The 35th Annual European Society of Medical Oncology (ESMO) was held in Milan, the international capital of fashion, from October 8 to 12, 2010. This year’s meeting presented several recent developments in the clinical treatment of bevacizumab in advanced non-squamous non-small cell lung cancer (NSCLC). The announcement of these studies not only reaffirmed the efficacy of bevacizumab, but also eliminated previous concerns regarding the safety of the drug. This article provides a compilation of several clinical studies that were of interest to the Congress for the reference of our colleagues. ARIES study: broadening the population for first-line treatment with bevacizumab Several large III clinical studies have demonstrated that the anti-angiogenic agent bevacizumab in combination with chemotherapy prolongs overall survival (OS) and progression-free survival (PFS) in patients with advanced non-small cell lung cancer (NSCLC) with a favorable safety profile. At this year’s ESMO annual meeting, Brahmer et al. reported the results of a subgroup analysis of the histologic classification of the large observational cohort study (ARIES). The study further validated the efficacy and safety of combining bevacizumab in advanced NSCLC in a large population that more closely resembles the real clinical situation. A total of 1967 patients with advanced non-squamous NSCLC were enrolled in the study, of which 69.2% (1361/1967) were adenocarcinoma patients and 24.3% (478/1967) were non-adenocarcinoma patients. Among them, the pathological types of non-adenocarcinoma patients were 391 cases of undifferentiated non-small cell lung cancer (NSCLC NOS) and 87 cases of large cell carcinoma, respectively. The most common first-line combination chemotherapy regimen for all patients was a platinum-containing two-drug regimen, and the first-line chemotherapy regimen combined with bevacizumab was similar in both groups. The final results of this histologic subgroup analysis showed that both adenocarcinoma and non-adenocarcinoma patients benefited from bevacizumab treatment, with slightly higher median survival (OS) and median progression-free survival (PFS) in adenocarcinoma patients than in non-adenocarcinoma patients (median OS 13.7 months vs. 12.0 months, P=0.058; median PFS 6.8 months vs. 6.3 months, P= 0.48). Also in terms of 1-year survival, adenocarcinoma patients outperformed non-adenocarcinoma patients with 54.7% vs. 49.8%, respectively. In the ECOG 4599 study, the median survival for all non-squamous non-small cell lung cancer patients treated with bevacizumab was 12.3 months, and subgroup analysis showed that adenocarcinoma patients had a further 14.2 months, the longest survival benefit of any previous clinical study. The results of ARIES, which evaluated the efficacy and safety of bevacizumab under real-life clinical conditions, and which directly compared the efficacy of bevacizumab in patients with adenocarcinoma to those without adenocarcinoma, again suggest that the efficacy advantage of bevacizumab in patients with adenocarcinoma is more pronounced. OS in both groups reached statistical significance (P=0.02) before correction, while the P-value corrected for baseline prognostic factors was 0.058, which was at a critical level. Although further confirmation of the final efficacy difference is still needed, in any case, the study reaffirms the unique therapeutic status and favorable efficacy benefit of bevacizumab in non-small cell lung cancer as a fait accompli. SAiL Study: Study Data Validate Safety of Bevacizumab Maintenance Therapy Bevacizumab is now the standard first-line treatment option for patients with non-squamous non-small cell lung cancer. Several large clinical studies have confirmed that the current regimen of continuing bevacizumab maintenance therapy after the completion of first-line platinum-containing chemotherapy provides the longest survival benefit. However, there have been no studies to confirm whether receiving bevacizumab maintenance therapy increases the incidence of adverse events in patients. Of the 2,212 patients in the large phase IV clinical study SAiL, 880 patients did not receive bevacizumab maintenance therapy for various reasons and 1,332 patients received maintenance therapy. The ESMO meeting then presented safety data from this study in patients receiving bevacizumab maintenance therapy, which confirmed that extending the duration of bevacizumab did not increase the safety burden on patients. A total of 314 patients with advanced non-squamous Asian