The future is BRiTE.Introduction
In metastatic colorectal cancer, the traditional lines of 5-fluorouracil-based combination therapy have become blurred by the use of newer cytotoxic agents and monoclonal antibodies. In addition, the availability of sequential therapy and predictive testing has created new challenges in determining an actual overall or progression-free survival benefit for any new agents or regimens. The relative wealth and availability of drugs (cost considerations aside), the use of breaks in therapy, as well as maintenance and the complexities of combination therapy, have called into question the likelihood that any new intervention will allow for evidence-based recommendations supporting the use of any particular regimen as the gold standard of success leading to improvement in progression-free (PFS) or overall survival (OS).
Bevacizumab (Avastin) is a monoclonal antibody directed against vascular endothelial growth factor receptor, and although expensive, it is steadily becoming one of the world's most widely marketed drugs, particularly as atorvastatin is genericised. Its blockbuster status will extend despite the recent well-publicised failure of the C-08 study, in which over 2000 patients with resected stage II or III colon cancers were randomly allocated to treatment with standard chemotherapy (FOLFOX) with or without bevacizumab. There were no significant improvements in any survival parameters, and subgroup analyses even suggest that other adjuvant bevacizumab studies in colon cancer are not worthwhile.
Bevacizumab was first licensed for the treatment of metastatic colorectal cancer (approved by the US Food and Drug Administration [FDA] in February 2004), advanced non-small-cell lung cancer (approved in October 2006) and metastatic breast cancer (2007 in Europe and February 2008 in the USA). It is also approved for other indications, the main ones being second-line metastatic colorectal cancer (June 2006), metastatic kidney cancer (August 2009) and advanced gliomas (May 2009). Recently, the RIBBON-2 data in second-line metastatic breast cancer were presented and showed a survival advantage . This indication will be filed with the FDA shortly.
In AVF2107G, the trial of bevacizumab that led to approval of its use in metastatic colorectal cancer, the median PFS with bevacizumab was 10.6 months versus 6.2 months with chemotherapy alone; OS was 20 months with bevacizumab versus 15 months without. In this study, however, IFL chemotherapy was used, which is not now considered gold-standard therapy. In another trial of bevacizumab use in metastatic colorectal cancer, NO16966, PFS was 9.4 months in the bevacizumab arm versus 8 months for chemotherapy alone. Gold-standard chemotherapy (XELOX or FOLFOX) was used and the results are therefore a better comparator to the newer trials.
In the non-small-cell lung cancer trial, ECOG4599, the progression-free benefit was 6.2 months with bevacizumab versus 4.5 months for chemotherapy alone and in the ECOG2100 trial of bevacizumab use in metastatic breast cancer, the time-to-progression benefit measured 11.3 months versus 5.8 months with chemotherapy alone. These trials were highly statistically significant for their primary endpoints and response rates. Results for overall survival were confounded by subsequent crossover.
At September's ECCO 15 and 34th ESMO Multidisciplinary Congress (ECCO 15-34th ESMO) in Berlin, we heard about the main competition for this drug, cetuximab (Erbitux), a monoclonal antibody directed against the human epidermal growth factor receptor. Surprisingly, this medicine was recently rejected by the European Medicines Evaluation Agency (EMEA) for use in lung cancer, despite the 1346-patient randomised FLEX data  showing a survival but not progression-free survival advantage in nonsmall-cell lung cancer. In metastatic colon cancer, cetuximab is used in patients who have KRAS wild-type tumours. While this represents the majority of individuals, those who have a KRAS mutant status will not respond. This underlies an important concept across oncology: one can predict resistance but not response.
Results of both the COIN and PRIME studies were presented at ECCO 15-34th ESMO. COIN is a first-line colorectal cancer study, similar to the original CRYSTAL study using cetuximab in first-line colorectal cancer , but using different chemotherapy backbones, and there were two comparisons: standard therapy of FOLFOX or XELOX with or without cetuximab  as well as continuous versus intermittent therapy . This trial has been run by the UK's Medical Research Council with a primary end point of overall survival at 2 years. Most overall survival trials fail due to crossover following progression, that is, once the disease becomes worse a patient leaves the study and receives the antibody. However, as this trial is run in the UK, it has been historically difficult to obtain these other targeted agents on the NHS so there will be less crossover. Therefore, the beauty of this study was that we might have seen positive overall survival data. However, there was no bevacizumab arm in the COIN study. Furthermore, when COIN was commenced in March 2005, KRAS testing was not undertaken and a critical determinant here would be the data in the KRAS wild-type patients, those who we know may respond. In particular, would these individuals achieve a 13-month progression-free survival advantage? While KRAS status is not traditionally used or required with bevacizumab, those with tumours that have a wild-type status do better and there is speculation that the PFS measures 13 months with first-line bevacizumab treatment, though this has not been published.
