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PGx at ASCO to Include Glaxo s Tykerb, Genentech and OSI s Herceptin, Tarceva

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The American Society of Clinical Oncology annual meeting, beginning this week in Atlanta, offers about as many sessions related to pharmacogenomics and targeted therapies as the 2005 meeting, with the exception of the developmental therapeutics track, which has approximately doubled the number of sessions in these areas to a total of six.

GlaxoSmithKline and Genentech, along with partner OSI Pharmaceuticals, figure heavily in this year's proceedings. Several discussions will be devoted to the potential of Glaxo's multi-kinase inhibitor Tykerb to behave as a diagnostic-guided breast cancer therapy, or as a competitor to existing therapies like Herceptin.

Of course, Genentech and OSI's breast cancer drug Herceptin and Tarceva, indicated for non-small cell lung cancer and pancreatic cancer, will also feature at this year's meeting, along with new introductions from those shops. But overall, there will be much familiar territory in this year's ASCO, as researchers continue to sort out prognostic gene profiles and drug-response associations.

In the "Therapies for Renal Cell Cancer" session on June 3, GlaxoSmithKline's Tykerb will make an appearance in a presentation by Alain Ravaud of the Institut Claudius Regaud in Toulouse, France. The discussion will present phase III trial data showing efficacy linked to high tumor EGFR expression.

As a multi-kinase inhibitor active against both EGFR and Her2, Tykerb shows promise as an up-and-coming pharmacogenomic therapy. In April, Glaxo halted enrollment for a phase 3 trial involving Tykerb when the study reached its primary endpoint — time to disease progression — early in women who had failed Herceptin therapy.


Tykerb is also featured in a June 3 scientific special session in which four researchers will discuss the drug's possible replacement of Genentech's Herceptin in some patients.

Tykerb is also featured in a June 3 scientific special session — "Lapatinib in Trastuzumab-Resistant Breast Cancer" — in which four researchers will discuss whether the drug can be used instead of Herceptin in some patients.

Two more talks that day, both during the session "Her2-Directed Therapy for Breast Cancer" will discuss the results of two phase II trials: a study of Tykerb in patients with relapsed or refractory inflammatory breast cancer; and a study of Tykerb in patients with brain metastases and Her2-positive breast cancer. The talks will be delivered by Neil Spector, director of exploratory medical sciences-oncology at Glaxo, and Nancy Lin, a researcher at the Dana Farber Cancer Institute in Boston, respectively.

"Biomarker Prediction of Clinical Response," a June 5 session, features discussions about molecular markers associated with two compounds following phase II trials: Genentech's Omnitarg, which is the first of a class of drugs called Her dimerization inhibitors, and Wyeth's temsirolimus, a drug whose phase III trial in metastatic breast cancer the company stopped in March due to low efficacy. Lukas Amler of Genentech and Amit Oza of Princess Margaret Hospital in Toronto, Canada, will present these studies, respectively.

The June 5 session entitled "Are [EGFR] Biomarkers Getting Us Closer to or Further from the Target?" will feature discussions in two separate talks of different biomarkers of response to Tarceva — EGFR expression, copy number, and mutation, as well as K-ras mutation status — led by Vincent Miller of the Memorial Sloan-Kettering Cancer Center in New York and Ming-Sound Tsao of Princess Margaret Hospital.

A third talk in this session, by Benjamin Solomon, a researcher at St. Vincent's Hospital in Melbourne, Australia, is surprisingly the only one to discuss research on the pharmacogenomics of AstraZeneca's lung-cancer drug Iressa. His talk will outline the use of MALDI-TOF mass spectrometers for predicting clinical outcome in non-small cell lung cancer patients treated with the drug.

Within the developmental therapeutics track, the most obvious session for personalized medicine is "Pharmacogenomics: Targeting the Tumor and the Patient," a session occurring on June 4. Focusing on breast cancer, Lajos Pusztai, a researcher at the University of Texas MD Anderson Cancer Center in Houston, will discuss biomarkers predictive of response to 5-fluorouracil, doxorubicin, and cyclophosphamide. Later during that session, Stacey Knox of the Duke Comprehensive Cancer Center will present a study on the ability of CYP450 2D6 status to predict breast cancer relapse in women receiving tamoxifen.

Because of cancer's extremely redundant protein pathways, it is widely recognized that combinations of targeted therapies might prove more effective than single targeted agents. At the June 5 session "Combining Targeted Therapies," Glenn Preston of the Brooke Army Medical Center will present data on the combination of EGFR inhibitors and VEGFR inhibitors in a phase I study of the treatment of solid tumors. Later in that same session, Jose Baselga will report on the combination of two anti-EGFR drugs — cetuximab and gefitinib — in patients with advanced colorectal cancer, head and neck cancer, and non-small cell lung cancer.

Drugs targeting epigenetic changes in tumors seem to be gaining ground in oncology — while last year's ASCO meeting did not address epigenetics, there are two sessions devoted to the subject this time around — and these non-genetic, chemical modifications to DNA may prove to be factors that can first be detected using molecular diagnostics. The June 3 session "Epigenetic Targeting as a Novel Anticancer Intervention" features discussions about three histone deacetylase inhibitors, including Merck's Vorinostat. That drug is the furthest along of the three, having finished a phase IIb trial in advanced cutaneous T-cell lymphoma.

Tumor Biology Track

As it did last year, the Tumor Biology track has some pharmacogenomics offerings in both drugs and diagnostics.

On June 4, during the Evolving Use of Molecular Diagnostics in the Classification of Breast Cancers, Jodi Grabinski will discuss tamoxifen metabolism in adjuvant breast cancer treatment and the effect of CYP450 2D6 and ER-alpha polymorphisms.

Kit Lau will present research Celera Diagnostics has been conducting to rival Genomic Health's Oncotype Dx with its own gene-expression profile for predicting distant metastases in node-negative, estrogen-receptor positive breast cancer. Christos Sotiriou, head of the Functional Genomics & Translational Research Unit of the Jules Bordet Institut in Brussels, Belgium, will contend in his discussion that the proliferation captured by gene expression grade index is a stronger prognostic indicator than clinical and pathological factors.

— Chris Womack ([email protected])

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