Abstract
Angiogenesis is a complex biological process that plays a relevant role in sustaining the microenvironment, growth, and metastatic potential of several tumors, including non-small cell lung cancer (NSCLC). Bevacizumab was the first angiogenesis inhibitor approved for the treatment of patients with advanced NSCLC in combination with chemotherapy; however, it was limited to patients with non-squamous histology and first-line setting. Approval was based on the results of two phase III trials (ECOG4599 and AVAIL) that demonstrated an improvement of about two months in progression-free survival (PFS) in both trials, and in the ECOG4599 trial, an improvement in overall survival (OS) also. Afterwards, other antiangiogenic agents, including sunitinib, sorafenib, and vandetanib have been unsuccessfully tested in first and successive lines. Recently, two new antiangiogenic agents (ramucirumab and nintedanib) produced a significant survival benefit in second-line setting. In the REVEL study, ramucirumab plus docetaxel prolonged the median OS of patients with any histology NSCLC when compared with docetaxel alone (10.4 versus 9.1 months, hazard ratio (HR) 0.857, p = 0.0235). In the LUME-Lung 1 study, nintedanib plus docetaxel prolonged the median PFS of patients with any tumor histology (p = 0.0019), and improved OS (12.6 versus 10.3 months) in patients with adenocarcinoma. As a result, it became a new option for the second-line treatment of patients with advanced NSCLC and adenocarcinoma histology. Identifying predictive biomarkers to optimize the benefit of antiangiogenic drugs remains an ongoing challenge.
Highlights
Lung cancer is the leading cause of cancer deaths worldwide [1]
An Italian randomized phase III trial (ERACLE) compared the quality of life (QoL) of patients with non-squamous tumor histology treated with bevacizumab plus carboplatin and paclitaxel followed by bevacizumab maintenance or cisplatin plus pemetrexed followed by pemetrexed maintenance [13]
Ramucirumab is a fully human immunoglobulin G1 that selectively binds with high affinity to the extracellular domain of the vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2), which blocks the interaction of VEGFR-2 and VEGF ligands, inhibiting their signaling pathways and the consequential endothelial proliferation and migration [51]
Summary
A better understanding of the biology of this cancer in recent years has led to the development of therapies that have changed the treatment of non-small cell lung cancer (NSCLC), in particular when molecular alterations are. A four-month survival benefit with the addition of bevacizumab was observed in the subgroup of patients with adenocarcinoma histotype (14.2 versus 10.3 months, HR 0.69; 95% CI: 0.58–0.83) [9]. The AVAIL trial compared bevacizumab with a non-taxane-based chemotherapy with a non-taxane-based chemotherapy alone in 1043 patients with non-squamous NSCLC in the first-line setting, and demonstrated that bevacizumab significantly extended PFS and improved the response rate versus a placebo when added to cisplatin plus gemcitabine, but did not significantly extend OS (Table 1), probably because of a higher rate of post-study treatments than in the ECOG4599 trial [10]. Main adverse events (AEs) associated with bevacizumab included hypertension, proteinuria, bleeding, and neutropenia
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