GlaxoSmithKline may soon be selling a pharmacogenomic competitor to Herceptin.
"The results that we've reported have been in studies that have been specific to women with breast cancer [whose] cancer cells are overexpressing [Her2]," a GlaxoSmithKline spokesperson told Pharmacogenomics Reporter this week. "It's like Herceptin in that way."
Glaxo halted enrollment for a phase 3 trial involving its breast-cancer drug Tykerb when the study reached its primary endpoint — time to disease progression — early in women who had failed Herceptin therapy.
It is still unclear what sort of diagnostic platform might work best in guiding the prescription of Tykerb, which is known by the generic name lapatinib. The drug acts on Herceptin's target, Her2, as well as Iressa's target, the epidermal growth factor receptor, and diagnostics supporting those drugs are slowly shifting toward FISH from immunohistochemistry.
Besides helping patients who failed with Herceptin, Tykerb has other advantages over that drug: since it targets EGFR, as well as Her2, it stands to compete with cancer drugs beyond Herceptin, potentially giving it a larger share of the market. In addition, Tykerb is taken orally, while Herceptin is administered intravenously. Herceptin is made by Roche and Genentech.
"The results that we've reported have been in studies that have been specific to women with breast cancer [whose] cancer cells are overexpressing [Her2]."
The recent trial studied the use of Tykerb in combination with Roche's Xeloda, known generically as capecitabine, versus Xeloda alone in women with "refractory advanced or metastatic breast cancer who have documented [Her2] overexpression and whose disease progressed following treatment with [Herceptin], as well as other cancer therapies," according to clinical trial information from the US National Institutes of Health. The trial's independent data-monitoring committee recommended that GSK stop enrollment after its planned interim analysis of 321 patients showed a 50-percent increase in time to progression in Tykerb and Xeloda arm, versus the Xeloda-only arm.
The company plans to file the drug for regulatory approval separately through the US Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products on the basis of this study, as well as "other data," Paolo Paoletti, senior vice president of GSK's Oncology Medicine Development Center, said this week in a statement.
But the recent trial's requirements did not specify how Her2 should be measured to qualify patients for enrollment, only that they should have "Documented ErbB2 [another name for Her2] overexpression" of the gene. While immunohistochemistry was the original method for determining Her2 and EGFR overexpression, it has slowly fallen out of favor as fluorescent in situ hybridization methods began to appear more reliable, especially in EGFR detection. This could mean that Glaxo could opt to use FISH for the time being while studying pharmacogenomics-based response triggers.
Although IHC is probably the most dominant test preceding Herceptin treatment, "the FISH test by Abbott is now widely regarded to be even more sensitive and specific for assessing true Her2 status than any immunohistochemical assay," Andrew Seidman, associate attending physician for the Breast Cancer Medicine Service at Memorial Sloan Kettering Cancer Center, told Pharmacogenomics Reporter last January.
Of the 28 clinical trials involving Tykerb listed by the NIH, three are phase 3 studies calling for Her2 overexpression testing or inclusion of patients in the study based on overexpression. However, only a trial testing patient response to Tykerb and paclitaxel (Taxol, marketed by Bristol-Myers Squibb) versus placebo and paclitaxel, and organized by GSK, calls for Her2 testing by FISH specifically. The majority of phase 1 and 2 trials also do not specify a method when calling for EGFR or Her2 testing.
Interestingly, a phase 2 trial organized by the Dartmouth-Hitchcock Medical Center proposes to use either FISH or IHC to identify only patients who lack Her2 overexpression.
GSK did rely on a metabolism test to identify patient populations not likely to experience adverse reactions to Tykerb, Allan Roses, senior vice president of genetics research at GlaxoSmithKline, said last week at the Bio-IT World Life Sciences Conference and Expo in Boston, according to Pharmacogenomics Reporter sister publication GenomeWeb News.
Roses explained that in a previous study with the cancer drug, around 15 percent of 107 patients experienced diarrhea and skin rash, which GSK was able to attribute to particular CYP2C19 alleles. Furthermore, three out of four patients who withdrew from the trial because they experienced more-severe adverse events were found to be homozygous for the CYP2C19 allele.
GSK now knows that it should lower the dosage of the drug for those patients with the mutation, a factorthat can influence the drug's performance in the clinic and in upcoming clinical trials — similar to the choice of diagnostics for identifying responder populations. GSK officials were unable to provide additional information on the Tykerb's pharmacogenomic possibilities before press time.
Herceptin is currently indicated only for metastatic — or stage IV — breast cancer, either in combination with paclitaxel or as a stand-alone treatment for women who have had chemotherapy. In February, Genentech submitted a Biologics License Application to the FDA to allow the drug to be prescribed as an adjuvant therapy for early-stage Her2-positive breast cancer. Roche submitted a similar application to the EMEA.
In the NIH list of 28 clinical trials involving Tykerb, the drug is under study mostly for Herceptin's indication — metastatic breast cancer. However, among the three phase 3 trials, the GSK study involving paclitaxel and Tykerb in patients testing Her2 positive by FISH is enrolling patients with newly diagnosed breast cancer. Other indications being studied include glioblastomas, male and recurrent breast cancer, recurrent and late-stage prostate cancer, biliary tract cancer, head and neck cancer, adenocarcinomas, and ovarian epithelial or peritoneal cancer.
Herceptin is sold by Genentech in the United States, and by Roche in the rest of the world. US sales of Herceptin increased 123 percent to $290 million, from $130 million in the first quarter of 2005, according to documents Genentech filed this week with the US Securities and Exchange Commission. Sequential quarter-over-quarter Herceptin sales increased 16 percent from fourth quarter 2005 sales of $250 million, the company said.
The drug is under investigation in several clinical trials, but very few involve an indication other than breast cancer. These include: ovarian cancer; adult soft tissue sarcoma; salivary gland cancer; and endometrial cancer.
In its annual report for 2005, Roche reported worldwide Herceptin sales of CHF 2.15 billion ($1.64 million), up from CHF 1.44 billion in 2004. Sales in 2005 were driven by longer average treatment duration and increased first-line penetration, said Roche.
— Chris Womack ([email protected])