Breast cancer patients sometimes end up dying when their tumors spread all the way to the brain. Some very good drugs already exist for patients with breast cancer, especially ones with tumors that overexpress the HER2 marker, but that success has raised a new question: Can drugmakers take another step, and fight those deadly brain metastases that get people in the end?
Seattle-based Cascadian Therapeutics is testing that idea this week with researchers gathered at the San Antonio Breast Cancer Symposium. Cascadian is reporting today that patients who got conventional capecitabine and trastuzumab, plus an experimental small-molecule drug, tucatinib (aka ONT-380), lived a median of 7.8 months without their tumors getting worse. About 61% of patients on that triple-drug combo saw tumors shrink. It’s an impressive result, given that these patients were especially ill when they enrolled in the study, having already received a median of three prior rounds of HER2-targeted therapy. The data are also holding up over time: a snapshot of the data from June showed patients living a median of 6.3 months without their tumors spreading.
“The more mature dataset from the Phase 1b trial continues to show tucatinib may be combined with other current targeted therapies to achieve durable responses in patients who have received multiple prior lines of therapy,” said Erika Hamilton, director of breast and gynecology cancer research at Sarah Cannon Research Institute in Nashville, Tenn. “Tucatinib in combination appears to be well-tolerated, potentially making it a highly desirable HER2 therapy for a patient population that vitally needs new options.”
Still, these are early days. It’s way too early to declare the drug a winner. There was no control group in the study, so there’s no way to make a valid comparison between these patients and others on a different course of treatment. Only 27 patients enrolled–a small sample. There’s also no definitive test that experts can agree shows the drug is doing what’s it’s supposed to do, crossing the blood-brain barrier and shrinking those dangerous secondary brain tumors. That last point is crucial. Crossing the blood-brain barrier, and doing it safely to fight tumors, is the main reason to go forward with a small-molecule drug like tucatinib. Some of the successful HER2 targeted drugs today–Genentech’s trastuzumab, trastuzumab-DM1 and pertuzumab–are genetically engineered antibodies that can circulate widely through the body, but are too large to cross the blood-brain barrier and fight brain metastases.
Partly because Cascadian’s drug is a conventional small-molecule with a chance to fill that void, it is being given a chance to essentially shoot the moon at the FDA. The company has gotten the go-ahead from the FDA to expand an ongoing 180-patient trial to a full 480 patients. That study will have a control group, will enroll patients with and without existing brain metastases, and will measure how long patients on the new drug are able to live without their disease getting worse. If enrollment goes as planned, the company should have results by the end of 2019 or early 2020 that can serve as the basis for a new FDA-approved medicine that could be combined with existing capecitabine chemotherapy and another HER2-targeted drug such as trastuzumab, said CEO Scott Myers. Expanding the trial this way, as opposed to running two trials back to back, probably shaves at least a year off the company’s development timelines.
The clear regulatory path is something new for Cascadian. The company licensed the drug candidate two years ago from Boulder, Colo.-based Array Biopharma, and many investors wondered if this drug was a pipe dream. The FDA would probably want at least two well-controlled clinical trials, they said. Competition in the HER2-targeted breast cancer category is ferocious, with Genentech/Roche and Novartis in the game, and Puma Biotechnology knocking on the door, further along in development in than Cascadian. The clinical trials would probably take too much time and money for a little company like Cascadian to pull off, investors said. Convinced it needed to find a way forward with tucatinib, Cascadian brought in Myers, a former UCB and Johnson & Johnson executive, as CEO in March. He heard all the doubts, and took it on as motivation.
“I love it when people say we can’t do things. It makes us work even harder,” Myers said.
Side effects of the drug were mostly mild, researchers are reporting in San Antonio. There were three reports of Grade 3 (moderate-to-severe) diarrhea out of 27 patients (11%). That’s considerably fewer cases of diarrhea than has been reported from patients on Puma Biotechnology’s neratinib, a competing small-molecule HER2 inhibitor. Puma has reported that the diarrhea can be mitigated when patients take loperamide (Imodium). Cascadian has countered that its drug doesn’t require an anti-diarrheal co-medication. But there were other side effects–one patient reported a cerebral edema that required a dose reduction, and three of 27 (11%) were reported to have moderate-to-severe elevated liver enzymes. The elevated liver enzymes, which can be a sign of liver damage, were brought back down when researchers reduced the dose of the Cascadian drug, researchers said.
Shares in Cascadian are down 54% year-to-date, worse than the biotech industry average, but the stock gained 11% in trading yesterday afternoon, just before today's update on its regulatory path and updated Phase Ib clinical trial results.
