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Genentech Follows Fast at ASCO as Cancer Immunotherapy Picks Up

Xconomy San Francisco — 

Genentech made its name in cancer by creating targeted antibody drugs that zero in on tumor cells while mostly sparing healthy tissue. Now it’s seeking to compete in the next wave of cancer immunotherapies, which are designed to spark the immune system to attack tumors like a virus.

South San Francisco-based Genentech, a unit of Roche, is releasing results from an early-stage clinical trial today of an experimental antibody designed to hit a target called PD-L1. By aiming for this molecular target, the Genentech antibody is supposed to stop a cloaking mechanism that tumors use to disguise themselves from the immune system. This way, the body’s immune T cells recognize tumors as foreign invaders that should be destroyed like viruses or bacteria.

The drug, code-named MPDL3280A, showed that it was able to shrink tumors by at least half for 29 out of the first 140 patients (21 percent) in a study of cancer patients whose disease had worsened after prior therapies. The Genentech drug appeared to work for many different malignancies, including lung cancer, melanoma, and kidney, colorectal, and gastric cancers. The responses appeared to be long-lasting, although more long-term follow-up will be needed before researchers can say how long the drug might be working.

Like other drugs in this class, the Genentech antibody unleashed the power of the immune system, which can sometimes go too far, damaging healthy tissues. About 39 percent of patients had moderate to severe side effects, including toxicity to the liver, skin, and gut. The results are also still preliminary, so researchers can’t say whether the drug helped patients live longer. A summary of the study has been posted online today by the American Society of Clinical Oncology, as a preview before more detailed results are discussed at ASCO’s annual convention in Chicago.

Still, the results are encouraging enough that Genentech has decided to leap ahead into the final phase of clinical trials with this drug, putting it in the hunt with a number of other major drugmakers. Bristol-Myers Squibb, Merck, and GlaxoSmithKline are all racing to develop what you could call second-generation immunotherapies. Seattle-based Dendreon won FDA approval in 2010 for the first immunotherapy, sipuleucel-T (Provenge), that was shown to extend lives with a minimum of side effects for men with prostate cancer. Bristol-Myers followed that up a year later with another product, ipilimumab (Yervoy), that fights melanoma by releasing a brake on the immune system.

The newer wave of immunotherapies, to be presented this year at ASCO, are homing in on a target called PD-1, in one way or another. Bristol-Myers generated lots of buzz last year with its experimental drug in this category, which appeared to shrink tumors for multiple kinds of cancer. The Genentech antibody is designed to lift the same tumor-cloaking mechanism, but in a different way, because it binds to the PD-L1 ligand instead of directly to the PD-1 protein itself. Genentech hopes that specific form of targeting will make it a safer product, said Chris Bowden, a Genentech vice president of product development for oncology.

Roy Herbst

“We are impressed with the frequency and duration of the responses in these patients with very difficult-to-treat tumors. So far, almost none of the patients that have had tumor shrinkage have progressed,” said Roy Herbst, the Ensign professor of medicine at Yale Cancer Center and an investigator on the study, in a statement. “This drug is part of an exciting new generation of drugs that unlock the power of the immune system to attack the cancer.”

Mitch Gold, the former chief executive of Dendreon and a board member of the nonprofit Cancer Research Institute in New York, said the data from Genentech’s drug looks encouraging for multiple tumor types. Payers will also want to see if Genentech can increase the response rate in future trials, whether it can select patients most likely to benefit, and whether the drug can extend survival time, to ensure they are getting good value for the money, Gold said.

“If you look at Provenge and first-generation immunotherapies being like a proof of concept, it’s sort of like what Netscape was for the Internet,” Gold said. “We’ve shown immunotherapy is a valuable tool in the fight against cancer. The next-generation compounds are going to look even better. They’ll be like Apple and Google against cancer.”

It’s still far too early to proclaim Genentech is making that kind of advance, based on the data released today. But here’s what is known so far:

—The Genentech antibody appeared to work quickly for some patients, but not all who responded. Some patients had a “delayed response” in which their tumors first appeared to spread, and then shrink later, as if it took a while for the immunotherapy boost to kick in. Researchers don’t know why some patients responded quickly and others had the delay.

—Patients whose tumors shrank appeared to have long-lasting remissions. Scientists said 26 of the 29 who responded saw their tumors remain in check for long periods of time, between three and 15 months of follow-up. As time goes on, researchers will gather more complete statistics on how long-lasting the responses really are.

—Side effects of the treatment weren’t trivial, and they were consistent with what researchers have seen with Bristol-Myers’ ipilimumab. About 39 percent of patients had moderate to severe side effects, including toxicities to the liver (hepatitis), the skin (rash), and the gut (colitis).

—Genentech, through working internally with Roche diagnostic colleagues, is seeking to develop a companion diagnostic that can help doctors sort out which patients are most likely to respond to the immunotherapy. In this study, Genentech asked whether patients were overexpressing the PD-L1 target on their tumors, and whether that made them more likely to respond. The answer wasn’t clear-cut. Researchers saw that 13 of 33 patients deemed to be PD-L1 overexpressers (39 percent) responded to the anti-PD-L1 antibody, while 8 of 61 patients (13 percent) who were classified as having PD-L1 “negative” tumors ended up responding to the drug. More research is being done to develop the diagnostic test and study the way the drug is working, Bowden says.

Like with all immunotherapies, there was quite a bit of variability in responses, which researchers still don’t understand well. The patients were heavily pre-treated, and many had weakened immune systems, which didn’t appear to stop them from responding to the immunotherapy, Bowden said.

Based on the data Genentech has gathered thus far, the company has decided to forge ahead into the third and final phase of clinical trials required for FDA approval—the kind of studies which take the most time and money, and which generate the most thorough datasets. Genentech is going ahead to that phase in lung cancer and kidney cancer, Bowden said. A mid-stage study is currently enrolling 100 patients with non-small cell lung cancer on the new immunotherapy, according to a posting on clinicaltrials.gov.

This year at ASCO, Bowden said he’ll be watching several other companies make presentations about their various immunotherapies in the works. The progress of this new mode of therapy is likely to be one of the big stories to watch at the big convention this year.

“The story continues to build,” Bowden said. “We’re going to start seeing more data, and people are going to start talking about combinations and how you can move the needle even further. If you talk to oncologists in general, immunotherapy is now in their oncologist’s lexicon. They understand it. The science is moving forward.”

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