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PTK787: A Small Molecule Inhibitor of VEGF-Receptors

Reviewer: Christopher Dolinsky, MD
University of Pennsylvania School of Medicine
Ultima Vez Modificado: 2 de noviembre del 2005

Presenter: J. Randolph Hecht, MD
Presenter's Affiliation: UCLA GI Oncology Program, Los Angeles, California
Type of Session: Scientific

Background

• Growing tumors need access to nutrients and a blood supply, and the process of new blood vessel formation is called angiogenesis.
• Considerable research has demonstrated the importance of angiogenesis for tumor growth and development.
• Growing tumors secrete molecules that signal for the initiation and maintenance of angiogenesis.
• One of the main molecules that signals for angiogenesis is called vascular endothelial growth factor (VEGF).
• VEGF has 3 known receptors by which it can transmit the signal for angiogenesis to occur.
• A novel strategy to control tumors involves disrupting tumor angiogenesis by either decreasing VEGF levels or blocking VEGF receptors.
• PTK787/ZK 222584 (PTK/ZK, vatalinib) is a small molecule which blocks all 3 VEGF receptors.
• PTK787 is orally available and has a half life of 3-6 hours.
• Laboratory experiments have shown that PTK787 can decrease tumor growth and metastasis formation.
• Phase I studies have shown that PTK787 can reduce the perfusion of tumors when measured by a special type of MRI known as a dynamic contrast enhanced MRI.
• Phase II data have demonstrated that PTK787 is safe in human beings.
• The regimen of 5-fluorouracil/oxaliplatin/leukovorin (FOLFOX 4) has been proven useful for the management of metastatic colorectal cancer.

Materials and Methods

• Two large randomized, placebo controlled phase III trials were designed to test the efficacy of the PTK787 molecule in patients with metastatic colorectal cancer.
• The CONFIRM-1 trial enrolled 1168 patients who were previously untreated and stratified them by performance status and LDH level.
• Patients were randomized to either FOLFOX4 with PTK787 or FOLFOX4 plus placebo.
• Primary endpoints included overall survival (OS) and progression free survival (PFS).
• PFS was determined every 8 weeks by both investigators at enrolling institutions and by an independent central radiology review.
• Disease and demographic characteristics were well balanced among both arms.
• The CONFIRM-2 was similar in design to CONFIRM-1, except that it looked at patients who had been previously treated with 5FU and irinotecan.

Results

• The results of CONFIRM-1 were presented at ASCO 2005 and discussed today, but the results of CONFIRM-2 have not been presented formally except in a brief press release.
• For CONFIRM-1, on central review, there was no statistically significant difference in progression free survival between the two arms (hazard ration 0.88, p=0.118).
• Using investigator review, there was a small statistically significant difference noted in favor of the experimental arm for progression free survival (hazard ratio 0.82, p = 0.019)
• In an exploratory analysis, patients with high serum LDH had a 40% risk reduction of progression in the experimental arm (hazard ratio 0.6, p=0.01).
• Grade 3 adverse events that were more common in the PTK787 arm than the placebo arm included: hypertension (21% vs. 6%), dizziness (7% vs. 2%), and venous thrombosis (7% vs. 4%).
• Both pulmonary embolism and arterial thromboembolism were seen more commonly in the PTK787 arm than the placebo arm.
• The rate of death within 28 days of last study drug was similar in both regimens (PTK787- 5% vs placebo 6%).
• The press release for CONFIRM-2 stated that no difference was seen between arms in terms of overall survival and that LDH level correlated with clinical benefit.

Author's Conclusions

• For CONFIRM-1, PFS based on central review showed a modest benefit of adding PTK787 to FOLFOX which did not reach statistical significance.
• Preplanned secondary analysis of PFS based on investigator assessment showed a statistical improvement favoring PTK787.
• PTK787 in combination with FOLFOX is generally well tolerated.
• High LDH levels may predict which patients are most likely to benefit from PTK787.

Clinical/Scientific Implications

While the concept of using an inhibitor of all three VEGF receptors is certainly elegant, one must remember that CONFIRM-1 is essentially a negative trial. Centrally reviewed radiologic analysis for progression (the primary endpoint) did not produce a statistically significant difference between the experimental arm and placebo.  The magnitude of the difference noted in median survival (7.7 months versus 7.6 months) is 3 days, and may be due to random chance. Although the investigator assessment of progression did favor the experimental arm, this was not a completely blinded analysis. Investigators may have had some idea which patients were receiving the experimental compound (based on side effect profiles), and this may have produced bias in their assessment of response and progression.

This agent does not appear to compare favorably with other agents used to inhibit the VEGF receptor pathways (such as bevacizumab) that have shown significant activity in colorectal cancer.  While it is true that overall survival data and further analyses are required to fully characterize the efficacy of PTK787, these data do not predict success in the future using this compound for metastatic colorectal cancer.

An important question raised by this trial is, why doesn't it work? Multiple hypotheses exist, including: the agent is not sufficiently active, the drug was not dosed properly, or patients were not chosen properly. The drug has a fairly short half-life, and no one knows what sorts of trough levels are needed to sufficiently inhibit VEGF for tumor control. The fact that patients with high LDH responded to this compound is certainly interesting, and may speak to the biology of this agent. Perhaps in the future, this drug can be tested in only patients with elevated LDH. Finally, one can speculate that this agent may be effective in patients who have already failed bevacizumab. The PTK787 story is not over, and the study of this compound will continue to move oncology forward, both in terms of its specific use and more broadly in term of how biologic agents are developed and tested in the future.