NEW YORK – Researchers in France are evaluating whether Amgen's KRAS inhibitor Lumakras (sotorasib) could be a potential treatment for patients with arteriovenous vascular malformations (AVM), a rare overgrowth disorder that causes blood vessels to form incorrectly and are driven by a KRAS G12C mutation.
In a study published in the New England Journal of Medicine in July, researchers described their efforts to explore whether Lumakras could be a treatment for vascular malformations in mouse models and in two patients.
Arteriovenous vascular malformations can be caused by either inherited or somatic genetic mutations, with most being driven by mutations in MAPK or PI3K pathway genes, like KRAS or PI3KCA. The prevalence of KRAS-driven vascular malformations is unknown, but several small studies have found a high rate of KRAS mutations in AVM. This condition leads to a high flow of arterial blood through blood vessels and can cause masses to grow that affect other tissues and bodily functions and lead to pain, increased bleeding, and skin conditions.
The discovery of the genetic drivers of AVM is relatively recent, said Guillaume Canaud, senior author of the NEJM paper and chief of the overgrowth syndromes and vascular anomalies unit at Necker-Enfants Malades Hospital in Paris.
He noted that KRAS G12C mutations, like those discussed in the NEJM report, only represent a minority of KRAS-driven AVM cases, as most patients are carrying other KRAS variants like G13, G12D, and G12V.
Sarah Sheppard, an investigator in the unit on vascular malformations at the National Institute of Child Health and Human Development, who was not involved with the NEJM study, said genetic testing for this rare disease is "essential" to guide treatment in this setting. "Knowledge of the pathogenic variant will allow for targeting of the dysregulated signaling pathway," she said. "Many of the same pathways dysregulated in AVMs are also dysregulated in cancer, providing an opportunity to repurpose [US Food and Drug Administration]-approved medicines in this rare disease."
She added that patients with complex AVMs often do not have the option of surgery or embolization to treat their condition, two common treatment approaches in this setting. So, a precision medicine treatment "targeting the underlying genetic cause is a promising approach," she said.
Canaud said this latest research stemmed from a patient who was referred to his team in 2020, who had severe arteriovenous malformation on his face. Canaud and his team biopsied the malformation and found a KRAS G12C mutation in the tissue.
Based on this observation, Canaud's team developed mouse models with KRAS G12C-driven vascular malformations to test the potential efficacy of Lumakras to treat this condition. They found that mice receiving Lumakras lived longer than those receiving a control agent. Based on this preclinical insight, Canaud's team asked French regulatory agencies for permission to prescribe Lumakras to two patients, including that initial patient from 2020.
The first patient previously underwent 11 endovascular procedures to address the malformation on his face, but the painful lesion kept growing and causing recurring headaches and hemorrhages. The patient had persistent cellulitis for which he was receiving opioids and antibiotics. The patient had previously enrolled in a clinical trial for another targeted therapy, Pfizer's mTOR inhibitor sirolimus, for the treatment of arteriovenous malformations. However, the treatment was ineffective, and the patient's condition continued to deteriorate after leaving the sirolimus study.
Within four weeks of starting Lumakras at the 960 mg dose, however, this patient's symptoms improved. He had less pain, the bleeding stopped, he wasn't as tired, and the malformation on his face started shrinking. After three months on Lumakras, the patient was able to discontinue opioid and antibiotic treatment.
Cell-free DNA (cfDNA) analysis before and after this patient received Lumakras showed that six months after receiving the drug, the KRAS G12C mutant allelic fraction in cfDNA was undetectable. Prior to treatment, the KRAS G12C mutant allelic fraction in cfDNA was estimated at 1 percent in his sample. The researchers reported that this patient experienced no adverse events from Lumakras.
Researchers gave Lumakras to a second patient with a vascular malformation on her face that affected her mouth and ear. She had previously undergone 20 endovascular and surgical procedures, but the lesion continued growing, causing pain, deafness in her right ear, dysphagia, and slurred speech. Her symptoms also quickly improved with a 960 mg dose of Lumakras. She started to hear again in her right ear, the pain disappeared, and the facial malformation started to also go away.
Imaging before treatment and after six months of Lumakras showed a 19.8 percent reduction in the vascular infiltration in the mastoid cells surrounding her vestibulocochlear system, a system of cranial nerves responsible for balance, eye movements, and hearing. However, when this patient developed grade I diarrhea, researchers reduced the Lumakras dose to 720 mg per day after two months and have maintained that for the rest of her treatment. They also evaluated cfDNA for this second patient but found that the KRAS G12C mutation was undetectable in baseline cfDNA.
Canaud noted that the first patient in the study has been on Lumakras for about three years and the second patient for about one year, and neither patient has seen disease progression or developed resistance to Lumakras. While cancer patients on KRAS inhibitors commonly develop resistance, Canaud noted this is less likely in patients with KRAS-driven vascular malformations.
"We are seeing patients who have a single mutation; we don't have multiple mutations [in AVM] like in oncology," which provides less opportunity for affected cells to escape by exploiting other molecular pathways, he said. "It seems that these patients do not have this DNA instability that you find in cancer. The [affected cells] are not able to escape the KRAS inhibition."
In Sheppard's view, the results from this case series and the use of cfDNA to monitor treatment response are "exciting advancements" in the field. "It also provides evidence for the use of allele-specific inhibitors in the treatment of vascular anomalies," she added. "Further systematic studies will help evaluate the efficacy of allele specific inhibitors in comparison to MEK inhibition or anti-angiogenics, like thalidomide."
Her lab is exploring the utility of KRAS inhibitors alone and in combination with MEK inhibitors in complex lymphatic anomalies using the zebrafish model. Their goal is to translate this preclinical work into clinical studies.
Lumakras is not the first oncology drug to be tested in an overgrowth syndrome like AVM. Previously, Canaud and his team tested Novartis' PI3K inhibitor alpelisib in patients with PIK3CA-related lymphatic vascular malformations, which cause lymphatic vessels to form incorrectly and lead to similar issues with the growth of masses and the flow of lymphatic fluid. The FDA originally approved alpelisib under the brand name Piqray for treating hormone receptor (HR)-positive, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer. But in 2022, the agency approved the same agent for treating PIK3CA-related overgrowth spectrum with the brand name Vijoice based on research conducted by Canaud's team.
Similar to their AVM study, Canaud's team first identified the PIK3CA mutation in some patients with lymphatic vascular malformations and tested Vijoice in mouse models with the same mutation before treating patients. They then conducted retrospective analysis of real-world data from 57 patients treated with Vijoice for PIK3CA-related overgrowth spectrum through a compassionate-use program. They found that 37.5 percent of patients experienced a greater than 20 percent reduction in target lesion volume and that all patients experienced some reduction in lesion volume.
Canaud hopes pharma companies will continue investing in KRAS inhibitors and begin testing them in this setting.
Amgen declined to comment on whether it would pursue studies of Lumakras in KRAS G12C-driven vascular malformations.
As the field continues evolving, Canaud encouraged physicians to continue performing genetic testing to identify precision medicine approaches for these patients. "If you find that kind of mutation in patients, then you can explain the reason for their malformations, … if they are at risk of [passing on] the condition to their children, and [about] new opportunities for targeted therapies," he said.