Clinical Course of Patients with Non–Small Cell Lung Cancer and Epidermal Growth Factor Receptor Exon 19 and Exon 21 Mutations Treated with Gefitinib or Erlotinib

Abstract

Purpose: In patients with non^small cell lung cancer (NSCLC), mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain have been associated with sensitivity to erlotinib and gefitinib.We undertook this study to explore the relationship between EGFR mutation type and clinical variables, including treatment with gefitinib and erlotinib. Experimental Design: In patients with NSCLC, EGFR exon 19 deletion mutations and EGFR L858R point mutations were analyzed by nonsequencing PCR-based methods from paraffin blocks of tissue obtained before treatment. The results were correlated with clinical information (sex, pathologic subtype, race/ethnicity, treatment, and overall survival).Results: The two most common EGFR mutations were identified in 24% (70 of 291; 95% confidence interval, 26%-38%) of tumors from patients with NSCLC. EGFR mutation was associated with Asian ethnicity (P = 0.0023) and being a''never smoker'' (P = 0.0001). Among patients with EGFR mutations, 39% (27 of 70) had EGFR L858R, whereas 61% (43 of 70) had an EGFR exon 19 deletion. After treatment with erlotinib (n = 12) or gefitinib (n = 22), patients with EGFR mutations had a median overall survival of 20 months. After treatment with erlotinib or gefitinib, patients with EGFR exon 19 deletions had significantly longer median survival than patients with EGFR L858R (34 versus 8 months; log-rank P = 0.01). Conclusions: EGFR mutations in exons 19 or 21are correlated with clinical factors predictive of response to gefitinib and erlotinib. Those with EGFR exon 19 deletion mutations had a longer median survival than patients with EGFR L858R point mutation. These observations warrant confirmation in a prospective study and exploration of the biological mechanisms of the differences between the two major EGFR mutations.

Predictive factors associated with prolonged survival in patients with advanced non-small-cell lung cancer (NSCLC) treated with gefitinib

“…This led to the conclusion that the essential factor associated with survival is EGFR mutation status. Though better MST has been reported in L858R cases in a comparison of survival between exon 19 deletion and L858R missense , recent reports have shown better survival in patients with exon 19 deletion (Jackman et al, 2006;Riely et al, 2006). Incidentally, we found MST to be better in L858R cases.…”

EGFR and KRAS status of primary sarcomatoid carcinomas of the lung: Implications for anti‐EGFR treatment of a rare lung malignancy

“…32 Several studies have shown that increased EGFR gene copy number by FISH and/ or EGFR gene mutations are reliable markers for the prediction of clinical benefit from anti-EGFR drugs such as gefitinib, erlotinib, or cetuximab in typical NSCLC. 13,[15][16][17][18][19][20][21][22][23][24][25][26][27][28] The rare occurrence of these molecular events in lung SC suggests that these tumors are not ideal candidates for anti-EGFR therapy. This is consistent with the high rate of KRAS mutations observed in our series (38%).…”

“…There are several lines of evidence indicating that biomarkers such as EGFR protein expression, 13,14 EGFR gene copy number, 13,[15][16][17][18][19][20] EGFR mutations 13,15,[21][22][23][24][25][26][27][28] and KRAS mutations 22,[28][29][30] may be used to predict which patients with NSCLC will respond to EGFR tyrosine kinase inhibitors.…”

Selecting Lung Cancer Patients for Treatment with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors by Immunohistochemistry and FluorescenceIn situHybridization—Why, When, and How?

“…In the study of Cappuzzo et al, patients harboring EGFR mutations had prolonged survival (21 versus 8 months); the difference was, however, not statistically significant (3). A recent study indicated that patients with exon 19 deletions have longer survival compared with patients with exon 21 point mutations (28). Table 2 shows the available data on predictive significance of EGFR protein expression, EGFR copy number by FISH, and EGFR mutations in large randomized placebocontrolled trials with a brief explanation of the trial design.…”