Bevacizumab and erlotinib (BE) first-line therapy in advanced non-squamous non-small-cell lung cancer (NSCLC) (stage IIIB/IV) followed by platinum-based chemotherapy (CT) at disease progression: A multicenter phase II trial (SAKK 19/05)
Introduction
Standard first-line treatment for patients with advanced NSCLC consists of platinum-based CT in combination with agents such as vinorelbine, gemcitabine, paclitaxel, docetaxel and pemetrexed. However, these CTs cause variable toxicities for a modest survival benefit [1], [2].
Various targeted agents are under investigation [3]; the VEGF-targeted recombinant humanized monoclonal antibody bevacizumab has shown progression-free survival (PFS) and overall survival (OS) benefits when combined with CT for the treatment of advanced non-squamous NSCLC patients, with little additional toxicity [4], [5], [6], [7], [8]. Erlotinib, an orally active inhibitor of EGFR-associated tyrosine kinase, is generally safe and well tolerated, and its role as single agent in second- and third-line therapy is well established [9]. In addition, a prior SAKK trial showed the related compound gefitinib is active as first-line therapy in an unselected NSCLC patients’ population [10]. Both TKIs have shown impressive activity in front-line treatment of EGFR mutated NSCLC patients [11], [12].
Preclinical studies have demonstrated that simultaneous inhibition of EGFR and VEGF pathways may result in synergistic anti-tumor activity [13]. In a previous phase I/II trial, 40 patients with relapsed or refractory non-squamous NSCLC were treated with BE with promising results [14].
Our large phase II trial, with 101 evaluable advanced non-squamous NSCLC patients, aimed to evaluate the efficacy of BE as first-line treatment and eventually identify novel predictive biomarkers for BE activity.
Section snippets
Eligibility criteria
Eligibility criteria included pathologically confirmed and untreated patients with non-squamous NSCLC stage IIIB and IV (TNM 6th edition), age > 18 years, WHO PS 0 or 1, adequate bone marrow, kidney and liver function, measurable disease, no large centrally located tumors, no pre-existing tumor cavitations, no brain metastases, no history of hemoptysis, coagulopathy or thrombosis, no concomitant full dose anticoagulants or non-steroidal anti-inflammatory drugs with anti-platelet activity.
Patients’ characteristics
From January 2006 to April 2009, 103 patients from 14 Swiss institutions were enrolled. Two patients were retrospectively found ineligible shortly after receiving trial medication, due to GI cancer and brain metastases at baseline, respectively. Thus, 101 evaluable patients were available for analysis. Patients’ characteristics are summarized in Table 1.
BE treatment
Baseline WHO PS was 0 (52.5%) and 1 (47.5%). Median treatment duration for BE was 4.2 months (range 0.6–32.7+ months). Fifty-five out of 101
Discussion
In this trial the combination of BE in first-line treatment of non-squamous NSCLC patients shows an acceptable toxicity profile, DSR at 12 weeks of 54.5%, median TTP of 4.1 months and OS of 14.1 months. These results are in range with modern first-line CTs in similar patient populations [6], [7], [20]. However, our patients were highly selected and the DCR was inferior to what is expected form standard chemotherapy. It was also disappointing, that only 63% of our patients proceeded to second
Ethical approval
This work has been approved by the appropriate ethical committees related to the institution(s) in which it was performed and that subjects gave informed consent to the work.
Conflict of interest statement
The following authors have declared a conflict of interest: FZ, DB, RvM, LB, AO, MP (Roche).
Role of the funding
This work was supported by the Swiss State Secretariat for Education and Research (SER) and Roche Pharma (Schweiz) AG.
Acknowledgments
We would also like to thank Barbara Hugli (Inselspital Bern) for laboratory work, Andrew Webb (DxS Ltd, Manchester, UK) for Therascreen EGFR test kits, Dr. Michel Bihl, Alex Rufle and Sandra Schneider (Institute for Pathology of the University Hospital Basel) for their expert help in EGFR gene mutation and FISH analysis, Dr. Coya Tapia (Institute for Pathology of the University Hospital Basel) for managing the EGFR gene mutation and FISH analysis and Dr. Stefanie Lerch Grossen (SAKK) for her
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