NSCLC were enrolled in the study and were given bevacizumab in combination with different first-line chemotherapy regimens for six cycles, followed by maintenance bevacizumab therapy until progression. The results showed that among the specific adverse reactions associated with bevacizumab treatment, the most common were grade 1-2 proteinuria (35.7%) and epistaxis (36.6%), and the incidence of grade ≥3 proteinuria (7.6%), epistaxis (1%), hypertension (4.8%), hemoptysis (0.6%), and thromboembolism (2.2%) were low. No grade ≥3 CNS bleeding occurred in Asian patients. A similar spectrum of adverse reactions was seen in Chinese patients. Efficacy data showed an overall remission rate of 57.7% and a disease control rate of 94.1% in Asian patients. The median time to disease progression (TTP) was 8.3 months, longer than the 7.8 months for the overall population in the SAiL study. Median OS was 18.9 months, also significantly higher than the overall population of 14.6 months, and efficacy data from Chinese patients showed similar efficacy benefits (TTP of 8.8 months and OS of 18.5 months). Subgroup analysis of the different chemotherapy regimens in the SAiL study found that the TTP efficacy of bevacizumab combined with cisplatin-containing doublet (7.8 months), carboplatin-containing doublet (7.6 months), non-platinum doublet (7.8 months), and single-agent regimen (7.2 months) chemotherapy was essentially the same, with median OS in the cisplatin-containing doublet (15.3 months), carboplatin-containing doublet (14.6 months), and single-agent regimen ( 14.7 months) group and only 8.7 months in the non-platinum two-drug regimen group, lower than the 14.6 months in the overall population, but notably, only 13 patients in the study were treated with this regimen. In terms of the incidence of ≥3-degree hemoptysis, which was of most interest in the results of this study, it was 1.0% for patients not receiving maintenance bevacizumab and 0.5% for those receiving maintenance therapy. The incidence of other ≥3 degree bevacizumab-related adverse reactions was similar in both groups: proteinuria 2.2% vs 3.6%; hypertension 4.0% vs 6.8%; thromboembolism 11.9% vs 5.0%; gastrointestinal perforation 2.0% vs 0.7%; and congestive heart failure 0.9% vs 0.2%, respectively. Notably, the incidence of SAEs was significantly higher in patients not receiving maintenance therapy than in those receiving maintenance therapy, 18.1% vs 9.7%, respectively. This subgroup analysis provides some confirmation that continuation of bevacizumab maintenance therapy after the end of first-line chemotherapy did not significantly increase the incidence of adverse events. Compared to the overall population, no unintended adverse effects were observed with bevacizumab maintenance, and the overall safety profile was good. Meta-analysis: high level of evidence confirms the survival benefit and safety of bevacizumab Meta-analysis is known to have the highest level of evidence and the most reliable interpretation of results among all studies in evidence-based medicine. In this year’s ESMO, the results of a Meta-analysis conducted by J.C. Soria et al. on bevacizumab in combination with platinum-containing chemotherapy in the first-line treatment of patients with advanced non-squamous non-small cell lung cancer were presented. The study covered all of the more important phase II/III clinical trials of bevacizumab to date and included a total of 2,194 patients, of whom 1,876 had experienced disease progression and 1,563 had died. There is a consensus that survival is the gold standard for evaluating the presence of clinical benefit in oncology patients in clinical trials. In this study, patients treated with bevacizumab in combination with chemotherapy had a significantly lower risk of death compared to chemotherapy alone, HR=0.90, p=0.03. In terms of PFS, patients treated with bevacizumab also had a significantly longer time to disease progression, HR=0.72, p<0.001. There was no difference in the efficacy between the 7.5 mg/kg and 15 mg/kg groups. In terms of safety, the combination of bevacizumab may increase the incidence of proteinuria, hypertension, bleeding events, and neutropenia, but the overall safety was manageable. The results of the above meta-analysis reconfirmed that bevacizumab-based therapy resulted in a significant survival benefit and significantly prolonged disease remission in patients with advanced non-squamous non-small cell lung cancer with a predictable, easy-to-manage, and well-tolerated safety profile.