Elsevier

Lung Cancer

Volume 78, Issue 3, December 2012, Pages 239-244
Lung Cancer

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)

https://doi.org/10.1016/j.lungcan.2012.08.017Get rights and content

Abstract

Purpose

This phase II trial aimed to evaluate feasibility and efficacy of a first-line combination of targeted therapies for advanced non-squamous NSCLC: bevacizumab (B) and erlotinib (E), followed by platinum-based CT at disease progression (PD).

Methods

103 patients with advanced non-squamous NSCLC were treated with B (15 mg/kg day 1 of each 21-day cycle) and E (150 mg daily) until PD or unacceptable toxicity. Upon PD patients received 6 cycles of CT (cisplatin/carboplatin and gemcitabine). The primary endpoint was disease stabilization rate (DSR) after 12 weeks of BE treatment.

Results

101 patients were evaluable. Under BE, DSR at week 12 was 54.5%. 73 patients had at least stable disease (SD), including 1 complete remission and 17 partial responses (PR). No unexpected toxicities were observed. Median time to progression (TTP) under BE was 4.1 months. 62 patients started CT; 35 received at least 4 cycles (6 PR, 32 SD). At a median follow-up of 36 months, median overall survival (OS) was 14.1 months.

Conclusions

First-line BE treatment followed by a fixed CT regimen at PD is feasible with acceptable toxicity and activity. In a non-squamous NSCLC population unselected for EGFR status, we found OS rates similar to standard CT.

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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