First-line platinum-based doublets is established as the standard of care for advanced non–small-cell lung cancer (NSCLC). Nevertheless, in this field a plateau of effectiveness has been reached during the last years. One new area of exploration in NSCLC therapeutics lies in the use of tyrosine-kinase inhibitors (TKIs) or monoclonal antibodies (mAbs) to target vascular endothelial growth factor (VEGF) and its receptors, and epidermal growth factor receptor (EGFR). The results of randomized trials testing mAbs against VEGF (bevacizumab) and EGFR (cetuximab) are challenging the paradigm of the platinum doublets as the gold standard in advanced NSCLC. Despite the interesting results that have thus far been collected, the benefit of these new agents, both in terms of balancing between advantages and toxicity and the associated health economic burden, is modest. Here we discuss the use of bevacizumab and cetuximab, the mAbs for which the largest amount of data in the treatment of advanced NSCLC exists. However, despite our having a significant amount of data on these two mAbs, we still have much to learn: Which patients are appropriate for these treatments; for how long are the treatments beneficial, and what are the molecular and clinical predictors? We must continue to study these important problems in treating NSCLC.
The treatment of advanced non–small-cell lung cancer (NSCLC), including squamous cell carcinoma, adenocarcinoma, and large cell carcinoma has reached a plateau of effectiveness with platinum-based doublets, which today are considered the standard of care.[1-3] However, the development of targeted therapies—in particular against the vascular endothelial growth factor (VEGF) and its receptors and the epidermal growth factor receptor (EGFR)—seems likely to improve overall outcomes of advanced NSCLC. In particular, tyrosine-kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) can both be used to block these molecular targets. Bevacizumab (directed against VEGF), and cetuximab (against EGFR) are the mAbs which have the largest amount of available data for study. However to date, only bevacizumab has been licensed (in combination with chemotherapy) for first-line treatment of advanced NSCLC. Many questions remain concerning the benefits of these new agents in terms of maintaining a balance between advantages and toxicity and the associated health economic burden. Notwithstanding, many unsolved questions still exist regarding patient selection, the length of benefit, and molecular and clinical predictors. In this review we will address some of these issues.
Bevacizumab is an anti-VEGF recombinant humanized mAb. Thus far, two randomized phase III trials have compared the combination of bevacizumab with chemotherapy versus chemotherapy alone in the treatment of advanced non-squamous NSCLC.[4-6] In both trials, enrollment was limited to non-squamous histology patients because of the elevated risk of bleeding for squamous lung cancer shown in a previous phase II randomized study. Also those patients with brain metastases were excluded due to the potential risk of bleeding.
In the Eastern Cooperative Oncology Group (ECOG - E4599) study, 878 patients were randomized to either receive paclitaxel and carboplatin plus bevacizumab (15 mg/kg), or the same chemotherapy regimen plus placebo. Patients receiving bevacizumab reported a statistically significant advantage in overall survival (OS of 12.3 versus 10.3 months; P = .003), progression-free survival (PFS of 6.2 versus 4.5 months; P < .001) and objective response rate (ORR of 35% versus 15%; P < .001). Rates of clinically significant bleeding were 4.4% and 0.7% (P < .001), respectively. There were 15 treatment-related deaths in the bevacizumab group, including five from pulmonary hemorrhage. In the AVAiL (AVAstin in Lung) trial, the chemotherapy regimen included cisplatin plus gemcitabine, recycled every three weeks.[5,6] In this trial, chemotherapy plus placebo was compared with chemotherapy plus two different doses of bevacizumab; 7.5 and 15 mg/kg. A total of 1,043 patients with non-squamous NSCLC were randomized to the three arms. Median PFS, the main endpoint of the trial, was significantly prolonged with the bevacizumab administration, the hazard ratios (HRs) were 0.75 (6.7 versus 6.1 months for placebo; P = .003) in the low-dose group and 0.82 (6.5 versus 6.1 months for placebo; P = .03) in the high-dose group compared with placebo. ORRs were 20.1%, 34.1%, and 30.4% for placebo, low-dose bevacizumab, and high-dose bevacizumab plus chemotherapy, with a response duration of 4.7, 6.1, and 6.1 months, respectively. Median OS was 13.1 months for chemotherapy alone, 13.6 months for bevacizumab at 7.5 mg/kg plus chemotherapy (HR versus placebo 0.93, 95% CI 0.78–1.11) and 13.4 months for bevacizumab at 15 mg/kg plus chemotherapy (HR versus placebo 1.03, 95% CI 0.86–1.23). Incidence of grade > 3 adverse events was similar across arms. Grade > 3 pulmonary hemorrhage rates were < 1.5% for all arms despite the fact that 9% of patients received therapeutic anticoagulation.
Both studies reached their primary endpoint (Table 1), however only the E4599 study showed a clinically relevant influence on PFS and OS. Based on these data, several questions were raised:
Should squamous histology and brain metastases really be excluded from bevacizumab therapy?
Due to safety concerns, bevacizumab use is restricted to a selected category of patients which may limit its indication to < 30% of all NSCLC patients.[4-7]. Thus, there is interest in determining if patients with brain metastases and with squamous histology can be, at least partially, re-candidated to this effective targeted therapy. The risks related to these two conditions, although not negligible, are not completely known. It is currently unclear whether histology alone or the central localization of the tumor are the risk factors for bleeding. A retrospective evaluation of the clinical and radiographic risk factors associated with severe pulmonary hemorrhage in first-line advanced NSCLC patients treated with carboplatin plus paclitaxel plus bevacizumab reported only the baseline tumor cavitations as a potential risk factor, and not the influence of squamous histology and tumor central localization. In a prospective phase II study, 44 patients with squamous cell histology were treated with two cycles of carboplatin plus paclitaxel regimen and then received carboplatin plus paclitaxel and bevacizumab for an additional four cycles. A total of 27 patients received at least one dose of bevacizumab with an acceptable observed rate of severe pulmonary hemorrhage (1 in 27 patients, or 3.7%). Furthermore, a phase II study in patients with squamous histology completed the accrual; results are pending.
With regard to brain metastases, several data strongly suggest the safety of bevacizumab in advanced NSCLC patients with treated metastases to the brain. Moreover, further safety data showed that the risk of bleeding in patients with untreated brain metastases is similar for patients who receive bevacizumab and for those who do not, across various tumor types. As a consequence, the European Medicines Agency (EMEA) has removed the contraindication concerning the use of bevacizumab in untreated central nervous system (CNS) metastases. Finally, the Food and Drug Administration (FDA) has indicated bevacizumab, in combination with carboplatin and paclitaxel, in advanced non-squamous NSCLC regardless of the presence of brain metastases. However, the last updated American Society of Clinical Oncology (ASCO) guidelines continue to advise against the use of bevacizumab in patients with brain metastases.
To conclude, bevacizumab can be administered in the presence of brain metastases, however further prospective data is needed before we can truly assess its use in non-squamous histology. Next we will turn our attention to tumor cavitations, regardless of histology.
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