A randomized, double-blind, placebo controlled, phase III study in patients (Pts) with metastatic adenocarcinoma of the colon or rectum receiving first-line chemotherapy with oxaliplatin/5-fluorouracil/leucovorin and PTK787/ZK 222584 or placebo (CONFIRM-1).

Reviewer: Christopher Dolinsky, MD
University of Pennsylvania School of Medicine
Ultima Vez Modificado: 15 de mayo del 2005

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Presenter: J.R. Hecht
Presenter's Affiliation: UCLA School of Medicine, Los Angeles, California
Type of Session: Plenary

Background

- A potential method for inhibiting tumor growth is to block a tumor's production of blood vessels (angiogenesis) that supply it with oxygen and necessary nutrients.
- A novel strategy that has recently emerged in oncology uses various compounds to inhibit angiogenesis pathways involving a class of cell surface receptors known as VEGF (vascular endothelial growth factor) receptors.
- PTK787/ZK 222584 (PTK/ZK) is compound that has been shown in laboratory models to block tyrosine kinase signaling from VEGF receptors.
- The inhibition of VEGF signaling pathways has proved useful in previous studies of metastatic colorectral cancer.
- The regimen of 5-fluorouracil/oxaliplatin/leukovorin (FOLFOX 4) has been proven useful for the management of metastatic colorectal cancer.

Materials and Methods

- A multinational, phase III, double-blind, placebo-controlled study randomized 1168 patients to either FOLFOX 4 with 1250mg of PTK/ZK or FOLFOX 4 with placebo.
- Primary endpoints include overall survival and progression free survival.
- Progression free survival was determined every 8 weeks by both investigators at enrolling institutions and an independent central radiology review.
- Disease and demographic characteristics were well balanced among both arms.
- This abstract only discussed the progression free survival endpoint.

Results

-  On central review, there was no statistically significant difference in progression free survival between the two arms (PTK/ZK 7.7 months vs. placebo 7.6 months, p=0.118).
-  Using investigator review, there was a small statistically significant difference noted in favor of the experimental arm for progression free survival (PTK/ZK 7.7 months vs. placebo 7.5 months, p = 0.026)
-  In an exploratory analysis, patients with high serum LDH had improved progression free survival in the experimental arm (PTK/ZK 9.6 months vs. placebo 5.8 months, p=0.002)
- Grade 3 adverse events that were more common in the PTK/ZK arm than the placebo arm included: hypertension (20.6% vs. 5.9%), diarrhea (14.5% vs. 10.3%), dizziness (6.6% vs. 2.1%) and DVT (4.7% vs. 3.0%).
- Both pulmonary embolism and arterial thromboembolism were seen more commonly in the PTK/ZK arm than the placebo arm.

Author's Conclusions

-  The results suggest some beneficial effect of PTK/ZK as first line therapy on progression free survival in metastatic colorectal cancer when combined with FOLFOX 4.
-  Patients with high serum LDH seemed to derive the most benefit from PTK/ZK.
- Once overall survival data are available, further analysis will better characterize the efficacy of PTK/ZK as a first line agent for metastatic colorectal cancer.

Clinical/Scientific Implications

This abstract presents data from a well designed phase III, randomized, double blind, placebo controlled trial.  Although the authors suggest that PTK/ZK produces a positive effect, the data presented do not agree with this conclusion.   This is essentially a negative trial. Centrally reviewed radiologic analysis did not produce a statistically significant difference in progression free survival between the experimental arm and placebo.  The magnitude of the difference noted (7.7 months versus 7.6 months) is 3 days, and may be due to chance.  This agent does not appear to compare favorably with other agents used to inhibit the VEGF receptor pathways (such as bevacizumab) which 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 PTK/ZK, 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? Various hypotheses will eventually be tested, and this line of inquiry will certainly increase our knowledge of the biology of these tumors and effective strategies to control them.

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