Phase II Study of Efficacy and Safety of Bevacizumab in Combination With Chemotherapy or Erlotinib Compared With Chemotherapy Alone for Treatment of Recurrent or Refractory Non–Small-Cell Lung Cancer

Herbst, Roy S.; O’Neill, Vincent; Fehrenbacher, Louis; Belani, Chandra P.; Bonomi, Philip; Hart, Lowell L.; Melnyk, Ostap; Ramies, David A.; Lin, Ming Hsien; Sandler, Alan

doi:10.1200/jco.2007.12.3026

Cited by 376 publications

(250 citation statements)

References 16 publications

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“…This was recently confirmed by Manegold et al (2008). Moreover, a phase I/II trial combining the epidermal growth factor receptor (EGFR) inhibitor erlotinib or chemotherapy with bevacizumab resulted in higher response rates and longer median progression-free survival (PFS) in both bevacizumab containing arms (Herbst et al, 2007).…”

mentioning

confidence: 56%

CD133+ circulating haematopoietic progenitor cells predict for response to sorafenib plus erlotinib in non-small cell lung cancer patients

et al. 2009

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Background: Blood-based biomarkers may be particularly useful for patient selection and prediction of treatment response for angiogenesis inhibitors. Circulating endothelial cells (CECs) and haematopoietic progenitor cells (HPCs) might have a role in tumour angiogenesis and in tumour growth. Measurement of CECs and HPCs in the blood of patients could be a simple, non-invasive way to monitor or predict responses to treatment. Methods: (VEGFR2 + ) CECs , (CD133 + ) HPCs, plasma vascular endothelial growth factor (VEGF) and erythropoietin were measured in blood from 25 non-small cell lung cancer (NSCLC) patients before and during treatment with sorafenib plus erlotinib (SO/ER). In order to assess the drug specificity of changes in CECs and HPCs, 18 patients treated with bevacizumab plus erlotinib (BV/ER) and 10 patients with erlotinib (ER) monotherapy were studied. Response was measured in all patient groups by Response Evaluation Criteria in Solid Tumors (RECIST). Results: At day 7, SO/ER-treated patients showed a three-fold increase in CECs ( P <0.0001) comparable to BV/ER-treated patients ( P <0.01), and the CECs did not change with erlotinib treatment ( P =0.8). At day 7, CD133 + /HPCs decreased with SO/ER treatment ( P <0.0001). HPC numbers did not change with either BV/ER or erlotinib. In SO/ER-treated patients pre-treatment CD133 + /HPCs were significantly lower in responders ( P =0.01) and pre-treatment CD133 + /HPC numbers lower than the median correlated with a longer time-to-progression (TTP) ( P =0.037). Conclusion: Pre-treatment CD133 + /HPCs are a promising candidate biomarker to further explore for use in selecting NSCLC patients who might benefit from SO/ER treatment.

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confidence: 56%

CD133+ circulating haematopoietic progenitor cells predict for response to sorafenib plus erlotinib in non-small cell lung cancer patients

et al. 2009

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“…In that trial, 28% of patients discontinued treatment in the bevacizumab-chemotherapy arm as a result of adverse effects, versus 24% of patients treated with only chemotherapy. The progressionfree survival (PFS) intervals were similar in the bevacizumaberlotinib and bevacizumab-chemotherapy arms (4.4 months versus 4.8 months) [21].…”

Section: Other Investigational Combination Therapiesmentioning

confidence: 89%

Bevacizumab

2010

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“…Unlike EGFR-tyrosine kinase inhibitors, antiangiogenic agents combined with conventional chemotherapy have demonstrated clinical benefit in NSCLC (Herbst et al, 2007), and recent studies have demonstrated the safety of enzastaurin combination with cytotoxic drugs (Rademaker-Lakhai et al, 2007), including pemetrexed (Hanauske et al, 2006). Furthermore, our findings are novel because they show that the synergistic interaction seems to be mediated by several mechanisms, summarised in Figure 6, which enhanced the sensitivity to pemetrexed and should be used as predictive biomarkers for the future clinical development of enzastaurin-pemetrexed combination.…”

Section: Discussionmentioning

confidence: 99%

Molecular pathways involved in the synergistic interaction of the PKCβ inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells

et al. 2008

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Conventional regimens have limited impact against non-small cell lung cancer (NSCLC). Current research is focusing on multiple pathways as potential targets, and this study investigated molecular mechanisms underlying the combination of the PKCb inhibitor enzastaurin with the multitargeted antifolate pemetrexed in the NSCLC cells SW1573 and A549. Pharmacologic interaction was studied using the combination-index method, while cell cycle, apoptosis induction, VEGF secretion and ERK1/2 and Akt phosphorylation were studied by flow cytometry and ELISAs. Reverse transcription -PCR, western blot and activity assays were performed to assess whether enzastaurin influenced thymidylate synthase (TS) and the expression of multiple targets involved in cancer signaling and cell cycle distribution. Enzastaurin-pemetrexed combination was highly synergistic and significantly increased apoptosis. Enzastaurin reduced both phosphoCdc25C, resulting in G2/M checkpoint abrogation and apoptosis induction in pemetrexed-damaged cells, and GSK3b and Akt phosphorylation, which was additionally reduced by drug combination (À58% in A549). Enzastaurin also significantly reduced pemetrexed-induced upregulation of TS expression, possibly through E2F-1 reduction, whereas the combination decreased TS in situ activity (450% in both cell lines) and VEGF secretion. The effects of enzastaurin on signaling pathways involved in cell cycle control, apoptosis and angiogenesis, as well as on the expression of genes involved in pemetrexed activity provide a strong experimental basis to their evaluation as pharmacodynamic markers in clinical trials of enzastaurin-pemetrexed combination in NSCLC patients.

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Phase II Study of Efficacy and Safety of Bevacizumab in Combination With Chemotherapy or Erlotinib Compared With Chemotherapy Alone for Treatment of Recurrent or Refractory Non–Small-Cell Lung Cancer

Cited by 376 publications

References 16 publications

CD133+ circulating haematopoietic progenitor cells predict for response to sorafenib plus erlotinib in non-small cell lung cancer patients

CD133+ circulating haematopoietic progenitor cells predict for response to sorafenib plus erlotinib in non-small cell lung cancer patients

Bevacizumab

Molecular pathways involved in the synergistic interaction of the PKCβ inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells

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