Randomised, double-blind multicentre phase III study of bevacizumab in combination with cisplatin and gemcitabine in chemotherapy-naïve patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC): BO17704

Abstract

LBA7514 Background: The ECOG 4599 phase III trial demonstrated that the addition of bevacizumab (B) to carboplatin/paclitaxel improved overall and progression-free survival (PFS) in patients (pts) with advanced NSCLC [Sandler et al. NEJM 2006]. Cisplatin/gemcitabine (CG) is a common combination in regions outside of the US. Methods: This randomised, placebo-controlled phase III study compared two doses of B plus CG versus CG plus placebo. The primary endpoint was PFS; secondary endpoints include overall survival, response rate (RR) and safety. Eligibility criteria: histologically or cytologically documented previously untreated advanced or recurrent non- squamous NSCLC; ECOG PS 0–1; no brain metastases. Between 2/05 and 8/06 1,043 pts were randomised to: C 80mg/m2 on d1 and G 1,250mg/m2 on d1 and d8 every 3 wks for up to 6 cycles plus B continued to progression at 7.5mg/kg every 3 wks, or 15mg/kg every 3 wks or placebo. The study was designed to include the number of patients required to observe a 30% reduction in the risk of a PFS event in the B arms compared with control using a two-sided logrank test (a=2.5%) with 80% power. Results: PFS was significantly prolonged as analysed both in a primary analysis (without censoring for non-protocol anti-neoplastic therapy [NPT] prior to progression) and in a prespecified analysis with censoring for NPT. The RR and response duration were also increased. Overall survival is immature due to short duration of follow up. Conclusions: Both doses of B significantly improved PFS and RR, consistent with the results of the earlier phase III trial E4599. No unexpected safety signals were detected. [Table: see text] [Table: see text]

Inhibition of angiogenesis in the treatment of non‐small cell lung cancer

“…Both doses of bevacizumab showed improvements in progression-free survival over chemotherapy alone, with hazard ratios of 0.75 (95% CI, 0.62-0.9, P = 0.002) and 0.82 (95% CI, 0.68-0.98, P = 0.03), respectively. (26) Toxicity Unique toxicities previously associated with bevacizumab included hypertension, delayed wound healing, thrombosis, and proteinuria. Due to the higher incidence of pulmonary hemorrhage seen in the phase II trial, patients with primary squamous cell histology, and significant hemoptysis were excluded from the phase III trial.…”

Potential Treatment Options After First-Line Chemotherapy for Advanced NSCLC: Maintenance Treatment or Early Second-Line?

“…Among the angiogenesis inhibitors, the anti-VEGF monoclonal antibody bevacizumab represents the most successful targeted therapy. In fact, in chemotherapy-naïve advanced NSCLC patients with nonsquamous histology, the combination of bevacizumab with chemotherapy has been demonstrated to have, in two large phase III randomized trials, efficacy superior to that seen with chemotherapy alone [4,5]. In these two trials, bevacizumab was administered in combination with chemotherapy from the beginning of treatment and was continued until disease progression, that is, as maintenance treatment after six cycles of chemotherapy.…”

“…In summary, the rates of hypertension, proteinuria, bleeding, neutropenia, febrile neutropenia, thrombocytopenia, hyponatremia, rash, and headache were significantly higher in the paclitaxel-carboplatin-bevacizumab group than in the paclitaxel-carboplatin group (p Ͻ .05). Another randomized, placebo-controlled phase III study (the Avastin in Lung Cancer [AVAIL] trial) has evaluated the addition of bevacizumab to chemotherapy (cisplatin plus gemcitabine) in the treatment of advanced nonsquamous NSCLC [5]. About 1,000 patients were randomized to receive cisplatin and gemcitabine every 3 weeks for up to six cycles plus bevacizumab continued until progression.…”

“…Approximately one third of patients obtain an objective response with first-line chemotherapy, and another 20% achieve temporary disease stabilization. Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, was demonstrated to have superior efficacy in combination with platinum-based chemotherapy in two phase III randomized trials, compared with chemotherapy alone in the treatment of nonsquamous advanced NSCLC (longer progression-free survival time and survival time in the first trial and only a longer progression-free survival time in the second trial) [4,5]. Cetuximab is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody approved for use in colorectal carcinoma and head and neck cancer treatment.…”

Beyond Monoclonal Antibodies: New Therapeutic Agents in Non-Hodgkin’s Lymphomas

“…Bevacizumab (Avastin; Genentech, San Francisco, CA) is a humanized murine anti-VEGF monoclonal antibody that is currently FDA approved for first-line therapy in metastatic colorectal cancer [118]. In fact, bevacizumab has been approved as first-line chemotherapy for advanced colorectal cancer in combination with 5-fluorouracil, folinic acid, and irinotecan [119], for advanced human epidermal growth factor receptor 2-negative breast cancer in combination with paclitaxel [120], for metastatic non-small cell lung cancer together with cisplatin [121] and gemcitabine, and with interferon-␣ for metastatic renal cancer [122].…”