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GSK Conducting PGx Trials for Newly Approved Tykerb; Monogram eTag Assays May Play Role

GlaxoSmithKline is hoping that pharmacogenomic studies of its newly approved targeted breast cancer drug Tykerb will help identify patients with other solid tumors likely to respond to the drug.
Separately, Monogram’s eTag dimerization assays may play a role in helping to identify these cohorts. Tykerb inhibits the tyrosine kinase components of the EGFR (ErbB1) and HER2 (ErbB2) receptors. Over-expression of these receptors is believed to reduce overall survival in cancer patients.
Monogram, which does not have a formal agreement with GSK, has said it will soon release data showing how the eTag test can gauge how patients with breast, colorectal, or lung cancer respond to drugs targeting the EGFR HER pathway.

GSK is using IHC or FISH to look at HER2-positive breast cancer and is using IHC to investigate EGFR and HER2 over-expression in other solid tumors.

The drug maker said that "no novel diagnostic is being developed for Tykerb," though added it “is exploring novel approaches to narrowing the patient population for the drug."

Following Tykerb’s approval last week by the US Food and Drug Administration, a GSK spokesperson told Pharmacogenomics Reporter that the drug is currently being studied in several ongoing pharmacogenomic studies.

Tykerb is indicated for use in combination with Roche’s Xeloda to treat patients with advanced or metastatic breast cancer whose tumors over-express HER2 and who have received prior therapy including an anthracycline and Herceptin.
In a study presented at the American Society of Clinical Oncology’s annual  meeting last year in Atlanta, 57 patients with relapsed or refractory inflammatory breast cancer were divided into two groups – ErbB2 over-expressors and non-over-expressors. Both groups received daily Tykerb treatment. The study results showed that 62 percent of the over-expressors had a clinical response to Tykerb.
Based on these results, the company is studying Tykerb in the adjuvant breast cancer population and in other solid tumor cancer settings “to better identify patient populations that may respond to” the drug.
The company did not reveal the details of the PGx studies being conducted for Tykerb.
However, Tykerb, generically known as lapatinib, has been shown in vitro to inhibit CYP3A4 and CYP2C8, and in its approval letter for the drug, the FDA noted that GSK had agreed to study in the post-market setting how Tykerb performs as a CYP2C8 inhibitor and impacts the pharmacokinetics of Bristol-Myers Squibb’s Taxol or GSK’s antidiabetic Avandia.
“Based on the ability of lapatinib to act as a CYP 2C8 inhibitor in vitro, GSK agrees to perform an in vivo drug interaction study of the ability of steady-state lapatinib dosing to alter the pharmacokinetics of a single does of [Taxol] or [Avandia],” the FDA said in its letter. “A positive finding in this study may initiate a need for further studies.”
The study is slated for completion in June.
Monogram Eyes Cancer Dx Market
According to Monogram, its eTag dimerization assays may help physicians home in on patients with a variety of solid tumors likely to respond to Tykerb.
In an interview with Pharmacogenomics Reporter this week, Chris Petropoulos, Monogram’s chief scientific officer, said that the company is using its eTag dimerization assay to help identify patients likely to respond to drugs like Tykerb that target the HER family of receptors.
Monogram, having made a name for itself through its Rx/Dx co-development program for Pifzer’s HIV tropism drug maraviroc, is expanding aggressively into oncology.
“I spend 75 percent of my time in oncology, because the need over there is even greater,” Petropoulos said. “There are some very promising drugs but they only work on a very small fraction of the patient population, so we’re trying to figure out why and [whether we] can identify those patients better than the tools they have now.”
Monogram has said it will soon release data showing how its eTag test can gauge cancer patients’ responses to drugs targeting the EGFR HER pathway in breast, colorectal and lung cancer [see PGx Reporter 12-06-06].
“We’re focused on breast cancer right now. We picked the low-hanging fruit to get into cancer since we’re brand new” in this space, Petropoulos said. “We’re looking at drugs like Tykerb and Herceptin, and focusing mostly on the EGFR HER pathway. We think if we develop those types of assays for breast cancer, that it’s a bridge to … [other] major solid tumor markets.”

“We’re looking at drugs like Tykerb and Herceptin, and focusing mostly on the EGFR HER pathway. We think if we develop those types of assays for breast cancer that it’s a bridge to … [other] major solid tumor markets.”

According to Petropoulos, the positive and negative predictive value of existing assays to identify patients for Herceptin “is just horrible.” Of the patients who test HER2 positive and are candidates to receive Herceptin, only 30 percent respond to the drug, he said. “So there has got to be more information and we’ve got to be able to do a little better than that.”
Tykerb Data
Tykerb is expected to become available in the US before March 27. GSK said it plans to market the drug in many countries outside the US, including nations in the EU, Switzerland, Canada, Brazil, Australia, and South Korea.
“Tykerb is a significant breakthrough for women with advanced HER2 positive breast cancer. The data clearly show that this small-molecule, oral, targeted agent, in combination with capecitabine, is effective for women whose disease has progressed on previous therapies, including anthracyclines, taxanes and trastuzumab,” said Paolo Paoletti, senior vice president of GSK’s Oncology Medicine Development Center.
The drug’s label recommends doctors to evaluate all patients’ left ventricular ejection fraction prior to and during Tykerb treatment. “As with other therapies for HER2 over-expression, Tykerb has been associated with reports of decreases in LVEF. Caution should be taken if Tykerb is to be administered to patients with preexisting cardiac conditions, including uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure,” the company said.
Additionally, Tykerb extends QT prolongation and physicians should be cautious when prescribing the drug to patients with severely impaired liver function “due to increased systemic exposure to the drug.”

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