Genentech Says Experimental Cancer Combo is Safe
Apr05

Genentech Says Experimental Cancer Combo is Safe

Genentech this week unveiled promising results from a Phase I study suggesting it is possible to safely combine two cancer drug candidates, its MEK inhibitor GDC0973 and its PI3K inhibitor GDC0941. In addition to a relatively clean safety profile, there were also early signs that the combination is combating cancer. Genentech is one of several companies running a trial to test the safety of combining inhibitors of the lipid kinase PI3K, part of the PI3K/AKT/mTor pathway, and drugs blocking the protein kinase MEK, part of the KRas/MAP signalling pathway. As we discuss in our upcoming April 11th cover story on PI3K inhibitors, the rationale for knocking down both pathways  is compelling: both are considered to be crucial in cancer cells’ survival, and blocking only one pathway has more often than not proven ineffective. As Robert Abraham, CSO of Pfizer’s oncology research unit, explains in Monday’s story: “KRas mutations are associated with many of the deadliest cancers,” including colorectal and pancreatic, Pfizer’s Abraham says. Yet they are incredibly resistant to conventional chemotherapy, and based on preclinical studies of the mutations, are expected to be resistant to the new batch of mTor/PI3K inhibitors as well, he adds. The working hypothesis is that knocking out two of the major drivers of cancer—the KRas and PI3K pathways—could have a significant effect on the most recalcitrant tumors. To date, there are at least six Phase I trials planned or ongoing that combine MEK inhibitors with compounds that block some aspect of the mTor/PI3K pathway. Merck and AstraZeneca made headlines in 2009 when they said they would partner to test Merck’s AKT inhibitor with AstraZeneca’s MEK inhibitor. Sanofi-Aventis has meanwhile teamed with Merck Serono to explore the potential of combining two of its PI3K inhibitors in combination with Merck Serono’s MEK inhibitor. GlaxoSmithKline has two of its own drugs in a combination trial, and its MEK inhibitor GSK1120212 is also being tested in combination with Novartis’ PI3K inhibitor BKM120. And while Pfizer has yet to initiate such a study, Abraham said the company is “keeping two eyes on that combination.” We go into much more detail in Monday’s cover story about the efforts to match PI3K inhibitors with other drugs, and the rationale behind different flavors of compounds (mTor/PI3K inhibitors vs. pan-PI3K inhibitors vs. single-isoform inhibitors). Stay...

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Provenge: Lessons Learned
May03

Provenge: Lessons Learned

Last week’s FDA approval of Provenge, the therapeutic prostate cancer vaccine, was a win for Dendreon, but also is a boon for companies involved in developing cancer immunotherapies. This morning at BIO, I spoke to Jens Oliver Funk, senior vice president, Merck Serono R&D, and global head of oncology for the company, about what it might mean for other immunotherapeutics in the pipeline. “This is great news and will change the field,” Funk said. “Until last Thursday, people said therapeutic vaccines could work. Now, they can say the therapeutic principle has been validated.” For its part, Merck Serono  is trying to push Stimuvax, a cancer vaccine that has hit a few road blocks during mid-stage trials, to the finish line. However, Funk cautioned that despite Dendreon’s success, there is still a long way to go towards making immunotherapies that are effective and viable in large patient populations. Provenge “is still a very laborsome, highly individualized therapy,” he noted. Now, companies need to build on the groundwork laid by Dendreon and evolve the science to make vaccines that are more effective and easier to make. Funk cited several key lessons learned from Provenge’s long road to FDA approval. First, it has become clear that clinical trials for therapeutic cancer vaccines need to be structured differently than studies for traditional drugs, like chemotherapies. “Historically, late-stage tumor patients were included in such studies, and we now know we need patients earlier on, when they have little tumor mass.” Second, in order to optimize an immunotherapy’s activity, companies need to pick patient populations carefully. You need to create “an environment in patients’ bodies for fostering T-cells,” Funk explained. Chemotherapy depletes the very T-cells that immunotherapies are trying to stimulate, meaning patients that have just undergone an intensive round of chemo aren’t primed to respond to the vaccines. Last, companies and regulatory authorities will need to reconsider the endpoints in clinical trials. Traditional cancer drug trials look at how quickly and by how much a tumor is shrinking, but its possible that a therapeutic vaccine can extend patients’ lives without ever actually reducing tumor mass. For anyone at BIO, run over to room S403b, where a panel discussion on cancer immunotherapies moderated by Funk is going on...

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