Genentech was at the center of controversy over the past year in the breast cancer world because of an argument about one of its top-selling antibody drugs. But now the biotech giant is hoping that a new antibody in the pipeline will get people talking again about clear-cut medical progress.
The South San Francisco-based unit of Roche is getting ready in the next week to unveil pivotal clinical trial results for pertuzumab at one of the big annual meetings in breast cancer therapy—the San Antonio Breast Cancer Symposium.
The feature presentation on pertuzumab, from a study of 808 patients, will show how much longer the new drug can keep the disease from worsening in patients getting their first round of treatment for breast cancer that has spread, and that overexpresses the HER2 protein. Genentech has long dominated the field of HER2 amplified breast cancer, with its blockbuster antibody trastuzumab (Herceptin). But by combining pertuzumab with the old standby, and also by pushing forward with a souped-up version of the original, the bet is that Genentech can fend off competitors like GlaxoSmithKline’s lapatinib (Tykerb) for the long haul and raise the bar again in patient care.
If these drugs can go on to win FDA approval, it could also help mute some of the controversy over use of bevacizumab (Avastin) in breast cancer patients who don’t overexpress the HER2 protein. Genentech had fought to retain FDA clearance of the drug for that condition, but FDA revoked the approval last month after it said new clinical evidence showed the benefits no longer outweigh the risks.
Genentech is probably still smarting from this loss, estimated at $873 million in revenue, but to use a football analogy here, you could say the best defense is a good offense with pertuzumab.
“This is going to be a really exciting San Antonio meeting for us and for pertuzumab in particular,” says Sandra Horning, Genentech’s senior vice president, and global head of clinical development for hematology/oncology. “Pertuzumab is going to represent a major advance in treating HER2 positive breast cancer.”
Anticipation for pertuzumab has been building for a while. The drug is designed to bind to a different place on the HER2 molecule than trastuzumab, which Genentech scientists have long theorized might create a more complete blockade of that tumor-signaling pathway. Evidence emerged last year to support this idea, at the same San Antonio conference. At that conference, researchers reported on a study of 417 patients, called Neosphere, in which tumors completely disappeared in 45.8 percent of women who got both antibodies along with chemo prior to surgery, compared with 29 percent who did that well on just the standard trastuzumab and chemo alone. There wasn’t a significant difference in side effects between the two treatment groups.
Still, as with any cancer drug, there were significant side effects to report. About 45 percent of patients in the Neosphere study experienced a moderate to severe depletion of their infection-fighting white blood cells (neutropenia), while 8.4 percent had a fever associated with low white blood cell counts (febrile neutropenia). Another 5.6 percent of patients reported moderate to severe diarrhea. But researchers said they didn’t see a significant increase in cardiac side effects. That’s important because heart risks are known to be associated in rare cases with use of Herceptin.
This year in San Antonio, researchers will get their first look at how the two-antibody combo strategy performs in the third and final phase of clinical trials usually required for FDA approval.
Results of the 808-patient study, known as Cleopatra, are expected on Friday, Dec. 9 at 10:30 am Central. The study is designed to ask whether a combination of pertuzumab, trastuzumab, and docetaxel chemotherapy is better at keeping tumors from spreading when compared to the standard combination of trastuzumab and docetaxel. Genentech has already said that this study met its main goal, but what everyone wants to know is how much better the combo regimen really is.
What won’t be available in San Antonio is complete data on whether the new pertuzumab regimen helps patients live longer. The data on that question are still immature, and probably won’t be ready until 2013, Horning says. It will take time to follow up all the patients to see how long they live, she says.
The other significant study to watch for at the San Antonio conference will be for the souped-up version of trastuzumab known as T-DM1. That drug, which I profiled in depth in June 2010, is designed to combine the specific HER2 targeting capability of the original antibody with an attached toxin that gives it more tumor-killing kick.
Data from a mid-stage study known as TDM4450g was presented at a European meeting back in September. The drug has already shown an ability to keep tumors from spreading for a median of 14.2 months, compared with 9.2 months for standard trastuzumab and docetaxel. And T-DM1 has shown an ability to get the greater effectiveness while also reducing side effects.
The new data in San Antonio will be focused on whether T-DM1 offers improvement in quality of life. That’s a notoriously subjective, you might say squishy, kind of thing to measure consistently in a clinical trial. Horning says Genentech is using well-validated metrics. The data will be based on patients’ own reports on how much energy they feel, how much time they spend in bed, and other questions that get at quality of life rather than just length of life. Regulatory bodies have traditionally looked askance at this kind of data, but Genentech says it has sought to measure quality of life because of feedback from all kinds of players in the breast cancer world.
“We’ve heard loud and clear from the patient community, the physician community, advisory communities, payers, there’s a lot of interest in quality of life,” Horning says.
Taken together, the pertzumab and T-DM1 data is mounting, Horning says. “We are on the verge of seeing another step forward in managing HER2 positive disease,” she says.
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