Drugs fail all the time in clinical trials, and usually are never heard from again. But Genentech is bringing back an old antibody drug that flunked its first clinical test years ago, having now found a new setting where it might be useful against breast cancer.
The antibody drug, pertuzumab, was added to a standard combination of another antibody, trastuzumab (Herceptin), and chemotherapy in a trial of 417 women newly diagnosed with breast cancer. Researchers saw that 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. Results are being presented today at the San Antonio Breast Cancer Symposium.
This new finding represents a comeback of sorts for pertuzumab, which appeared to hit a dead end back in May 2005. Scientists at South San Francisco-based Genentech led by Mark Sliwkowski had spent years trying to develop this new antibody to build on the pioneering work the company did with Herceptin. The original drug specifically zeroes in on a target known as HER2 that is abundant on the surface of breast cancer cells in about one-fourth of patients with a gene mutation. By creating a different antibody that binds to a different place on the HER2 molecule, Genentech hoped to achieve a more comprehensive blockade of members of the HER family, which are thought to help tumors proliferate and grow. But the pertuzumab program stalled when the company said the drug showed “limited activity” on its own in mid-stage clinical studies against ovarian, breast, and prostate tumors.
While the idea of pertuzumab as a single agent sputtered, Genentech is betting that it has found a niche for this second antibody in combination with the original trastuzumab. Based on the findings of this mid-stage study, called Neosphere, the company plans to start a pivotal clinical trial next year of this antibody combo regimen in women with early-stage breast cancer who have HER2 gene mutations. That’s in addition to a separate study, called Cleopatra, of the antibody combo regimen among women whose breast cancer has spread through the body.
“The findings of the Neosphere study suggested that this new approach was effective for early HER2-positive breast cancer,” said Luca Gianni, a researcher at the National Cancer Institute in Milan, Italy, and the study’s principal investigator, in a Genentech statement.
There are some noteworthy side effects that need to be considered in the presentation coming out today in San Antonio. About 45 percent of patients 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 importantly, 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.
The case for pertuzumab has been building for some time, and I gathered some of the company’s thinking about this during a recent chat with Mark “Kip” Benyunes, a senior group medical director of clinical hematology/oncology at Genentech.
Part of what put new wind in pertuzumab’s sails was a study known as 929 described back in March in the Journal of Clinical Oncology. That study looked at 66 women with the HER2 gene mutation whose disease had worsened after getting a round of the usual trastuzumab. This time, they were given another round of trastuzumab in a couple different dose cohorts, plus the pertuzumab antibody. Researchers saw in this tough patient population that 24 percent of patients had their tumors shrink by at least half or more, and exactly half (50 percent) of patients saw some clinical benefit. The combination of the two antibodies was well-tolerated, researchers said.
“That was the first medical evidence that the combination of Herceptin and pertuzumab is something special and different,” Benyunes says.
The women in the most recent study, Neosphere, were studied in the same way, as researchers looked for evidence of tumor shrinkage as an indication that the drug is providing some benefit. But because these women have had their cancer caught at an early stage, and have a relatively good prognosis by cancer standards, the study wasn’t designed to follow them for years and years to see if it offered a chance to live a longer, higher quality life. Tumor shrinkage, measured after 12 weeks, is what is known as a “surrogate endpoint” that is thought to correlate with the gold standard of cancer research—overall survival time—but it doesn’t always correlate.
“We think it correlates with better long term outcome,” Benyunes says.
Researchers will surely want to keep a close eye in further studies about whether combining the two antibodies adds extra side effects, and negates whatever extra benefit might be achieved. I also wonder whether, if pertuzumab passes all its further trials, and wins FDA approval as an expensive new antibody, insurers might balk at essentially paying for another costly new biologic medicine. That’s not really a question for a physician working on the clinical trial plan, but it’s certainly something all biotech developers need to consider. How much extra benefit does a second antibody need to provide patients in order to justify its considerable added cost?
Evidently, Genentech sees enough potential benefit with the extra antibody to justify the time, expense, and risk of putting it into the third and final stage of clinical trials. And for an antibody that looked like a failure five years ago, it’s a surprising turn of events.
“A lot of people had written off pertuzumab,” Benyunes says. “It’s been in development a long time. We’ve looked in lots of different tumors without really highly encouraging clinical benefit.” Based now on what Genentech is seeing, the company’s vision is to keep testing various combinations of its antibodies to find just the right mix. “The best you can do is wait and see on the data,” Benyunes says.
