Challenges and treatment options for EGFR-mutant non-small cell lung cancer patients

In this review, the authors summarized different treatment strategies based on clinical trial findings in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients.

NSCLC is the most common type of lung cancer. In advanced NSCLC patients, the EGFR gene (produces proteins involved in cell signalling) is often defective or mutated. A class of drugs that targets these mutations is known as epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Examples of EGFR-TKIs are Iressa and Tarceva. Administration of EGFR-TKIs has been the standard mode of treatment for EGFR-mutant patients. However, with the discovery of other gene mutations, several other strategies to treat advanced NSCLC have been reported and clinically tested.

Findings from six phase III clinical trials with NSCLC patients whose EGFR genes were mutated showed that treatment with an EGFR-TKI such as erlotinib (Tarceva) or gefitinib (Iressa) resulted in a 63% reduction in the odds of disease progression compared to chemotherapy. However, it did not significantly improve overall survival (30.5 months for EGFR-TKIs compared to 23.6 months for chemotherapy). 

In two other phase III clinical trials of NSCLC patients whose EGFR genes were mutated, afatinib (Galotrib), a newer form of EGFR-TKI was evaluated. Newer EGFR-TKIs permanently stop the mutated EGFR gene from replicating and producing mutated proteins. Afatinib had an average progression-free survival (length of time after treatment that the disease does not progress) of 11 months and response rate (at least some disappearance of signs and symptoms of cancer) of 60%.

It is estimated that 30% of EGFR-mutant patients do not respond to EGFR-TKI therapy due to presence of another genetic mutation known as T790M.  While the presence of this mutation indicates poorer progression-free survival compared to absence of this mutation when treated with EGFR-TKIs, treatment with chemotherapy before EGFR-TKIs eliminates this negative effect. 

Due to lack of sufficient data, the authors could not conclude which sequence of treatments would be effective for EGFR-mutant patients: EGFR-TKI followed by chemotherapy or vice versa. However, for elderly and bedridden patient population, chemotherapy as first-line of treatment is not well tolerated.

Combination treatment with EGFR-TKI and chemotherapy was usually met with higher toxicity, possibly due to lack of knowledge with regard to the type of genetic mutation of patients. As an alternative, intercalated combination therapy i.e. introduction of one drug in between the course of another, resulted in improved progression-free survival, overall survival and quality of life.

The authors concluded that EFGR-TKI therapy may be the first choice in the treatment of EFGR-mutant NSCLC since it is less toxic and results in better quality of life compared to chemotherapy.