By ecancer reporter Jo Armstrong

Avastin (bevacizumab) is a recombinant humanised monoclonal antibody that selectively binds to and neutralises the biological activity of VEGF, reducing tumour vascularisation and inhibiting tumour growth. It has shown efficacy in combination with chemotherapy in metastatic breast, colorectal and non-small cell lung carcinoma (NSCLC), and in combination with interferon in renal cell carcinoma. Until recently, bevacizumab has not been investigated in patients with central nervous system metastases because of early concerns of possible increased risk of cerebral haemorrhage. However, a recent study demonstrated that patients with CNS metastases treated with bevacizumab were at similar risk of developing cerebral haemorrhage as control patients.¹

At this year's ESMO conference in Milan, a number of posters were presented on the use of bevacizumab in mCRC. A Phase III trial of bevacizumab plus chemotherapy (FOLFIRI and/or FOLFOX) versus bevacizumab alone in 222 treatment-naive patients showed no statistical difference between the two treatment arms, with an equal response rate seen in just over one third of patients.² Preliminary results from TRIBE, a study of first-line bevacizumab in combination with FOLFIRI or FOLFOXIRI for a maximum of 6 months, show that both treatment arms are safe and feasible in 150 patients, with side effects occurring with the expected incidence and no unexpected toxicities.³

Bevacizumab has also been studied as a second-line treatment option in mCRC patients who failed prior-combination chemotherapy without bevacizumab.⁴ In this study, bevacizumab plus FOLFIRI showed similar efficacy to bevacizumab plus FOLFOX, and safety of additional bevacizumab with FOLFOX / FOLFIRI in 139 patients across 29 institutions in Japan.

Timing of bevacizumab therapy added to primary chemotherapy (CT) and radiotherapy (RT) is also critical. Initiation of 2 courses of bevacizumab 4 days prior to CT/RT versus 4 courses initiated 14 days prior to CT/RT in patients with rectal cancer resulted in a lower incidence of grade 3/4 neutropenia and a significant difference in tumour response (circulating endothelial cell levels [+6% versus -84% compared to basal levels, p<0.05]; reduction in metabolic tumour volume [-50% versus -75%, p<0.05%]).⁵

The results from two Phase II trials C were also reported at ESMO 2010. The first showed that irinotecan plus S-1 (IRIS) regimen combined with bevacizumab was safe and effective in 52 patients with mCRC.⁶ The second reported final safety and efficacy results from the A-CORRECT trial, where pre-operative chemoradiation with capecitabine, oxaliplatin and bevacizumab with standard doses of radiation in 43 patients with high risk rectal cancer was found to be safe but did not significantly increase pathological clinical response.⁷

A number of studies of bevacizumab in patients with recurrent glioblastoma (GBM) were also presented. Patients with recurrent HGG have a poor prognosis, and response to conventional treatment is limited. A French National retrospective cohort study of 224 patients from 8 centres found that bevacizumab combined with irinotecan administered at the time of recurrence may improve the natural course of GBM, with a median overall survival from time of initial diagnosis of 20.9 months. These results were based on prognostic factors at the time of recurrence and time of initial diagnosis.⁸ This was also seen in a retrospective analysis of 216 GBM patients who received bevacizumab as monotherapy or in combination with chemotherapy after prior treatment at 31 centres in Switzerland, Austria and Germany, with median overall survival of 8 months⁹ and in a retrospective cohort study of 264 patients with Grade III and IV glioma in real-life clinical practice.¹⁰ When compared to chemotherapy (procarbazine and temozolomide), bevacizumab was found to be well tolerated and was associated with an encouraging clinical response in 48 patients with GBM.¹¹ In a study of 70 patients with GBM treated with bevacizumab in combination with irinotecan, a Karnovsky Performance Status (KPS) of 70-100 at relapse versus ≤70 has been found to be associated with an increased overall survival.¹²

In the session titled "Targeted therapies in NSCLC: State-of-the-art and new developments" the favourable clinical outcomes in patients with NSCLC treated with bevacizumab were presented.¹³

