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.

Prognostic value of chemotherapy-resistant CK19mRNA-positive circulating tumor cells in patients with advanced/metastatic non-small cell lung cancer.

BACKGROUND: The detection of circulating tumor cells (CTCs) is of prognostic significance in several tumor types. The present study evaluated the detection and the clinical relevance of CK19mRNA(+) CTCs in patients with advanced/metastatic non-small cell lung cancer before and after front-line chemotherapy. PATIENTS AND METHODS: Peripheral blood was obtained from 642 patients with treatment-naïve unresectable stage IIIB and IV non-small cell lung cancer and from 455 patients after the completion of 1st line chemotherapy. RNA was extracted from peripheral blood mononuclear cells and the detection of CK19mRNA-positive cells was performed using a quantitative PCR assay. RESULTS: Based on the detection limit of the assay, 167 (26.0%) patients had detectable CK19mRNA(+) CTCs at baseline. The detection of CK19mRNA(+) CTCs before treatment was not associated with the clinical outcome, but their detection at the end of chemotherapy was associated with significantly decreased PFS and OS [PFS: 2.6 vs 3.8 months (p = 0.008); OS: 5.7 vs 10.0 months (p = 0.006) for CK19mRNA(+) vs CK19mRNA(-) patients, respectively]. Multivariate analysis revealed that the detection of CK19mRNA(+) CTCs both before and after chemotherapy emerged as an independent factor associated with reduced PFS (HR: 1.778; p < 0.001) and OS (HR: 1.608; p = 0.001). CONCLUSION: The detection of peripheral blood CK19mRNA(+) CTCs before and after the completion of front-line chemotherapy is an adverse prognostic factor associated with poor clinical outcome in patients with stage IIIB/IV non-small cell lung cancer.

A multicentre phase II trial of cabazitaxel in patients with advanced non-small-cell lung cancer progressing after docetaxel-based chemotherapy.

BACKGROUND: Cabazitaxel, a semisynthetic microtubule inhibitor, has shown antitumour activity in models resistant to paclitaxel and docetaxel, and it has been approved for the treatment of docetaxel-resistant prostate cancer. We investigated its activity in patients with advanced non-small-cell lung cancer (NSCLC) progressing under or after docetaxel-based regimens. METHODS: Patients with locally advanced unresectable or metastatic NSCLC, with an Eastern Cooperative Oncology Group performance status of 0-2, were enrolled; patients had to have received up to two prior chemotherapy regimens for the treatment of advanced disease, including one docetaxel-containing regimen. Treatment consisted of cabazitaxel (25 mg m(-2) intravenously, every 21 days) until disease progression. The primary end point was the overall response rate. RESULTS: Among the 46 evaluable patients, 28.3% had squamous cell carcinoma and 54.3% had adenocarcinoma. Eight (17.4%) patients had received one and 38 (82.6%) two prior chemotherapy regimens. Treatment compliance was 95%; 26 (16%) cycles were delayed because of toxicity, (n=13) and dose reduction was required in 6 (13%) patients because of haematologic toxicity. Six (13%) patients achieved a partial response and 17 (37.0%) stable disease. The median progression-free survival and overall survival were 2.1 (95% confidence interval (CI): 1.0-3.2) and 7.4 (95% CI: 5.2-9.6) months, respectively. Grade 4 adverse events included neutropenia (n=8; 17%), febrile neutropenia (n=6; 13%) and thrombocytopenia (n=3; 6.5%). There was one treatment-related death. CONCLUSIONS: Cabazitaxel exhibits activity in NSCLC patients pre-treated with docetaxel-based chemotherapy with a substantial but manageable toxicity profile. The drug merits further evaluation in this indication.