The advent of new targeted oncology therapies may benefit more than just cancer patients.
Two patients with severe arteriovenous malformations — an ultra-rare condition where a group of blood vessels forms incorrectly — saw their symptoms improve substantially after taking Lumakras, a pill developed by Amgen for cancers driven by a mutation in the cell growth regulator KRAS.
The same KRAS mutation was found in both patients with blood vessel tangles in their faces, and they received Lumakras under compassionate use in France. They no longer need frequent procedures in the hospital and one of the patients regained her hearing that she lost years earlier from the condition.
Guillaume Canaud“We need to provide to patients that have some vascular malformation — and particularly arteriovenous malformations — genetic tests. Because if you’re able to find a specific mutation, you can do some drug repositioning as we did,” said physician-scientist Guillaume Canaud of the Necker Enfants Malades Hospital in Paris, who led the study published Wednesday in the New England Journal of Medicine.
Canaud noted that while the drug is no cure for the blood vessel condition, it can improve symptoms and reduce the volume of the malformation.
He hopes Amgen continues to provide the drug for patients with arteriovenous malformations, or AVMs, though he added a clinical trial may not be feasible because it’s an ultra-rare condition, where it’s often not profitable for a company to study its drug.
Amgen declined to comment for this story.
Repurposing targeted cancer drugs
Canaud noted that the concept of conducting genetic tests for these blood vessel anomalies is relatively new — KRAS mutations were first reported in AVMs in the brain in 2018.
Mutations in KRAS have long been known to drive cancer, though, for a long time, they were exceedingly difficult to develop treatments for. In recent years, the first two drugs, Lumakras and Bristol Myers Squibb’s Krazati, have been approved to treat certain lung cancers with a specific KRAS mutation called G12C. Krazati in June also won accelerated approval in colorectal cancer.
In 2015, Canaud and his team began working with patients who had abnormal blood vessel and lymphatic system overgrowth tied to another mutation in PIK3CA. Like KRAS, that mutation is also known to promote cancer.
Under compassionate use, Canaud’s team dosed 19 patients with a Novartis drug called alpelisib, which was at the time in development for certain advanced breast cancers with that mutation and was later approved in 2019 by the FDA to be marketed as Piqray.
Then in 2022, the agency approved alpelisib as Vijoice for severe PIK3CA-related overgrowth spectrum, based on compassionate use data from Canaud and others who had given the drug to patients with the condition. Novartis’ two branded drugs are priced differently though, with Vijoice listed at about $10,000 more than Piqray for a 28-day supply.
Meanwhile, Canaud’s lab was studying KRAS in mouse models and found that in KRAS-mutated mice, administering Lumakras reduced blood vessel abnormalities. Mutant mice dosed with Lumakras also lived longer than those who were not.
The first patient in the new study had “severe and growing” AVM on the right side of his face since birth, for which he had received 11 surgeries that had led him to become blind in his right eye. He was receiving opioids for pain from the growth and faced frequent bleeding, but had no other options left and was suggested palliative care.
Then, after he started Lumakras, he stopped taking opioids and antibiotics in just three months. His pain, bleeding and fatigue improved. At two years, the volume of the growth on the right side of his face decreased by nearly a third, and his appearance looked noticeably different.
“This patient was in the ICU permanently,” Canaud said. “And right now he has not been hospitalized since two and a half years [ago], which is amazing for him.”
‘A little miracle’
The second patient, Claire, who asked Endpoints News to not use her full name to keep her identity confidential, said that she was diagnosed when she was nine and had 20 procedures for her AVM located by her right jaw in the ensuing decade. After which, the growth “became quiet for years,” she said.
But, about two decades later, it started acting up again. She was in pain and lost her hearing, so she wore a hearing aid. She was introduced to Canaud, who told her that he had a treatment for her mutation. She has now been taking Lumakras for the past year.
“The AVM was invading my internal ear and was completely stuck the whole time,” she said. “It came back suddenly after one month, like, ‘wow!’ So that was a little miracle for me.”
“It’s really a game changer,” she said, adding that Canaud told her “it’s gonna work progressively, but slowly and surely — so that is actually what’s happening.”
After one month, she did have to go down to a lower dose — seven pills of Lumakras instead of the typical eight — due to diarrhea, but she noted she experienced few other side effects.
Currently, there are no approved drugs for the condition, and it is typically treated with surgery.
“This is very encouraging for people who have my condition, who have been to surgery, who have no hope for treatment,” Claire said. “If I had it when I was nine, my life would have been totally different.”
The mutation that Lumakras addresses, G12C, is one of the less common KRAS mutations that Canaud sees in AVM patients. He noted that KRAS G12D and G13 mutations were more common.
“Unfortunately, we are able to treat only a minority of patients,” Canaud said. “But of course, we have other things in mind and the other things in hand for other patients.”