Flashback Foreword: Bevacizumab and FOLFOX4 for Colorectal Cancer and Bevacizumab Versus Placebo Plus Oxaliplatin-Based Chemotherapy in Metastatic Colorectal Cancer

In 2007, Journal of Clinical Oncology published a manuscript by Giantonio et al¹ evaluating the addition of bevacizumab to oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) compared with FOLFOX4 or bevacizumab alone, in a 3-arm 829-patient randomized phase III trial in previously treated colorectal cancer. A median overall survival advantage was observed for FOLFOX4 and bevacizumab at 12.9 months compared with 10.8 months for FOLFOX4; hazard ratio [HR], 0.75; P = .0011. Subsequently, in 2008, Journal of Clinical Oncology published a manuscript by Saltz et al² evaluating the addition of bevacizumab versus placebo to frontline oxaliplatin-based therapy, either capecitabine/oxaliplatin or FOLFOX4, in a 1,401-patient 2 × 2 factorial design trial. The key conclusion from this latter study was that the addition of bevacizumab led to an improvement in progression-free survival (9.4 months v 8.0 months; HR, 0.83; P = .0023) the primary study end point, although neither overall survival nor response rates were improved relative to chemotherapy alone.

THE TAKEAWAY

In 2007 and 2008, Giantonio et al¹ and Saltz et al² reported that the addition of bevacizumab combined with oxaliplatin-based therapy in metastatic colorectal cancer led to improvement in overall survival in second-line treatment and improvement in progression-free survival in first-line therapy, respectively. These studies established bevacizumab and cytotoxic therapy as a reference standard in this disease, upheld and widely used on a global basis to this day.

These two studies have had a profound influence on the treatment of advanced colorectal cancer and firmly established the value of bevacizumab, a recombinant monoclonal antibody targeting the vascular endothelial growth factor (VEGF), in frontline and second-line therapy for metastatic colorectal cancer. Furthermore, these studies explored different doses of bevacizumab and did not clearly observe a dose-response outcome leading to the ubiquitous use of the 2.5 mg/kg/wk dose. Today, over 16 years since the publication of these studies, it is both a testament to the strength of their scientific value and also sobering that bevacizumab and FOLFOX4 remain a standard-of-care treatment and is typically the regimen of choice as the initial therapeutic option in right-sided colon cancer.

Major therapeutic refinements over the past decade and a half in colorectal cancer have accrued consequent of the understanding of the molecular subdivisions of the disease, including the integration of antiepidermal growth factor receptor therapies for ras-wild-type disease, particularly as it applies to left-sided colorectal cancer underpinning the importance of sidedness and more recently the utilization of immune checkpoint blockade in the small subset of patients with mismatch repair deficiency. A seminal national clinical trials network study, CALGB 80405, further demonstrated that no statistically significant overall survival difference was observed for chemotherapy (FOLFOX or fluorouracil, leucovorin, and irinotecan) with either of the two monoclonal antibodies, bevacizumab or cetuximab, in first-line metastatic disease.

The importance of these studies by Giantonio et al¹ and Saltz et al² is substantial and cannot be overstated and directly built on the US Food and Drug Administration (FDA) approval of bevacizumab in colorectal cancer in 2004. Both studies endorsed the use of bevacizumab with infusional/oral fluoropyrimidine/oxaliplatin combinations (over bolus regimens) and supported a precedent for evaluation and subsequent FDA approval of other antivascular therapies in this disease, including ziv-aflibercept, ramucirumab, and regorafenib, although arguably none have had the same degree of impact as bevacizumab. Notwithstanding all the successes accrued for VEGF targeting in colorectal cancer, it is sobering that biomarkers for selection of antivascular therapy and strategies for addressing resistance to these therapies are lacking and thus provide continued opportunity and challenge for the future.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Flashback Foreword: Bevacizumab and FOLFOX4 for Colorectal Cancer and Bevacizumab Versus Placebo Plus Oxaliplatin-Based Chemotherapy in Metastatic Colorectal Cancer

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