In this trial, the addition of AE-941 to standard chemoradiotherapy did not improve overall survival, progression-free survival, or response rates in patients with locally advanced NSCLC. To better understand the ramifications of these results, it is worthwhile to briefly review the genesis of this clinical trial. The study drug, AE-941, was selected independently by the NCI Cancer Therapy Evaluation Program as a shark cartilage–derived product that merited advanced clinical testing based on preclinical and clinical data supporting antiangiogenic activity and improved outcome in patients with advanced NSCLC (7
). It is noteworthy that AE-941 was developed as a pharmaceutical agent through the standard process of clinical trial testing, and AE-941 has never been available as an over-the-counter dietary supplement.
Dating back to 1976, more than 40 publications in the medical literature, including high-impact journals beyond the scope of cancer, were related to shark cartilage and its possible use for cancer treatment. The willingness of the NCI to fund this trial was influenced by the widespread use of poorly regulated complementary and alternative medicine products by patients likely to be vulnerable to unsubstantiated marketing claims. Products such as shark cartilage–derived agents are widely used among patients with various types of advanced cancer (16
). Rigorous clinical testing of a standardized shark cartilage–derived compound was deemed to be a priority because results of such a study could have a broad public health impact.
To our knowledge, this report represents the first published phase III trial of a shark cartilage–derived pharmaceutical agent. Although this trial was ongoing, AE-941 was evaluated in another phase III trial in metastatic renal cell carcinoma patients refractory to immunotherapy, but the results were presented only in abstract form and as a press release from the manufacturer (Aeterna Zentaris, Inc, Quebec City, Quebec, Canada) (18
). Unfortunately, this latter trial also failed to reach its primary endpoint of improving overall survival, and AE-941 is no longer in clinical development.
One limitation of this trial is the lack of available pharmacokinetic and pharmacodynamic correlative studies. AE-941 is a standardized extract of a natural product, and currently, the active molecules in this extract remain poorly understood. Therefore, there have been no human pharmacokinetic studies or validated pharmacodynamic or predictive biomarkers of activity. The absence of validated pharmacokinetic and pharmacodynamic assays clearly limits our ability to investigate potential explanations for AE-941’s lack of activity observed in our study. The absence of predictive biomarkers also resulted in a study population of unselected NSCLC patients, and this type of trial design may further compromise the ability to demonstrate efficacy of targeted agents.
Several shark cartilage crude extracts, sold over the counter as dietary supplements, have also been tested in clinical trials (20
). Unlike drugs, dietary supplements do not require FDA approval before marketing. A phase III trial of Benefin Shark Cartilage (LaneLabs, Allendale, NJ) in advanced cancer patients was conducted, although it was closed early because of lack of accrual. With a total of 83 evaluable patients, the study failed to demonstrate an improvement in its primary endpoint of overall survival (20
). Another shark cartilage dietary supplement was tested in a phase I–II trial in 60 patients with previously treated advanced cancers. No responses were observed, and the investigators concluded that there was no indication of anticancer activity (21
Although our study did not reach its original accrual goal, it is nevertheless the largest phase III study ever conducted, to our knowledge, of a shark cartilage–derived agent, and the study outcome is unambiguous. Unlike the aforementioned shark cartilage dietary supplements, AE-941 was manufactured and developed as an anticancer drug. Therefore, these results represent the highest level of clinical data available for the role of a shark cartilage–derived agent as a cancer therapy. Another strength of our study is the recruitment of subjects from both academic and community oncology centers, which enhances the generalizability of these findings. We hope that this trial will provide physicians with relevant evidence-based information that can be conveyed to cancer patients who inquire about the activity of shark cartilage in their disease.
Although the results of our study were negative, other antiangiogenic drugs have demonstrated clinical activity in NSCLC. A phase III trial of bevacizumab, a monoclonal antibody against vascular endothelial growth factor, in selected patients with nonsquamous NSCLC demonstrated a statistically significant survival benefit when combined with paclitaxel and carboplatin (5
), leading to approval for first-line treatment in the United States. Several oral small molecules, such as vandetanib, sorafenib, and sunitinib, which target vascular endothelial growth factor receptors and other receptor tyrosine kinases, are in advanced phase III testing in NSCLC after phase II studies yielded encouraging results (22
). Other antiangiogenic compounds in different stages of clinical development include thalidomide analogues, integrin inhibitors, and small-molecule vascular disrupting agents (26
This study reports a rigorous attempt to address a valid scientific question related to the use of a shark cartilage product in a specific and common treatment setting. The addition of AE-941 to chemoradiotherapy did not improve overall survival in patients with unresectable stage III NSCLC, and therefore, these results do not support the use of shark cartilage–derived products as a therapy for lung cancer.