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Should we move beyond VEGF inhibition in metastatic colorectal cancer? Lessons from early phase clinical trials
Sukeshi R Patel1, Anand B Karnad1, Norma S Ketchum1
1University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA.
Abstract:
Data from recent clinical trials utilizing bevacizumab or other anti-VEGF agents in patients with metastatic colorectal cancer (mCRC) show improvements in progression-free survival (PFS) but modest, if any, improvements in overall survival (OS). Despite modest improvements, use of bevacizumab beyond first and second progression is routinely done in clinical practice. Recently, the CORRECT trial using regorafenib, a multi-kinase inhibitor with VEGF inhibitory properties, reported modest improvements in PFS and OS when compared to placebo, leading to FDA approval in the third-line setting. Prior to regorafenib, heavily pre-treated patients were often enrolled onto early phase clinical trials with many of these studies reporting efficacy amongst patients with mCRC; however, a collective efficacy analysis of mCRC patients enrolled into early phase clinical trials stratified by class of agents and their mechanism of action has not been done. To assess this, we performed an analysis of efficacy and stratified these findings based on VEGF inhibition versus non-VEGF inhibition in mCRC patients enrolled onto phase I trials at our institution from 3/2004-9/2012. Similar to many reported clinical studies, our data showed that VEGF inhibitors have a statistically significant improvement in PFS when compared to non-VEGF targeting agents; however, no differences in OS were observed between these two different classes of agents. We were not able to identify predictive biomarkers that correlate with efficacy of VEGF inhibitors. This should be further explored in prospective studies in order to identify active agents in this heavily pre-treated population that improve efficacy while minimizing cost and toxicity.
Insights
VEGF inhibitors improved progression-free survival but not overall survival in metastatic colorectal cancer (mCRC) patients in early phase trials. Biomarkers for efficacy were not identified, requiring further research for targeted treatments.
Area of Science:
- Oncology
- Clinical Pharmacology
- Translational Medicine
Background:
- Anti-VEGF agents like bevacizumab show limited overall survival benefits in metastatic colorectal cancer (mCRC).
- Regorafenib, a multi-kinase inhibitor, gained FDA approval for third-line mCRC treatment, highlighting ongoing research in this area.
- Previous efficacy analyses of early-phase trials in heavily pre-treated mCRC patients are lacking, particularly stratified by mechanism of action.
Purpose of the Study:
- To analyze the efficacy of early-phase clinical trial agents in metastatic colorectal cancer (mCRC).
- To stratify findings based on VEGF inhibition versus non-VEGF inhibition.
- To identify potential predictive biomarkers for VEGF inhibitor efficacy.
Main Methods:
- Retrospective analysis of efficacy data from Phase I clinical trials involving mCRC patients treated between March 2004 and September 2012.
- Stratification of patient outcomes based on whether agents targeted VEGF or not.
- Exploration of potential correlations between biomarkers and treatment response.
Main Results:
- VEGF inhibitors demonstrated a statistically significant improvement in progression-free survival (PFS) compared to non-VEGF targeting agents.
- No significant difference in overall survival (OS) was observed between the VEGF inhibitor and non-VEGF inhibitor groups.
- No predictive biomarkers correlating with VEGF inhibitor efficacy could be identified in this analysis.
Conclusions:
- While VEGF inhibitors offer PFS benefits in mCRC, they do not improve OS in the context of early-phase trials.
- Further prospective studies are essential to identify predictive biomarkers for targeted therapies.
- Optimizing treatment strategies requires balancing efficacy with cost and toxicity in heavily pre-treated mCRC populations.
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