Inhibitors of VEGF Signaling
Researchers at AstraZeneca (www.astrazeneca.com) discussed some of the challenges in the clinical development of small molecule inhibitors of VEGF signaling. “We spoke specifically of two compounds we have in the clinic, ZD-6474 (Zactima) and AZD-2171 (Recentin™),” said Charles Morris, vp, clinical development projects, oncology. “As early as Phase I, we saw clinical response in non-small cell lung cancer for ZD6474. We went into this open-minded, but this early clinical signal guided the further development direction of this compound, which is also being investigated in other tumor types.”
Phase II trials were randomized studies for both monotherapy and combination therapy. The design and evidence yielded enough to send ZD6474 to Phase III studies looking at monotherapy, and in combination with cytotoxic chemotherapy. “We had interesting results,” Morris said. “Historically, EGFR-TKIs had demonstrated activity in monotherapy, but not combination therapy. However, with the lung cancer patients, there seemed to be signs that the combination therapy was also working, suggesting that the targeting of two pathways—EGFR and VEGFR—was producing a differentiated profile for the drug. In addition, the RET-kinase inhibitory activity of the drug has led to initial investigation in medullary thyroid carcinoma where preliminary data has shown calcitonin reductions and radiographic responses. Phase II work is also ongoing in other tumor types including breast, glioma, and prostate cancers.”
The preclinical data for Recentin showed relatively selective inhibition of VEGF receptors 1, 2, and 3. “Demonstration of biological activity is a challenge, but extensive use of biomarkers early in the development process has allowed us to define a biologically active dose range despite the relatively low numbers of radiographic responses seen with this class of agents. The biomarker data gave us the confidence to make go/no go decisions, and this agent is now under investigation in a broad range of settings,” Morris said.
“We still don’t know whether it’s more important to have a specifically targeted compound than something that hits multiple targets,” Morris added. “When you have something that hits multiple targets, you may be more likely to see efficacy through inhibition of multiple pathways, but there may equally be an increased likelihood of off-target toxicity.”