Abstract
BackgroundThe SAKK 19/05 trial investigated the safety and efficacy of the combined targeted therapy bevacizumab and erlotinib (BE) in unselected patients with advanced non-squamous non-small cell lung cancer (NSCLC). Although activating EGFR mutations were the strongest predictors of the response to BE, some patients not harboring driver mutations could benefit from the combined therapy. The identification of predictive biomarkers before or short after initiation of therapy is therefore paramount for proper patient selection, especially among EGFR wild-types. The first aim of this study was to investigate the early change in blood gene expression in unselected patients with advanced non-squamous NSCLC treated by BE. The second aim was to assess the predictive value of blood gene expression levels at baseline and 24h after BE therapy.MethodsBlood samples from 43 advanced non-squamous NSCLC patients taken at baseline and 24h after initiation of therapy were profiled using Affymetrix’ exon arrays. The 24h gene dysregulation was investigated in the light of gene functional annotations using gene set enrichment analysis. The predictive value of blood gene expression levels was assessed and validated using an independent dataset.ResultsSignificant gene dysregulations associated with the 24h-effect of BE were detected from blood-based whole-genome profiling. BE had a direct effect on “Pathways in cancer”, by significantly down-regulating genes involved in cytokine–cytokine receptor interaction, MAPK signaling pathway and mTOR signaling pathway. These pathways contribute to phenomena of evasion of apoptosis, proliferation and sustained angiogenesis. Other signaling pathways specifically reflecting the mechanisms of action of erlotinib and the anti-angiogenesis effect of bevacizumab were activated. The magnitude of change of the most dysregulated genes at 24h did not have a predictive value regarding the patients’ response to BE. However, predictive markers were identified from the gene expression levels at 24h regarding time to progression under BE.ConclusionsThe 24h-effect of the combined targeted therapy BE could be accurately monitored in advanced non-squamous NSCLC blood samples using whole-genome exon arrays. Putative predictive markers at 24h could reflect patients’ response to BE after adjusting for their mutational status.Trial registration ClinicalTrials.gov: NCT00354549
Highlights
The SAKK 19/05 trial investigated the safety and efficacy of the combined targeted therapy bevacizumab and erlotinib (BE) in unselected patients with advanced non-squamous non-small cell lung cancer (NSCLC)
Several trials have shown the beneficial effect of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer patients (NSCLC) harboring activating EGFR mutations leading to the adoption of EGFR-TKI as standard treatment in this population [3, 4]
The SAKK 19/05 trial from the Swiss Group for Clinical Cancer Research showed that first-line combined BE treatment followed by chemotherapy regimen is feasible with acceptable toxicity and activity in an unselected advanced nonsquamous NSCLC population [11]
Summary
The SAKK 19/05 trial investigated the safety and efficacy of the combined targeted therapy bevacizumab and erlotinib (BE) in unselected patients with advanced non-squamous non-small cell lung cancer (NSCLC). Recent clinical trials showed superior efficacy of the combined anti-angiogenesis bevacizumab (B) with the TKI erlotinib (E) in EGFR mutated patients compared to E alone [7, 8]. These trials showed that first line treatments combining BE improved the progression free survival (PFS)—but not overall survival (OS)—of patients harboring an EGFR driver mutation in comparison with E alone [7, 9]. The phase II TASK study did not show a benefit in terms of PFS for the combination BE in unselected first line advanced non-squamous NSCLC compared with chemotherapy plus B [10, 12]
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