ASCO: AstraZeneca's Baselga on tailoring treatments and the march to cure cancer

AstraZeneca posted promising data for its AKT inhibitor capivasertib paired with the hormonal therapy Faslodex in patients with ER-positive breast cancer. The combo staved off cancer for 10 months—double the time Faslodex plus placebo logged—and helped patients live a median of six months longer. 

The phase 2 data, presented Tuesday at the annual meeting of the American Society for Clinical Oncology, show that “blocking AKT—a critical pathway that regulates estrogen receptor (ER) function—along with anti-estrogen therapy is resulting in improved outcomes in these patients,” José Baselga, AstraZeneca’s oncology R&D chief, told FierceBiotech. 

The company will turn to a phase 3 study to answer questions, like, “Is this going to be better than CDK4/6 inhibitors with estrogen therapy?”

“The answer is, we don’t know,” Baselga said. “But what we do know is this is an option that makes a lot of sense. It’s exciting because now we have a non-chemotherapy, a targeted therapy with incredibly strong science that has shown activity in patients.” 

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AKT is a node in the PI3K/AKT/mTOR signaling pathway, which is known to promote cancer cell growth and resistance to chemotherapy. And because it’s downstream of PI3K, it could be a safer target for drugs aiming at this pathway. 

“I think one thing that defines AKT inhibitors as opposed to PI3K inhibitors is that they have a much better safety profile … the reason is that PI3K is more upstream; it’s a far more central node than AKT, so cells don’t like PI3K to be messed with. It’s a critical node in multiple cell pathways, as opposed to AKT,” Baselga said. 

That said, no matter which pathways a drug targets, Baselga is “convinced” we need better ways to figure out which patients would benefit most from, say, an AKT inhibitor, or a CDK4/6 drug. 

"When you begin to have so many tailored therapies, then the role of tailor becomes important,” he said. “Then, we will need to be able to choose how to treat every patient, and I think the notion of first-line, second-line, third-line therapies—this is an option that's not going to be here down the line.” 

Baselga doesn’t think in lines of therapy; rather, he focuses on which patients will benefit from which treatments, an approach he calls “preferred line.” 

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Like people, tumors change over time: “The tumor today is a different tumor than the tumor it was a year ago before you exposed it to a therapy,” Baselga said. So we should stop thinking about lines of therapy being fixed, because biology isn’t fixed. 

“That’s, of course, easier said than done, but at least we need to talk about it. And we have the technology to do it.” 

At AstraZeneca, Baselga is spearheading a push to look earlier in the cancer care sequence. 

Baselga said the “safe way”—and here, he literally used air quotes—to develop a cancer drug is to look at late stages of therapy. And that’s fine, he said. But if R&D teams come forward with a program aiming for approval in the third-line setting and no plan for early-stage approval, he’s deprioritizing that drug in favor of others that have an early-stage approval plan ready to go. 

“Because I want to cure patients."

That’s not to say there aren’t hurdles. 

"The challenge is that this is terra incognita, people have not done that. We need to find endpoints that will give us an indication early on that this thing is really going to help patients in early disease,” he said. “We need to make sure that these drugs are safe so you are not inducing potential toxicities in patients that otherwise can be potentially cured.  And we will need to work with regulatory agencies so that they accept and understand what we are trying to achieve. 

“When you talk to people, they will give you a list of hurdles. I understand hurdles, but we have to do what’s right. If we don’t commit to this, we are not pushing the envelope.”