Washington Editor

While the FDA's approval of Tykerb (lapatinib) earlier this week won't mean much to sales of Herceptin (trastuzumab) in the short term, there eventually could be changes on the horizon, but that's many years away.

"It's unclear how to compare these two agents," said Jason Kantor, an analyst with RBC Capital Markets in San Francisco, "and I don't think anybody is going to swap out Herceptin at this point until they have a better handle on the efficacy."

That's because the newest targeted cancer therapy, developed by GlaxoSmithKline plc, is indicated as a second-line treatment for metastatic breast cancer. Specifically, the FDA gave the tyrosine kinase blocker the green light to treat HER2-positive breast cancer patients whose tumors have advanced despite prior therapy with three other drugs: an anthracycline, a taxane and Herceptin. That translates to about 28,000 patients annually in the U.S. with relapsed, HER2-positive, metastatic breast cancer.

"There is some use in that setting," Kantor told BioWorld Today, noting that "it's not necessarily a small group of people."

In addition, the London pharmaceutical firm has filed marketing applications around the world, including the European Union, Switzerland, Canada, Brazil, Australia and South Korea. About 25 percent to 30 percent of breast cancer patients have tumors that overexpress the HER2 protein, a potent oncogene that drives tumor growth, according to the American Cancer Society.

But "there's not a lot of data yet on Tykerb," Kantor said, "in any relevant setting."

On the other hand, Herceptin, one of Genentech Inc.'s flagship antibodies, has been more widely studied and used. Specifically indicated for adjuvant treatment as well as single-agent and combination therapy in patients with metastatic disease, the weekly injectable drug has been used to treat 300,000 women in nearly nine years since reaching the market, and last year generated more than $1.2 billion in sales.

Those numbers shouldn't suffer because of Tykerb, at least not yet. Many analysts generally feel that most of Herceptin's growth is in the adjuvant and first-line settings - the majority of its prescriptions are outside the refractory setting - and understandably aren't yet ready to forecast substantial Tykerb use in earlier-stage breast cancer right now. Off-label use in adjuvant treatment isn't particularly common.

But therein lies the opportunity for Tykerb to eventually make inroads into Herceptin's turf, and GSK is positioning its oral small molecule to do just that.

A large Phase III study called the TEACH trial, enrolling 3,000 patients, is under way to secure a label for adjuvant use down the road, recruiting those with positive and negative node involvement. It will be conducted in more than 30 countries, and additional trials are aimed at broadening into first-line settings.

An adjuvant label is most lucrative, Kantor said, because of the number of patients that receive such treatment and the lengthy duration they get it. But finishing that study could take years; Herceptin just received FDA approval for adjuvant use last fall. (See BioWorld Today, Nov. 20, 2006.)

So the principal concern for South San Francisco-based Genentech, of course, arises if Tykerb's efficacy eventually proves equivalent to Herceptin. The former's convenience factor "has advantages in the adjuvant setting," Kantor said. "But it's a big if' to say that it's going to be a better drug in breast cancer."

The data simply aren't yet known for any setting, he added. Kantor also noted that antibodies "tend to be more potent" than small molecules when binding to the same target.

Herceptin works against the target in three ways to continuously suppress HER2 activity that may lead to tumor proliferation, leading to cell stasis and death. One mechanism relates to its binding site on HER2's extracellular domain, near the transmembrane region, where the drug blocks the shedding of HER2 and prevents the receptor from breaking off into patients' serum. In addition, it impacts HER2's role in activating the AKT/PI3 kinase pathway, downregulating the intracellular cell survival mechanism, and the drug engages FC gamma receptors that are found on white blood cells to activate antibodies such as monocytes, macrophages and natural killer cells.

"Herceptin binding to extracellular domain can manifest itself on effects within the cytoplasmic domain as well," Mark Sliwkowski, Genentech's director of translational oncology, told BioWorld Today.

On the other hand, Tykerb binds to the inside of HER2 and inhibits the tyrosine kinase components of the EGFR (ErbB1) and HER2 (ErbB2) receptors, dampening their effects on cell proliferation, tumor progression, invasion and metastases. Kantor questioned the relevance of blocking EGFR in breast cancer, adding that such inhibition isn't necessarily that strong with Tykerb.

But Sarah Alspach, GSK's manager of product communications, said the drug's intracellular action is advantageous. "In the case of loss or shedding of the external domain of the receptor," she told BioWorld Today, "Herceptin could lose the ability to bind whereas the internal domain is still available to be blocked by Tykerb."

GSK plans to launch Tykerb within two weeks, and it will cost about $2,900 per month, on average. The company is offering a service to help patients figure out insurance reimbursement and alternative financial support, as well as a patient access program with a lower threshold for eligibility than exists for other GSK cancer drugs.

The company also has expansion plans for Tykerb in other solid tumor types, with clinical testing under way in head and neck cancer, as well as renal cell carcinoma.