung cancer with EGFR mutations.