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5.1. BAY 43-9006 (Sorafenib)

BAY 43-9006 is an orally available inhibitor of Raf-1 with additional activity against VEGFR-2, -3 and PDGFR-β kinases and others.

Clinical phase I trials in several oncologic indications showed promising signs of efficacy with regards to tumor regression.35 A dosing regimen of 400 mg bid was established to be safe. Encouraging results of the phase II program led to the launch of a randomized phase III trial in advanced renal cell carcinoma (RCC). The preliminary analysis of progression free survival (PFS) showed an increase from 12 weeks in the best supportive care group to 24 weeks in the BAY 43-9006 treatment group (p < 0.00001, HR = 0.44). The trial is ongoing for final analyses of overall survival (OS). Predominant side effects are rash, diarrhea, hand-foot skin reaction, fatigue and hypertension.36 Rash, as an adverse event, may pinpoint to a residual inhibition of EGFR kinase in dermal tissue, whereas hypertension seems to occur as adverse event in all therapies effectively targeting the VEGF pathway.

BAY 43-9006 is currently in clinical testing in randomized phase III trials in advanced melanoma and hepatocellular carcinoma, as well as in phase II studies in thyroid cancer and prostate cancer. Filing of a New Drug Application for Sorafenib for patients with advanced RCC based on the PFS data has been completed in mid-2005.

5.2. PTK/ZK (Vatalanib)

PTK/ZK is an orally available inhibitor of VEGFR-1, -2 and -3 tyrosine kinases which, less potently, also targets PDGFR-β and c-kit. Phase I/II studies in colorectal cancer, glioblastoma multiforme (GBM), RCC, prostate cancer, ovarian cancer and mesothelioma showed a safe sideeffect profile and promising activity.37−41 A continuous oral dosing regimen of 1250 mg qd without the need for treatment interruption has been established to be safe.

Two randomized, placebo-controlled, double-blinded phase III trials in colorectal cancer (CONFIRM 1 and CONFIRM 2) have been launched, investigating the safety and efficacy of PTK/ZK added to the FOLFOX4 regimen in the first (CONFIRM 1) and second (CONFIRM 2) line treatment of metastatic colorectal cancer. In the analysis

of PFS based on a central assessment of CONFIRM 1, PTK/ZK did not demonstrate a statistically significant improvement in the overall patient population, although a statistically significant improvement was reached in the investigator assessment. A strong treatment benefit can be observed in the patient population with high LDH levels at baseline. The trial is ongoing for evaluation of OS, which is the subsequent primary endpoint. Predominant side effects in the PTK/ZK group were hypertension, nausea, vomiting, fatigue, dizziness and thrombembolic events.42

Efficacy of PTK/ZK is also currently investigated in a phase II study in advanced non-small cell lung cancer (NSCLC) and in a randomized phase II study in newly diagnosed GBM.

For the phase I studies, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used as a pharmacodynamic marker of activity. A bidirectional transfer constant Ktrans, which is a measure of the extravasation of the MRI contrast medium Magnevist® into the tissue was found to be reduced up to 50% after dosing higher than 750 mg qd. Changes in Ktrans represent alterations in blood vessel permeability, vascularity, blood flow and extracellular space.43

5.3. SU11248 (Sunitinib)

SU11248 is an orally available broad activity kinase inhibitor with high activity against VEGF receptor tyrosine kinases, c-Kit and FLT-3. The phase I program in different patient populations showed efficacy with regard to tumor regressions and established a safe dosing schedule of 50 mg qd for four weeks followed by a two-week interruption. Two consecutively conducted phase II trials showed that SU11248 has substantial efficacy as second line therapy in RCC. Side-effect profile comprises mainly fatigue, nausea, diarrhea and stomatitis.44 The need for a treatment interruption may be a consequence of the broader kinase inhibition activity as shown in Fig. 1 and does not permit to completely exploit the potential of anti-angiogenic treatment. SU11248 also showed clinical activity in imatinib refractory gastrointestinal stromal tumors (GIST) and metastatic neuroendocrine tumors (NET).

