Genentech has spent more than a decade developing a souped-up version of its multi-billion dollar breast cancer drug, and today it is delivering hard evidence on cancer R&D’s biggest stage that it works.
The South San Francisco-based biotech company, a unit of Roche, has shown that its experimental drug trastuzumab emtansine (T-DM1) hit its main goal in a study of 991 patients with breast cancer that overexpresses the HER2 protein, and who have previously been treated with the original trastuzumab (Herceptin) and a taxane chemotherapy. The new drug, which combines the targeting capability of the original trastuzumab with a toxin to give it more tumor-killing punch, was able to keep cancer from spreading a median time of about 3.2 months longer than a combination of two other drugs. The new Genentech drug—which uses a chemical linker from Waltham, MA-based ImmunoGen—caused tumors to shrink for more patients, kept them in remission longer, and caused fewer significant side effects than the combo treatment, according to research presented today at the American Society of Clinical Oncology meeting in Chicago.
What’s potentially more important is that the drug appears to be helping people live longer, although final statistics aren’t available yet to say that for sure. What researchers do know at this point is that 65.4 percent of the T-DM1 patients were still alive after two years of follow-up, compared with 47.5 percent of patients on the combo of GlaxoSmithKline’s lapatinib (Tykerb) and capecitabine (Xeloda) chemotherapy. Since only about 30 percent of the patients in the study had died as of the most recent data analysis, more follow up time will be required to see just how big of an advantage T-DM1 might provide in median survival time, and for statisticians to say with confidence that it isn’t a fluke. But even without that final survival data in hand, the findings are encouraging enough for Genentech to submit an application for FDA approval, and to start talking with confidence about how it’s ushering in a new era of cancer therapy with “empowered antibodies.”
“This is a really impressive data set,” says Dietmar Berger, Genentech’s vice president of clinical hematology/oncology. “All of it validates what we’ve seen before. The clear surprise was the extent of the 2-year survival difference, which I believe is outstanding.”
Genentech had previously sought FDA approval for T-DM1 on the basis of smaller studies, and was turned down, so that regulators would get a chance to review a data package that includes results from this study, known as Emilia. Here are some of the key details being reported today.
First, patients who enrolled in this study were randomly assigned to get an intravenous infusion of T-DM1 every three weeks, or a combination of GlaxoSmithKline’s pill and the chemo drug. Researchers found that T-DM1 was able to keep the cancer from spreading for a median time of 9.6 months, compared with 6.4 months for those on the combo regimen—a difference that was statistically significant. Like any drug, though, it comes with side effects. About 12.9 percent of patients on the new Genentech treatment had moderate to severe depletion of their clot-forming platelet blood cells (thrombocytopenia), compared with 0.2 percent in the control group. The new product also was linked to increases in liver enzymes in the blood, which can be a sign of liver damage, although there were no severe cases of patient’s reaching Hy’s Law, a sign of significant liver injury, Berger says.
While those effects are something for doctors and patients to watch for, many will be happy to hear that the new Genentech drug caused far fewer cases of diarrhea, hand/foot rashes, and vomiting than the other treatments. The overall rate of moderate to severe adverse events was 40.8 percent for the new Genentech drug, compared with 57 percent on the combo treatments.
These new results will be a critical part of Genentech and Roche’s regulatory application to start selling T-DM1 around the world. About 229,000 women in the U.S. are diagnosed with breast cancer each year, and the new drug, if approved, could be a potent new option for about one-fourth of patients whose tumors overexpress the HER2 protein.
The findings from the Emilia study show T-DM1’s advantages in a very sick group of those HER2-positive patients, but the company has its eye on expanding the drug into other populations with less advanced forms of disease as well. Last September, Genentech reported from a study called ‘4450, which showed T-DM1 outperformed the original trastuzumab in a head-to-head study among 137 patients getting their first round of therapy. Genentech is also conducting a pivotal study, called Marianne, which is asking whether a combo of T-DM1 and another new Genentech antibody called pertuzumab could be even more effective in HER2-positive breast cancer patients getting their first round of treatment.
Now with the original trastuzumab, pertuzumab, and T-DM1, Genentech is thinking a lot about how to best tackle HER2-positive breast cancer in its many stages, including the “adjuvant” setting where doctors seek to attack the cancer at an early stage and keep it from coming back.
“About 28,000 patients have been cured in the adjuvant by using Herceptin (trastuzumab),” Berger says. “We’re asking ourselves, ‘Can we further improve on that?”
Beyond the potential implications for this specific subset of breast cancer patients, Genentech’s scientists have been emboldened by their ability to solve the tough technical challenges with creating a new kind of therapy that works like a targeted “smart bomb” against cancer. While Pfizer’s gemtuzumab ozogamicin (Mylotarg) was the first of these antibody-drug conjugates approved by the FDA more than a decade ago, it was linked to significant side effects, was never widely used, and was recently taken off the market. Many researchers struggled to keep the targeted antibody stable and linked together with the toxin, so the toxin could be selectively unleashed on tumors, while largely sparing healthy tissues.
Last August, Seattle Genetics won FDA approval for another one of these antibody-drug conjugate drugs, which showed striking anti-tumor effectiveness for a couple of rare lymphomas. That success, combined with Genentech’s results with T-DM1, have inspired a wave of new companies to attempt to make new and different kinds of these more potent cancer drugs. Genentech alone has 25 of these antibody-drug conjugates at various stages of development, and nine are in clinical trials.
The data that’s being presented today is the kind of thing that has helped set Genentech’s priorities in its R&D pipeline, Berger says. The clinical results are spawning all kinds of new lines of scientific exploration. Suddenly, when good drug targets are identified on cancer cells, scientists will immediately think about making not just “naked antibodies” but also “empowered antibodies” against them. “This is important to us as a company as we believe in ADCs [antibody-drug conjugates] as a platform,” Berger says. “It’s a platform that we believe has the capacity in the mid and long-term to transform a lot of what we do.”
By posting a comment, you agree to our terms and conditions.