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Lung Cancer
Unmet Needs in the Treatment of Metastatic Non-small-cell Lung Cancer
a report by
Ji-Youn Han, MD, PhD
1
and Jin Soo Lee, MD, PhD
2
1. Chief, Lung Cancer Branch; 2. President, Research Institute and Hospital, National Cancer Center, Korea
Today, lung cancer remains the most common cause of cancer-related mortality (aged 70 years) was associated with a higher incidence of severe toxicity, but
in the world. Non-small-cell lung cancer (NSCLC) accounts for approximately no obvious improvement in OS.
6
Although these findings are limited by the
85% of lung cancer, and 40% of these patients present at an advanced stage, retrospective post hoc nature of analysis, elderly-specific prospective studies are
including patients with metastatic disease and those with locally advanced needed to establish the safety of combinations of novel agents for the
disease with malignant pleural or pericardial effusion.
1
Platinum-based treatment of advanced NSCLC.
chemotherapy with third-generation agents (gemcitabine, vinorelbine,
docetaxel, or paclitaxel) improves survival and quality of life compared with A European randomized phase III trial, Avastin
®
in Lung (AVAiL) BO17704, also
best supportive care alone. Despite these advances in treatment, a therapeutic confirms the role of bevacizumab in this selected patient population.
5
Both
plateau has been reached using conventional chemotherapy. Over the past bevacizumab doses (7.5 and 15mg/kg) in combination with gemcitabine and
decade, large randomized studies have demonstrated the relative equivalence cisplatin significantly improved PFS versus placebo (see Table 1). A recent
of platinum-based doublets, with response rates of 16–32% and median update also confirmed the clinically and statistically significant improvement in
survival ranging from eight to 11 months, with one- and two-year survival rates the primary end-point of PFS for the two different doses of bevacizumab
of 35–45% and 10–20%, respectively. The majority of patients experience studied in the trial compared with chemotherapy alone. However, this study
disease progression, generally after a median of three to six months of initiating did not demonstrate a statistically significant prolongation of OS, a secondary
chemotherapy, and the long-term prognosis is still poor.
2
Therefore, there is a end-point, for either dose in combination with gemcitabine and cisplatin
great unmet need to provide more effective therapeutic strategies to further chemotherapy compared with chemotherapy alone.
7
In this study,
improve outcome in patients with advanced NSCLC. the exclusion criteria were as outlined above for the ECOG 4599, with
additional exclusion criteria of radiological evidence of tumors invading or
Further understanding of cancer biology has allowed the development of abutting major vessels as a further safety precaution. Thus, no significant
several potential molecular targets for cancer treatment. Numerous targeted difference in pulmonary hemorrhage was observed among treatment arms.
agents have been evaluated in clinical trials of cancer treatment, and a number
of phase III trials have generated definite results. In particular, several agents On the basis of these data, the US Food and Drug Administration (FDA) and
that target the epidermal growth factor receptor (EGFR) and the angiogenesis the European Medicines Agency (EMEA) approved bevacizumab in
pathway have proved efficacious in the management of NSCLC. To further combination with platinum-based chemotherapy for first-line treatment in a
improve the outcome of first-line therapy for advanced NSCLC, there is much selected patient population. While trials assessing the safety and feasibility of
interest in adding these targeted agents to platinum-based chemotherapy. This bevacizumab in patients with squamous histology and brain metastasis are
article will focus on the potential beneficial role of these targeted agents in the ongoing, bevacizumab treatment with chemotherapy is currently suitable for
management of advanced NSCLC in the first-line treatment setting. patients with non-squamous histology, minimal baseline hemoptysis, and no
central nervous system (CNS) metastasis.
Bevacizumab
Vascular endothelial growth factor (VEGF) is a potent proangiogenic factor Epidermal Growth Factor Receptor Inhibitors
expressed by most cancer cell types and certain tumor stromal cells. As cancer The EGFR is a tyrosine kinase (TK) receptor that is overexpressed in 50–90% of
progression and metastasis are dependent on angiogenesis, VEGF-targeted NSCLC,
8
and its activation promotes cancer-cell proliferation, metastasis, and
therapies have become an important modality of cancer treatment.
3
angiogenesis. Monoclonal antibodies directed against EGFR, i.e. cetuximab,
Bevacizumab, a recombinant humanized monoclonal antibody against VEGF, target the extracellular domain of EGFR to prevent ligand binding and receptor
has demonstrated a clinical benefit when administrated in combination with activation. Small-molecule TK inhibitors (TKIs) such as erlotinib and gefitinib
chemotherapy in chemo-naïve advanced NSCLC patients with non-squamous bind the adenosine triphosphate (ATP)-binding pocket of the receptor to
histology and no brain metastases.
4,5
In a large randomized trial (Eastern prevent ligand-induced phosphorylation and downstream signaling.
9
Cooperative Oncology Group [ECOG] 4599), the addition of bevacizumab to
paclitaxel and carboplatin significantly improved overall survival (OS), Erlotinib and Gefitinib
progression-free survival (PFS), and response rate (see Table 1).
4
However, Both gefitinib and erlotinib, the first-generation EGFR-TKIs, have single-agent
toxicity was increased in the bevacizumab arm, including higher incidences of activity in NSCLC and are currently used for treatment of advanced NSCLC.
febrile neutropenia, hemoptysis, and hemorrhage. A recent subset analysis On the basis of pre-clinical data demonstrating that EGFR TKIs enhance the
of ECOG 4599 has shown that bevacizumab treatment in elderly patients efficacy of cytotoxic agents against a range of human tumor xenografts,
© TOUCH BRIEFINGS 2008
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