Long-term clinical benefit from salvage EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer patients with EGFR wild-type tumors

Background. Erlotinib has been approved for the management of NSCLC patients after failure of the first or subsequent line of chemotherapy. Although the efficacy of erlotinib is clearly associated with the presence of EGFR mutations, there is a subset of patients with EGFR wild-type (EGFRwt) tumors who impressively respond. Patients and methods. Patients with EGFRwt NSCLC who received salvage (≥2nd line) treatment with erlotinib for a prolonged period (>6 months), were sought from the database of the Hellenic Oncology Research Group. We retrospectively analyzed the clinical, pathological and molecular characteristics of the patients with available tumor material. Results. Forty-four patients that received erlotinib for >6 months (median 10.1 months) were enrolled in the study. The majority of them were male, never-smokers with adenocarcinoma histology and a good performance status. KRAS and PIK3CA mutations were detected in 21% (9/42 tested) and 13% (4/30 tested) of the patients, respectively. The ALK-EML4 translocation was found in 10% (2/20 tested); there was no patient with HER2 or BRAF mutated tumor. Twelve (54.5%) tumor specimens were considered positive for EGFR-overexpression. Eleven patients experienced a partial response (objective response rate 25%; 95% CI 12-38%) and the remaining 33 had stable disease. The median progression-free survival and overall survival were 10.1 (95% CI 8.6-11.6 months) and 24.1 (95% CI 11.2-37 months), respectively. Conclusions. Treatment with erlotinib significantly improves the clinical outcome in a subset of NSCLC patients with EGFRwt tumors. Further molecular analysis of such tumor specimens could provide a more comprehensive characterization of this particular group of patients. Nevertheless, the presence of other mutations should not prevent the treating physician from using erlotinib at later lines of salvage therapy for NSCLC patients (AU)

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Long-term clinical benefit from salvage EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer patients with EGFR wild-type tumors.

BACKGROUND: Erlotinib has been approved for the management of NSCLC patients after failure of the first or subsequent line of chemotherapy. Although the efficacy of erlotinib is clearly associated with the presence of EGFR mutations, there is a subset of patients with EGFR wild-type (EGFRwt) tumors who impressively respond. PATIENTS AND METHODS: Patients with EGFRwt NSCLC who received salvage (≥2nd line) treatment with erlotinib for a prolonged period (>6 months), were sought from the database of the Hellenic Oncology Research Group. We retrospectively analyzed the clinical, pathological and molecular characteristics of the patients with available tumor material. RESULTS: Forty-four patients that received erlotinib for >6 months (median 10.1 months) were enrolled in the study. The majority of them were male, never-smokers with adenocarcinoma histology and a good performance status. KRAS and PIK3CA mutations were detected in 21% (9/42 tested) and 13% (4/30 tested) of the patients, respectively. The ALK-EML4 translocation was found in 10% (2/20 tested); there was no patient with HER2 or BRAF mutated tumor. Twelve (54.5%) tumor specimens were considered positive for EGFR-overexpression. Eleven patients experienced a partial response (objective response rate 25%; 95% CI 12-38%) and the remaining 33 had stable disease. The median progression-free survival and overall survival were 10.1 (95% CI 8.6-11.6 months) and 24.1 (95% CI 11.2-37 months), respectively. CONCLUSIONS: Treatment with erlotinib significantly improves the clinical outcome in a subset of NSCLC patients with EGFRwt tumors. Further molecular analysis of such tumor specimens could provide a more comprehensive characterization of this particular group of patients. Nevertheless, the presence of other mutations should not prevent the treating physician from using erlotinib at later lines of salvage therapy for NSCLC patients.

Comparison of EGFR and K-RAS gene status between primary tumours and corresponding metastases in NSCLC.

In non-small-cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) and K-RAS mutations of the primary tumour are associated with responsiveness and resistance to tyrosine kinase inhibitors (TKIs), respectively. However, the EGFR and K-RAS mutation status in metastases is not well studied. We compared the mutation status of these genes between the primary tumours and the corresponding metastases of 25 patients. Epidermal growth factor receptor and K-RAS mutation status was different between primary tumours and corresponding metastases in 7 (28%) and 6 (24%) of the 25 patients, respectively. Among the 25 primary tumours, three 'hotspot' and two non-classical EGFR mutations were found; none of the corresponding metastases had the same mutation pattern. Among the five (20%) K-RAS mutations detected in the primary tumours, two were maintained in the corresponding metastasis. Epidermal growth factor receptor and K-RAS mutations were detected in the metastatic tumours of three (12%) and five (20%) patients, respectively. The expressions of EGFR and phosphorylated EGFR showed I 0 and 50% discordance, in that order. We conclude that there is substantial discordance in EGFR and K-RAS mutational status between the primary tumours and corresponding metastases in patients with NSCLC and this might have therapeutic implications when treatment with TKIs is considered.