Erlotinib in Lung Cancer - Molecular and Clinical Predictors of Outcome

Non-small-cell lung cancer (NSCLC) with mutations in the epidermal growth factor receptor (EGFR) is a distinct subgroup of NSCLCs that is particularly responsive to EGFR tyrosine-kinase inhibitors (TKIs). A weighted pooled analysis of available studies was performed to evaluate clinical outcome in patients with EGFR-mutated NSCLC who were treated with chemotherapy or EGFR TKIs. Median progression-free survival (PFS) times were pooled from prospective or retrospective studies that evaluated chemotherapy or single-agent EGFR TKIs (erlotinib or gefitinib) in patients with NSCLC and EGFR mutations. Among the studies identified for inclusion in the analysis, 12 evaluated erlotinib (365 patients), 39 evaluated gefitinib (1069 patients) and 9 evaluated chemotherapy (375 patients). Across all studies, the most common EGFR mutations were deletions in exon 19 and the L858R substitution in exon 21. In the weighted pooled analysis, the overall median PFS was 13.2 months with erlotinib, 9.8 months with gefitinib and 5.9 months with chemotherapy. Using a two-sided permutation, erlotinib and gefitinib produced a longer median PFS versus chemotherapy, both individually (P= 0.000 and P= 0.002, respectively) and as a combined group (EGFR TKI versus chemotherapy, P= 0.000). EGFR TKIs appear to be the most effective treatment for patients with advanced EGFR-mutant NSCLC. Ongoing prospective trials comparing the efficacy of first-line chemotherapy and EGFR TKIs in EGFR-mutant disease should provide further insight into the most appropriate way to treat this specific group of patients.

/pdf/clinical-outcomes-in-non-small-cell-lung-cancer-patients-3xc8txzif6.pdf

Clinical outcomes in non-small-cell lung cancer patients with EGFR mutations: pooled analysis

The efficacy of gefitinib for patients with non-adenocarcinoma non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations is unclear, because only a small percentage of patients enrolled in the clinical trials to evaluate the efficacy of gefitinib for tumors harboring EGFR mutation were non-adenocarcinoma NSCLC. A pooled analysis was conducted to clarify the efficacy of gefitinib for non-adenocarcinoma NSCLC patients harboring EGFR mutations. A systematic search of the PUBMED databases was conducted to identify all clinical reports that contained advanced non-adenocarcinoma NSCLC patients harboring EGFR mutations and treated with gefitinib. The selected patients were advanced non-adenocarcinoma NSCLC patients harboring EGFR mutations who were treated with gefitinib and described in reports containing the data of the histology, status of EGFR mutations and response to gefitinib. This study selected 33 patients from 15 reports. Twenty-seven and three of the 33 patients were squamous cell carcinoma and adenosquamous cell carcinoma, respectively. One patient each had large-cell carcinoma, pleomorphic carcinoma and spindle cell carcinoma. Twenty-one patients (64%) had sensitive EGFR mutations. The response rate (RR), disease control rate (DCR) and median progression-free survival (mPFS) was 27%, 67-70% and 3.0 months, respectively. These factors were statistically significantly inferior in the non-adenocarcinoma NSCLC patients harboring EGFR mutations to adenocarcinoma patients harboring EGFR mutations selected from the same published reports (RR: 27%vs 66%, P = 0.000028; DCR: 67-70%vs 92-93%, P = 0.000014; mPFS: 3.0 vs 9.4 months, P = 0.0001, respectively). Gefitinib is less effective in non-adenocarcinoma NSCLC harboring EGFR mutations than adenocarcinoma harboring EGFR mutations.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1349-7006.2011.01887.x

Efficacy of gefitinib for non‐adenocarcinoma non‐small‐cell lung cancer patients harboring epidermal growth factor receptor mutations: A pooled analysis of published reports

Clinical experience with the EGFR-TKI gefitinib in Asian patients with NSCLC will be reviewed, both in patients who have previously failed chemotherapy and in the first-line setting (gefitinib is currently not licensed for first-line treatment). Tolerability and specific adverse events in patients of Asian origin will be discussed. Differing objective response rates between patients of Asian and non-Asian origin when treated with gefitinib (and standard cytotoxics) will also be discussed along with EGFR mutations and drug resistance. Reports of Phase II/III clinical experience with gefitinib 250 mg/day in Asia were identified by searching in Medline and ASCO databases for publications between 1993 and 2008. Defined search criteria included (gefitinib OR Iressa OR ZD1839) AND NSCLC AND (Asia OR Japan OR China OR Taiwan OR Korea) or 'Clinical trial' type, with additional searches, including AND 'interstitial lung disease (ILD)' or 'EGFR mutation'. Numerous Phase II/III trials including patients of Asian origin with previously treated advanced NSCLC report a consistent clinical benefit of gefitinib. Gefitinib is generally well tolerated by patients with NSCLC although the incidence of ILD in Japanese patients must be noted. Studies analyzing EGFR mutations indicate that these mutations occur at a much higher rate in patients of Asian origin than in non-Asian patients. Data from several studies indicate that EGFR mutation-positive patients of Asian origin have better efficacy outcomes with first-line gefitinib when compared with those who are EGFR mutation-negative. Research is ongoing to evaluate the role of tailoring patients' treatment according to their genetic phenotype.

/pdf/overview-of-gefitinib-in-non-small-cell-lung-cancer-an-asian-4gmvn2ow1d.pdf

Overview of Gefitinib in Non-small Cell Lung Cancer: An Asian Perspective

Tissue factor (TF), the key regulator of haemostasis and angiogenesis, is also involved in the pathology of several diseases, including cardiovascular, inflammatory and neoplastic conditions. In the latter, TF is upregulated by cancer cells, as well as by certain host cells, and it is the interactions between these distinct pools of TF-expressing cells that likely influence tumour progression in several ways. Furthermore, the release of TF microparticles into the circulation is thought to contribute to the systemic coagulopathies commonly observed in cancer patients. The direct regulation of TF by oncogenic events has provided a plausible explanation for the relatively common overexpression of TF in various cancers and its involvement in tumour growth, angiogenesis, metastasis and coagulopathy. However, this constitutive influence is modified by the tumour microenvironment, cellular interactions and host factors rendering TF expression patterns complex and heterogeneous. It appears that in many biological contexts TF plays a central role in disease progression and thereby potentially constitutes an attractive therapeutic target, especially in scenarios where the risk of bleeding can be avoided by selecting appropriate medications, refined dosing or by targeting the signalling component of TF activity. The efficacy and safety of such approaches still awaits clinical verification.

Tissue factor and cancer.

Multicenter phase II trial of gefitinib first-line therapy followed by chemotherapy in advanced non-small-cell lung cancer (NSCLC) : SAKK protocol 19/03

M. Bihl

Papers

Multicenter phase II trial of gefitinib first-line therapy followed by chemotherapy in advanced non-small-cell lung cancer (NSCLC) : SAKK protocol 19/03