Summary Background Bevacizumab and erlotinib target different tumour growth pathways with little overlap in their toxic-effect profiles. On the basis of promising results from a phase 1/2 trial assessing safety and activity of erlotinib plus bevacizumab for recurrent or refractory non-small-cell lung cancer (NSCLC), we aimed to assess efficacy and safety of this combination in a phase 3 trial. Methods In our double-blind, placebo-controlled, randomised phase 3 trial (BeTa), we enrolled patients with recurrent or refractory NSCLC who presented to 177 study sites in 12 countries after failure of first-line treatment. Patients were randomly allocated in a one-to-one ratio to receive erlotinib plus bevacizumab (bevacizumab group) or erlotinib plus placebo (control group) according to a computer-generated randomisation sequence by use of an interactive voice response system. The primary endpoint was overall survival in all enrolled patients. Patients, study staff, and investigators were masked to treatment assignment. We assessed safety by calculation of incidence of adverse events and tissue was collected for biomarker analyses. This trial is registered with ClinicalTrials.gov, number NCT00130728. Findings Overall survival did not differ between 317 controls and 319 patients in the bevacizumab group (hazard ratio [HR] 0·97, 95% CI 0·80–1·18, p=0·7583). Median overall survival was 9·3 months (IQR 4·1–21·6) for patients in the bevacizumab group compared with 9·2 months (3·8–20·2) for controls. Progression-free survival seemed to be longer in the bevacizumab group (3·4 months [1·4–8·4]) than in the control group (1·7 months [1·3–4·1]; HR 0·62, 95% CI 0·52–0·75) and objective response rate suggested some clinical activity of bevacizumab and erlotinib. However, these secondary endpoint differences could not be defined as significant because the study prespecified that the primary endpoint had to be significant before testing of secondary endpoints could be done, to control type I error rate. In the bevacizumab group, 130 (42%) of 313 patients with safety data had a serious adverse event, compared with 114 (36%) controls. There were 20 (6%) grade 5 adverse events, including two arterial thromboembolic events, in the bevacizumab group, and 14 (4%) in the control group. Interpretation Addition of bevacizumab to erlotinib does not improve survival in patients with recurrent or refractory NSCLC. Funding Genentech.

LBA8002 Background: B when added to chemotherapy, and E alone, each lead to improved survival in the treatment of patients (pts) with NSCLC (Sandler et al, NEJM 2006, 355:2542–2550; Shepherd et al, NEJM 2005, 353:123–132). Pre-clinical and clinical data (Herbst, J Clin Oncol 2007, 25: 4743–4750) suggest that the combination of B and E may improve the efficacy of NSCLC treatment. This potential was demonstrated in the BETA (B in combination with E compared with E alone for treatment of advanced NSCLC after failure of standard first-line chemotherapy) trial, a phase III trial in which progression free survival (PFS) was improved for patients treated with B + E (Hainsworth, Thoracic Oncol 2008, 3(11) Supp. 4:S302). Methods: The ATLAS study was designed to evaluate B + E (150 mg daily) versus B alone, following B + platin-containing doublet chemotherapy, in pts with stage IIIb/IV NSCLC. Enrolled pts were B-eligible, including pts with treated brain metastases, and pts anticoagulated with low molecular weight heparin(s). Pts with peripheral and/or extra-thoracic squamous tumors were also eligible. Pts received 4 cycles of B (15 mg/kg every 3 weeks) with chemotherapy. Pts who had not experienced disease progression (DP) or significant toxicity were then randomized to receive B + E or B + placebo (P). The primary objective of ATLAS was to compare PFS in pts receiving B + E versus B + placebo. Secondary objectives included the assessment of safety, and overall survival. A data safety monitoring committee (DSMC) monitored safety and efficacy. Results: 1,160 patients were enrolled and 768 randomized from May 2005 to May 2008. The DSMC recommended stopping the trial at the second planned interim efficacy analysis, because it met the primary endpoint. The median PFS after randomization was 4.8 mos for (B + E) vs. 3.7 mos for (B + P), HR= 0.722 (95% CI: 0.592–0.881), p = 0.0012. The safety profile for B + E was consistent with known profiles for B and E. Conclusions: E added to B treatment after chemotherapy with B significantly improves the PFS of patients treated in the first-line setting for locally advanced, recurrent, or metastatic NSCLC. [Table: see text]

Kaposi’s sarcoma-associated herpes virus (KSHV) is a recently identified human γ2-herpesvirus associated with Kaposi’s sarcoma, primary effusion lymphoma, and Castleman’s disease. We reasoned that CTL responses may provide host defense against this virus, and consequently, KSHV may have evolved strategies to evade the CTL-mediated immune surveillance. In this study six B cell lines latently infected with KSHV were found to express reduced levels of HLA class I surface molecules compared with B cell lines transformed by the related γ-herpesvirus EBV. KSHV-infected cells also required higher concentrations of soluble peptides to induce efficient CTL-mediated lysis than control cell lines and were unable to process and/or present intracellularly expressed Ag. Incubation of the KSHV-infected cell lines with high concentrations of soluble HLA class I binding peptides did not restore the deficient HLA class I surface expression. To assess the underlying mechanisms of these phenomena, TAP-1 and TAP-2 gene expression was analyzed. While no attenuation in TAP-2 expression was observed, TAP-1 expression was significantly reduced in all KSHV cell lines compared with that in controls. These results indicate that KSHV can modulate HLA class I-restricted Ag presentation to CTL, which may allow latently infected cells to escape CTL recognition and persist in the infected host.