Response to gefitinib and erlotinib in Non-small cell lung cancer: a restrospective study

Abstract

Background: In Non-small cell lung cancer (NSCLC), an overactive epidermal growth factor receptor (EGFR) pathway is a component of the malignant phenotype. Two tyrosine kinase inhibitors (TKIs) of EGFR, gefinitib and erlotinib, have been used with variable benefit.

Methods: We have analyzed outcome data of a population of NSCLC patients that received these TKIs to determine the benefit derived and to define the clinical and molecular parameters that correlate with response. Tumor tissue from a subgroup of these patients was analyzed by immunohistochemistry to measure the expression level of EGFR and four activated (phosphorylated) members of the pathway, pEGFR, pERK, pAKT, and pSTAT3.

Results: Erlotinib was slightly superior to gefitinib in all measures of response, although the differences were not statistically significant. The most robust clinical predictors of time to progression (TTP) were best response and rash (p < 0.0001). A higher level of pEGFR was associated with longer TTP, while the total EGFR level was not associated with response. Higher levels of pAKT and pSTAT3 were also associated with longer TTP. In contrast, a higher level of pERK1/2 was associated with shorter TTP.

Conclusion: These observations suggest the hypothesis that tumor cells that have activated EGFR pathways, presumably being utilized for survival, are clinically relevant targets for pathway inhibition. An accurate molecular predictive model of TKI response should include activated members of the EGFR pathway. TKIs may be best reserved for tumors expressing pEGFR and pAKT or pSTAT, and little pERK. In the absence of molecular predictors of response, the appearance of a rash and a positive first scan are good clinical indicators of response.

Figure 1

Gefinitib vs. erlotinib. Kaplan-Meier analyses of time to progression (a) and survival since initiating TKI therapy (b) in months among gefitinib users (solid line) and erlotinib users (dashed line).

Figure 2

Rash vs. no rash. Kaplan-Meier analyses of time to progression (a) and survival since initiating TKI therapy (b) in months among patients that developed a skin rash (solid line) and patients that did not developed rash (dashed line).

Figure 3

Disease control vs. progressive disease. Kaplan-Meier analyses of time to progression (a) and survival since initiating TKI therapy (b) in months among patients that had a response or stable disease (solid line) and patients that had progressive disease (dashed line).

Figure 4

Immunohistochemistry. Immunohistochemical analyses of the five protein targets in four representative tumor samples. EGFR (total and phosphorylated) localized to the membrane. pStat 3 localized to nuclei and pErk1/2 and pAkt localized to both nuclei and cytoplasm.

Figure 5

Time to progression by expression level. Box Plot Analyses of the association between lengths of time to progression according to the expression levels of a) total EGFR, b) phosphorylated EGFR, c) phosphorylated Akt, d) phosphorylated Stat3 and e) phosphorylated Erk1/2. Time to progression is expressed in months. Expression levels are expressed in four categories zero, low, moderate, moderate-high, and high, where zero represents samples with no detected signal, low for scores between 1 and 10, moderate for scores between 11 and 100, moderate-high for scores between 101 and 200 and high for scores between 201 and 300. Each box represents the TTP values between the 1^st and the 3^rd quartile. The line across each box represents the median TTP. The dash at the end of the lines represents the maximum and minimum TTP. The crosses represent the mean TTP for each category.