However, at ESMO, the results of the COIN study were negative: there was no statistically significant PFS (or OS) advantage using cetuximab, even in KRAS wild-type patients. These data are difficult to reconcile with the results of CRYSTAL and OPUS; however, they indicate too the difficulty performing randomised studies. Furthermore, there may be a negative effect of combining oral chemotherapy (capecitabine) with cetuximab.
In the PRIME study , panitumumab, a fully humanised antibody against the epidermal growth factor receptor, was studied in first-line metastatic colorectal cancer in combination with FOLFOX chemotherapy. We already know that this achieved its primary end point of progression-free survival and that this difference was significant in KRAS wild-type patients (interestingly, those with mutant tumours fared worse with the antibody).
Crucially, these studies have not been undertaking head-to-head analyses versus bevacizumab, and crossstudy comparisons are always problematic: baseline characteristics of patients in different studies are never the same. Many of these questions, however, will be answered by CALGB/SWOG 80405, a very important study [7-9] designed to assess the optimal combination of biologic agents for first-line treatment of metastatic colorectal cancer, and a head-to-head of cetuximab versus bevacizumab with doctors prescribing FOLFOX or FOLFIRI. It is still recruiting patients (target n=2289) with a primary end point of overall survival.
In the interim, we have recently observed results of the Bevacizumab Regimens Investigation of Treatment Effects and Safety (BRiTE) study [10-12], which investigated the use of bevacizumab beyond progression (BBP). In this study, 1445 of 1953 previously untreated patients with metastatic colorectal cancer who were enrolled and who experienced disease progression (PD) were classified into three groups: no post-PD treatment (n=253); post-PD treatment without bevacizumab (no BBP; n=531); and BBP (n=642). Remarkably, median OS was 25.1 months (95% confidence interval [CI]: 23.4-27.5 months), while median PFS was 10.0 months in the overall BRiTE population. Median survival rates were 12.6, 19.9 and 31.8 months in the no post-PD treatment, no-BBP and BBP groups, respectively. In multivariate analyses, compared with no BBP, BBP was strongly and independently associated with improved survival (hazard ratio [HR]: 0.48; P<0.001). Hypertension that required medication was the only bevacizumab-related safety event that occurred more frequently in the BBP group (24.6% versus 19.2%). The authors concluded their analysis by stating that these results from a large, prospective, observational study suggest that continued vascular endothelial growth factor inhibition with bevacizumab beyond initial PD could play an important role improving the overall success of therapy for patients who have metastatic colorectal cancer .
This suggests that this well-tolerated medicine may be effective through multiple lines of therapy, data that require prospective confirmation. It is not immediately clear how or why this may be the case, but it seems analogous to trastuzumab in breast cancer, which is also active in metastatic disease beyond progression, as confirmed in randomised studies [13,14]. It would seem worthwhile for the bevacizumab studies to copy this trial design. Normally, patients who progress on bevacizumab-containing regimens would be switched to one containing cetuximab, provided their tumours are KRAS wild-type. The BRiTE observational data suggest an alternative.
Over the last decade, we have witnessed a radical change in the use of systemic therapy for metastatic colorectal cancer, with the introduction of three cytotoxic agents and three new better-tolerated monoclonal antibodies. New treatment paradigms have evolved that include the use of multiple chemotherapeutic agents in several lines of therapy, the ability to convert unresectable patients with liver metastases to resectable status, and the incorporation of these antibodies targeting vascular endothelial growth factor and the epidermal growth factor receptor into everyday practice. With this relative abundance of treatment options, it comes as no great surprise that both clinical researchers and clinicians have experienced increased difficulty defining a standard of care for patients with metastatic colorectal cancer, if indeed a single standard is either expected or desired. The discovery of B-RAF mutations predicting resistance will complicate the datasets further and this is a subject for more discussion . The CALGB/SWOG 80405 study is assuming increasing relevance, and data are eagerly awaited. As well as a head-to-head comparison of the right antibody, it also assesses the chemotherapy backbone, lest we forget about this.
