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ACT Biotech Investigating Predictive Biomarkers for VEGF Inhibitor Telatinib in Gastric Cancer

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By Turna Ray

After a Phase II study of the investigational antiangiogenic drug telatinib showed that gastric cancer patients with large decreases in VEGFR2 serum levels lived longer when treated with the drug than those with smaller decreases in biomarker levels, sponsor ACT Biotech is looking into whether it can use this marker to pick out best responders to the drug.

At a recent conference in San Francisco hosted by the American Association for Cancer Research, the National Cancer Institute, and the European Organization for Research and Treatment of Cancer, researchers led by Lori Kunkel, ACT Biotech's chief medical officer, found that gastric cancer patients treated with a combination regimen containing telatinib, capecitabine, and cisplatin who had a 33 percent or greater reduction in serum soluble VEGFR2 levels had median progression-free survival duration of nearly a year and have not reached their overall survival duration. Comparatively, patients with a VEGFR2 reduction of less than 33 percent experienced median progression-free survival of 4.7 months and median overall survival of 7.6 months.

In 28 gastric cancer patients treated with the telatinib/capecitabine/cisplatin regimen, "larger percentage decreases in the concentration of [soluble] VEGFR2 from baseline were associated with lower risk of progression and death compared to patients with smaller decreases or no decrease from baseline," Kunkel et al. concluded in an abstract presented at the AACR/NCI/EORTC meeting.

ACT, whose name stands for "accelerate cancer therapeutics," plans to incorporate its findings on the effect of serum VEGFR2 levels on telatinib treatment outcomes, as well as other markers, in randomized controlled trials in gastric cancer and other tumor types. Telatinib is an inhibitor of VEGFR 1, 2, 3, and PDGF receptors.

"In our study, we saw a marked decrease in sVEGFR2 in response to telatinib treatment and hence, sVEGFR2 may be a quantitative biomarker that will allow us to identify patients that achieve the best response to telatinib," Kunkel said in a statement.

"We intend to integrate this biomarker in upcoming trials of telatinib." Kunkel told PGx Reporter, noting that the identification of a predictive biomarker strategy for telatinib is "a high priority" for the firm.

She explained that the company previously had a tough time pinning down predictive biomarkers for the drug. "We did look at several markers; however none have been predictive at baseline, and to date no marker has been validated (with any anti-angiogenic agent) that will predict response," Kunkel said in an e-mail.

Other developers of anti-angiogenic drugs have also experienced difficulties identifying response markers for anti-VEGF therapies. For example, although Genentech claims to have evaluated more than 100 markers that could be potentially associated with patient response to its VEGF inhibitor Avastin, the search hasn't yielded any easy biomarker leads.

So far, varying levels of VEGF-A protein in the plasma of breast cancer patients treated with Avastin may be Genentech's most promising lead in terms of a predictive biomarker strategy. Studies have shown that breast cancer patients with elevated VEGF-A plasma levels have a better response to Avastin than those with low levels of the protein (PGx Reporter 6/29/2011).

However, data presented at a recent European conference painted a complex picture of this marker. Data from multiple studies presented in September at the European Multidisciplinary Cancer Congress showed that the predictive effect of VEGF-A may be limited to certain tumor types, such as gastric cancer and pancreatic cancer.

In their AACR/NCI/EORTC abstract, Kunkel et al. acknowledged the difficulties of gauging predictive markers for anti-angiogenic drugs. "Serum VEGF-A concentrations and association with metastasic disease/and or poor outcome has been well documented in gastric cancer patients," the researchers wrote in the abstract. "However, VEGF-A has not been a useful predictor for outcome of treatment with VEGF pathway inhibitors."

However, the improved outcomes observed in patients who experienced greater decreases in VEGFR2 levels with the telatinib-based regimen may offer some clues toward a predictive biomarker strategy. According to Kunkel, the company is hoping to identify a predictive marker by isolating molecular features unique to the VEGFR2 pathway and by comparing the effects of related molecular pathways in "high responders" of telatinib versus those who responded less robustly to the drug.

The US Food and Drug Administration in 2010 granted telatinib orphan drug status for stomach cancer and the drug is currently in Phase II studies for gastric cancer. ACT Biotech is also investigating the drug in colorectal cancer, for which the agent is in Phase I trials.


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