Source: Urology  |  Posted 5 years ago

By Chris Berrie

PRAGUE, CZECH REPUBLIC -- November 8, 2006 -- The combination of bevacizumab with either standard chemotherapy or erlotinib is associated with no new or unexpected safety concerns and has improved efficacy compared with chemotherapy alone, according to a study of patients with recurrent or refractory non-small-cell lung cancer (NSCLC).

The study compared the recombinant, humanised, antivascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab in combination with either docetaxel or pemetrexed, against the epidermal growth factor (EGF) tyrosine kinase inhibitor erlotinib.

Investigator Vince O'Niell, MD, medical director, clinical development, Genentech Inc., South San Francisco, California, presented the multicentre, randomised phase 2 trial here on November 8[^]th[] at the American Association for Cancer Research 18[^]th[] Symposium on Molecular Targets and Cancer Therapeutics - National Cancer Institute - 18[^]th[] European Organisation for Research and Treatment of Cancer (AACR -NCI-EORTC).

VEGF and the EGF receptor have been identified as key molecular targets in a range of tumour types that share common downstream signalling pathways. Thus, "With [bevacizumab] as an anti-angiogenic and [erlotinib] as an anti-EGF receptor, the data indicates that [these agents] should work well together," Dr. O'Niell said.

The primary objective of this study was to evaluate progression-free survival (PFS) with the combination of bevacizumab and either chemotherapy or erlotinib, relative to chemotherapy alone, in patients with previously treated advanced-stage NSCLC. The secondary objectives of the study included further measures of efficacy.

The inclusion criteria were histologically or cytologically proven non-squamous NSCLC that was recurrent and unresectable, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 2, life expectancy of 3 months or more, and adequate haematological, hepatic and renal function. Patients were assessed using the Response Evaluation Criteria in Solid Tumours (RECIST) criteria. Patients were excluded using a range of criteria relevant to previous treatments and metastases.

The researchers stratified 120 patients by baseline ECOG PS and smoking history (never vs current/ previous). These patients were then randomised as follows: arm 1, 40 patients received chemotherapy with docetaxel or pemetrexed plus placebo; arm 2, 40 patients received chemotherapy plus bevacizumab; arm 3, 39 patients received bevacizumab plus erlotinib. Patients remained on treatment until radiographic or clinical disease progression or for the 52 weeks of the study.

The full range of baseline patient demographics and characteristics were similar across the 3 treatment arms, with median age of 65.0, 63.5, and 68.0 years, respectively, and male gender in 61.0%, 57.5% and 43.6%, respectively. One patient had an ECOG PS of 2 (arm 1), and NSCLC histology profiles were as follows: large cell carcinoma, 9.8%, 22.5%, 0.0%; adenocarcinoma, 80.5%, 75.0%, 82.1%; other/not otherwise specified, 9.8%, 2.5%, 17.9%.

The primary objective of PFS was achieved in a median of 3.0, 4.8 and 4.4 months, respectively. Six-month PFS rates were 21.5%, 30.5% and 33.6%, respectively. These were seen as adjusted hazard ratios (HRs) of arms 2 and 3 versus chemotherapy alone (arm 1) of 0.66 (95% confidence interval [CI], 0.38-1.16) and 0.72 (95% CI, 0.42-1.23), respectively. Although not reaching significance, these data showed trends for these bevacizumab combinations over chemotherapy alone, according to the researchers.

The overall survival rates for 1 year were 34.8%, 53.6% and 57.1%, respectively, again showing beneficial trends of the bevacizumab combinations. Of note, PFS and overall survival for chemotherapy alone were consistent with previously published data. Similarly, overall response rates were in favour of the bevacizumab combinations: complete/partial response or stable disease, 39.0%, 52.5%, 51.3%, respectively.

As an exploratory analysis, comparison of chemotherapy alone (arm 1) with the combined bevacizumab treatments (arms 2 plus 3) further demonstrated these beneficial trends: median PFS, 3.0 versus 4.4 months; 6-month PFS rate, 21.5% versus 31.8%; HR versus chemotherapy alone, 0.67 (95% CI, 0.42-1.06). Similarly, overall survival rates were: median, 8.6 versus 13.3 months; 1-year rate, 34.8% versus 55.3%; HR versus chemotherapy alone, 0.74 (95% CI, 0.46-1.19).

The bevacizumab plus erlotinib combination generally showed a more favourable toxicity profile (arm 3 versus arms 1, 2), with rates of treatment discontinuation due to adverse events (AEs) of 13% versus 24%, 28%; serious AEs, 33% versus 55%, 41%; grade 5 drug-related AEs, 3% versus 5%, 8%.

While stressing that this phase 2 study was small and underpowered, and did not provide significant numbers, Dr. O'Niell did indicate that, "This novel biological combination looks to be on the face of it better than single-agent chemotherapy."

These overall beneficial trends in favour of both efficacy and safety for the combination of bevacizumab plus erlotinib could indicate its potential as an alternative to chemotherapy-based treatments in patients with relapsed NSCLC. A definitive, fully powered, phase 3 trial with this combination is now ongoing.

This study was conducted in collaboration with Genentech Inc., DSI Pharmaceuticals Inc. and Hoffmann-La Roche Inc.

[Presentation title: A Phase, Multicentre, Randomised Clinical Trial to Evaluate the Efficacy and Safety of Bevacizumab (Avastin(R)) in Combination With Either Chemotherapy (Docetaxel or Pemetrexed) or Erlotinib (Tarceva(R)) Compared With Chemotherapy Alone for Treatment of Recurrent or Refractory Non-Small-Cell Lung Cancer. Abstract 53]