[1.] Gonzalez-Martin A, Tercero A, Arranz J et al. Bevacizumab in combination with chemotherapy (CT) in previously treated metastatic breast cancer (MBC) patients. 2009 ASCO breast cancer symposium.
[2.] Pirker R, Szczesna A, von Pawel J et al. FLEX: a randomized, multicenter, phase III study of cetuximab in combination with cisplatin/vinorelbine (CV) versus CV alone in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol, 2008, 26 (Suppl), Abstr. 3.
[3.] Windsor AC, Cohen R, Jiao LR, Stebbing J. Cetuximab in the first-line therapy of metastatic colorectal carcinoma: not so CRYSTAL clear. Future Oncol, 2008, 4, 741-744.
[4.] Maughan T, Adams RA, Smith CG et al. Addition of cetuximab to oxaliplatin-based combination chemotherapy (CT) in patients with KRAS wild-type advanced colorectal cancer (ACRC): a randomised superiority trial (MRC COIN) (Abstr. 6LBA). Eur J Cancer Suppl, 2009, 7, 4.
[5.] Adams R, Wilson R, Seymour MT et al. Intermittent versus continuous oxaliplatin-based combination chemotherapy in patients with advanced colorectal cancer: a randomised non-inferiority trial (MRC COIN) (Abstr. 15LBA). Eur J Cancer Suppl, 2009, 7, 10.
[6.] Douillard J, Siena S, Cassidy J et al. Randomized phase 3 study of panitumumab with FOLFOX4 compared to FOLFOX4 alone as 1st-line treatment (tx) for metastatic colorectal cancer (mCRC): the PRIME trial. (Abstr. 10LBA). Eur J Cancer Suppl, 2009, 7, 6.
[7.] Venook AP, Blanke CD, Niedzwiecki D et al. Cancer and Leukemia Group B/Southwest Oncology Group trial 80405: a phase III trial of chemotherapy and biologics for patients with untreated advanced colorectal adenocarcinoma. Clin Colorectal Cancer, 2005, 5, 292-294.
[8.] Allegra C, Blanke C, Buyse M et al. End points in advanced colon cancer clinical trials: a review and proposal. J Clin Oncol, 2007, 25, 3572-3575.
[9.] Venook AP, Blanke CD, Niedzwiecki D et al. Revisiting the Cancer and Leukemia Group B/Southwest Oncology Group 80405 Trial: a phase III trial of chemotherapy and biologic agents for patients with untreated advanced colorectal adenocarcinoma. Clin Colorectal Cancer, 2007, 6, 536-538.
[10.] Ellis LM, Haller DG. Bevacizumab beyond progression: does this make sense? J Clin Oncol, 2008, 26, 5313-5315.
[11.] Kozloff M, Yood MU, Berlin J et al. Clinical outcomes associated with bevacizumab-containing treatment of metastatic colorectal cancer: the BRiTE Observational Cohort Study. Oncologist, 2009, 14, 862-870.
[12.] Grothey A, Sugrue MM, Purdie DM et al. Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). J Clin Oncol, 2008, 26, 5326-5334.
[13.] Valabrega G, Aglietta M, Montemurro F. Trastuzumab beyond disease progression: case closed? J Clin Oncol, 2009, 27, e121-122.
[14.] Montemurro F, Redana S, Viale G et al. Retrospective evaluation of clinical outcomes in patients with HER2-positive advanced breast cancer progressing on trastuzumab-based therapy in the pre-lapatinib era. Clin Breast Cancer, 2008, 8, 436-442.
[15.] Siena S, Sartore-Bianchi A, Di Nicolantonio F et al. Biomarkers predicting clinical outcome of epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer. J Natl Cancer Inst, 2009, 101, 1308-1324.
Justin Stebbing (1), Alastair Windsor (2) and Richard Cohen (2)
(1) Imperial College Healthcare NHS Trust, (2) University College London Hospitals NHS Trust
* Bevacizumab Regimens Investigation of Treatment Effects and Safety
Correspondence to: Justin Stebbing Consultant Medical Oncologist/Senior Lecturer Imperial College Healthcare NHS Trust Charing Cross Hospital, 1st Floor, E Wing Fulham Palace Road, London W6 8RF, UK Email: email@example.com