Results from the E4599 and AVAiL trials show that bevacizumab-based therapy followed by single-agent bevacizumab until disease progression significantly improves clinical outcomes, compared with chemotherapy alone in patients with advanced non-squamous NSCLC. Both trials met their primary endpoints: E4599, overall survival (OS, HR 0·79, p=0·003) and AVAiL, progression free survival (PFS, HR 0·75, p=0·003 and HR 0·82, p=0·03 for bevacizumab 7·5mg/kg and 15mg/kg, respectively). Nevertheless, AVAIL did not demonstrate an improvement in OS. Further, in a pre-planned retrospective analysis of E4599 patients with adenocarcinoma histology, bevacizumab increased median OS by 3.9 months from 10.3 months to 14·2 months (HR 0·69). Both phase III studies showed a consistent and acceptable safety profile for bevacizumab, with the majority of reported adverse events (AEs) and AEs of special interest (i.e., bleeding, hypertension, proteinuria, thromboembolism, congestive heart failure, gastrointestinal perforation) being grade 1 or 2, and the overall incidence of grade 3 AEs being similar across all arms. These safety and efficacy data have been evaluated in the real life clinical setting. SAiL (n=2,212) is an open-label, multicentre, single-arm study that included a wide range of chemotherapy regimens and a broad patient population, such as elderly, patients on concomitant anticoagulants and/or ECOG PS 2. The majority of AEs of special interest were resolved, and no new safety signals were reported. Final efficacy outcomes were also in line with pivotal phase III trials: median time to progression of 7.8 months and median OS of 14.6 months. How efficacy outcomes relate to histology is currently being determined in the ongoing observational cohort study, ARIES. Preliminary efficacy data from this 2,000 patient study are encouraging (OS of 13.6 months, PFS of 6.7 months), with no new safety concerns. However there are still many unanswered questions and areas of future development for bevacizumab including identification of markers of efficacy.

1. Besse B et al. Clin Cancer Res 2010; 16: 269-78.

2. GP Stathopoulos et al. Poster 606P: Chemotherapy with or without bevacizumab in advanced colorectal cancer: A Phase III trial .

3. G Masi et al. Poster 608P: Bevacizumab (BV) in combination with FOLFOXIRI compared with BV plus FOLFIRI as first-line treatment of metastatic colorectal cancer (MCRC): preliminary safety results of the TRIBE study by the Gruppo Oncologico Nord-Ovest (GONO).

4. T Moriwaki et al. Poster 609P: Efficacy and safety of second-line bevacizumab (BV) plus FOLFIRI / FOLFOX in patients with metastatic colorectal cancer (mCRC) who failed prior-combination chemotherapy without BV: Multicenter retrospective 2nd-BV study in Tsukuba Cancer Clinical Trial Group (TCTG).

5. A Avallone et al. Poster 658P: Critical role of bevacizumab schedule in combination with chemo-radiotherapy in neo-adjuvant treatment of rectal cancer: circulating endothelial cells and FDG-PET as markers for early prediction.

6. Y Komatsu et al. Poster 607P: Phase II trial of combined chemotherapy with irinotecan, S-1, and bevacizumab in patients with metastatic colorectal cancer.

7. H Kennecke et al. Poster 657P: Final safety and efficacy results of a phase II trial of bevacizumab, capecitabine, oxaliplatin, radiation rectal cancer trial (A-CORRECT).

8. S Taillibert et al. Poster 1056P: Bevacizumab (B) with irinotecan (I) in recurrent glioblastoma (GBM): a national retrospective cohort of the ANOCEF (Association des Neuro-oncologues d'Expression Française) Group.

9. S Hofer et al. Poster 1057P: Encouraging overall survival (OS) with bevacizumab (Bevacizumab) in patients with recurrent high-grade glioma (HGG) treated outside clinical trials.

10. F Grudé et al. Poster 1058P: Bevacizumab and irinotecan in recurrent malignant glioma: results of a French retrospective cohort study OMIT of 264 patients in real practice.

11. S Sahebjam et al. Poster 1059P: Efficacy, safety and pattern of relapse of bevacizumab (BEVACIZUMAB) versus chemotherapy for recurrent glioblastoma multiforme (GBM): A McGill University study.

12. JS Frenel et al. Poster 1060P: Clinical predictive factors of increased overall survival with bevacizumab/irinotecan for primary recurrent glioblastoma (GBM).

13. J-C Soria. Bevacizumab – the adolescent; bevacizumab achievements in non-small-cell lung cancer (NSCLC).