Forget the endpoint
Forget whether a study met its endpoint, having more clinical data is always a positive outcome.
The debate about whether patients with metastatic colorectal cancer (mCRC) should be treated with the vascular endothelial growth factor inhibitor bevacizumab (Roche's Avastin) or the epidermal growth factor receptor inhibitor cetuximab (Merck and BMS/Lilly's Erbitux) has been raging for years. Importantly, both companies appeared to be satisfied with their parallel clinical trial programmes without performing head-to-head trials, always leaving the door open for anecdotal evidence and indirect comparisons to rule when it came to making decisions about which treatment may be more efficacious. Accordingly, many gastrointestinal oncologists appeared to have clear personal preferences for using one treatment ahead of the other in the first-line treatment of mCRC.
In the meantime, a crude comparison of outcomes across a number of studies would have suggested that patients were broadly achieving similar survival outcomes with either treatment option. Furthermore, much of the debate was centring not on which targeted therapy was pound-for-pound the better therapy, but on which therapy was more effective with a FOLFIRI or FOLFOX chemotherapy backbone and whether or not to choose a therapy on the basis of KRAS status, as cetuximab is indicated for tumours with a KRAS wild-type genotype, but no biomarker has been identified for bevacizumab.
However, the underlying reality was that both therapies demonstrated improved efficacy compared with doublet chemotherapy in pivotal phase III clinical trials, and it has been an agonisingly long wait for independent clinical trial groups in Germany (FIRE-31) and the US (CALG-B/SWOG 804052) to report the results of head-to-head trials of cetuximab and bevacizumab, with the wait for data largely a result of median overall survival times in patients with mCRC now approaching 30 months.
Beauty is in the eye of the beholder
The primary endpoint was not reached in either head-to-head comparison of bevacizumab and cetuximab in mCRC, indicating that it is technically correct to refer to both trials as "negative" studies. However, to define these studies as negative is overly simplistic, and arguably devalues the impact that these results will have when gastrointestinal oncologists make treatment decisions in the wake of these studies.
Most doctors would be hard pressed to explain to their patients that the significantly greater median overall survival (OS) observed in patients treated with cetuximab versus bevacizumab reported in the FIRE-3 study could not be relied upon because OS was a secondary endpoint in a negative study. Therefore, would it be unreasonable for oncologists to ignore expert opinion advocating caution when interpreting the FIRE-3 results? Besides, labelling the outcome of a trial as negative implies a failure to improve the current standard of care. In contrast, FIRE-3 demonstrated that the two treatment options offered broadly comparable response rates and median progression-free survival, with a possibility that cetuximab may offer improved OS. This was undoubtedly a positive outcome for both patients and oncologists, who for the first time had a direct comparison between the two treatment options.
Not better, not worse, just different
As highlighted earlier, some gastrointestinal oncologists favour either cetuximab or bevacizumab when treating patients with mCRC. However, the drive to make treatment decisions on the basis evidence-based medicine almost demands that a trial must have a clear "positive" or "negative" outcome when assessing superiority or non-inferiority. Accordingly, the data from the CALG-B/SWOG-80405 study is somewhat of a victim of statistics in that the study failed to demonstrate superiority, but was not designed to assess non-inferiority, leaving the authors in a statistical no man's land, and having to defend the clinical relevance of the negative outcome of their trial.
However, would the same judgement be made if this trial was not presented in the context of the OS result in FIRE-3? Is it more appropriate to say that the result of 80405 is actually negative because it failed to confirm the FIRE-3 OS result? Arguably, a result that has largely confirmed the result of the FIRE-3 study should be referred to as being a positive outcome as it has further clarified the relative efficacy of cetuximab and bevacizumab, with no significant difference being observed between the two treatments, thereby justifying the experts warning to treat the OS outcome in FIRE-3 with caution.
This is literally a matter of life and death
Surely any new data that adds to the body of scientific knowledge and helps inform treatment decisions will improve the standard of care for cancer patients. For patients and doctors, making a decision between two treatments could literally be a matter of life and death, and no one wants to find out that they chose wrong. Therefore, rather than being disappointed that no clear 'winner' has been declared in the cetuximab-bevacizumab efficacy race, perhaps focus should return to the patients, in that oncologists should be comforted by the fact that there is no clear reason to believe that their patients would have consistently benefited if they had selected one treatment over the other.
To their credit, Venook and colleagues chose to conclude that in the absence of a consistent survival benefit of one therapy over another in the 80405 study, a greater focus should be on the adverse event profile and tolerability of cetuximab and bevacizumab. In fact, they chose to state that "Patients with KRAS wild type metastatic CRC have choices." Accordingly, surely having more data for patients to make these choices is truly valuable and positive outcome.
1. Heinemann V, et al. Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS wild-type metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3). J Clin Oncol 2013;31(Suppl):Abstract LBA3506.
2. Venook P, et al. CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). J Clin Oncol 2014;32(5 Suppl):Abstract LBA3.
About the author:
Blair Hesp is the Managing Director of Kainic Medical Communications Ltd., a New Zealand-based agency that specialises in providing on-demand professional medical writing support to overseas medical communications agencies and New Zealand-based biotechnology companies.
Blair has a PhD in Pharmacology from the University of Otago and a New Zealand Diploma in Business, and has been recognised as one of New Zealand's most innovative marketing and communications professionals. In addition to several years' experience working in the Global and European medical communications industry in the UK, he has also spent several years working in the international intellectual property industry.
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