328 K.-H. Thierauch & A. Chlistalla

SU11248 is currently investigated in a phase III trial comparing its monotherapy efficacy to interferon-α in first line treatment of metastatic RCC.

5.4. ZD6474

ZD6474 is an oral inhibitor of VEGFR-2 and the EGFR-tyrosine kinases. Safety and tolerability of ZD6474 have been evaluated in two phase I studies with refractory tumors including a large proportion of NSCLC cancer patients.45,46 An oral administration of doses of 300 mg or less was generally safe and well tolerated. Predominant side effects are diarrhea, rash and asymptomatic corrected QT interval prolongation. The characteristics of this side-effect profile (rash) is attributable to the EGFR-inhibiting properties, whereas the dominant side-effects caused by VEGF inhibition known from other compounds such as hypertension are not reported in high frequency. This leads to the hypothesis that the clinical activity of ZD6474 has a predominant component of EGFR inhibition.

ZD6474 had been investigated in a phase II trial in patients with previously treated metastatic breast cancer without objective responses at doses of 100 and 300 mg qd.47 Interestingly the Ktrans values obtained from MRI measurements of extravasating contrast media did not change with treatment outside the normal variability of the technique. Changes in Ktrans values are described for other compounds targeting the VEGF pathway.43 The lack of these changes again supports the hypothesis that ZD6474 exhibits its clinical effects primarily by targeting the EGFR pathway.

ZD6474 is currently investigated in two different dosing schedules in two randomized double-blinded phase II trials comparing the safety and efficacy of ZD6474 once added to docetaxel in second line NSCLC and in combination with paclitaxel/carboplatin in first line NSCLC. Preliminary PFS data of the second line docetaxel combination trial were reported in a corporate symposium at the World Congress of Lung Cancer 2005, which showed a statistically significant prolongation of PFS once 100 mg qd ZD6474 was combined with docetaxel. Interestingly in the combination the safe dose of 300 mg qd was less effective

than the dose of 100 mg qd. These results led to the launch of a phase III trial in second line non-small cell lung cancer evaluating the same regimen. An additional randomized phase II trial comparing the efficacy of ZD6474 with Gefitinib in the treatment of second or third line non-small cell lung cancer is also in progress.48 In another still ongoing randomized phase II trial, the efficacy of ZD6474 is compared to placebo in patients with small cell lung cancer who responded to previous treatments.49

5.5. AG-013736

AG-013736 is an orally available compound with strong inhibitory activity against VEGFR-1 and -2 and PDGFR-β. Phase I trials established an oral dosing regimen of 5 mg bid to be safe.50 In a phase II trial in cytokine refractory metastatic RCC, AG-013736 showed an impressive 46% response rate and 40% disease stabilization rate. Side-effect profile was characterized by hypertension, fatigue, nausea, diarrhea, hoarseness, anorexia and weight loss.51 The kinase inhibitory activity of this drug appears to be relatively broad.

The drug is currently in phase II development in thyroid cancer, melanoma and NSCLC.

5.6. AEE788

AEE788 is an orally active inhibitor of multiple tyrosine kinases, including EGFR, HER2 and VEGFR-2. EGFR kinase inhibition occurs at 100-fold lower concentration than VEGFR kinase inhibition, explaining a side-effect profile that is characteristic for EGFR blockade.

The compound is currently in several phase I studies in GBM, NSCLC and other solid tumors to establish a safe dosing schedule. Dose limiting toxicity seems to occur at dosing levels of 500 to 550 mg qd. The side-effect profile is characterized by diarrhea, fatigue, asthenia, anorexia, rash, nausea, vomiting and liver enzyme elevation.52 Interestingly, AEE788 does not show many side effects attributable to VEGFR inhibition paralleling the observations with ZD6474.