Sotorasib: The Promising Treatment for KRAS-Related Vascular Malformations

Sotorasib: The Promising Treatment for KRAS-Related Vascular Malformations

Treating KRAS G12C-Related Arteriovenous Malformations with Sotorasib

A small French study revealed that treating severe KRAS G12C-related arteriovenous malformations with sotorasib (Lumakras) was effective. The study showed that the KRAS inhibitor can significantly reduce symptoms and malformation size. This article will discuss the study in detail and its implications for treating vascular malformations.

What are Arteriovenous Malformations?

Arteriovenous malformations (AVMs) are abnormalities of the vascular system, in which arteries and veins are abnormally connected. This can cause a range of symptoms, from mild discomfort to severe bleeding and neurological deficits. AVMs are typically treated with surgery, radiation, or embolization. However, surgeons sometimes shy away from treating AVMs, due to the risks associated with the procedure.

The Study

Two adult patients suffering from KRAS G12C-related arteriovenous malformations were treated with sotorasib, in a groundbreaking study. Guillaume Canaud, MD, PhD, of the Hôpital Necker–Enfants Malades in Paris, and colleagues conducted the study. The researchers showed that sotorasib could reduce the volume of vascular malformations and improve survival in two mouse models carrying a KRAS G12C mutation.

They then administered the drug to the two human patients in whom lesion biopsy showed the mutation. Both patients received 960 mg of sotorasib (eight 120-mg pills) orally every morning during breakfast.

Patient 1 Case Study

The first patient was a 24-year-old man who had been affected by a growing arteriovenous malformation on the right side of his face since birth. He had undergone 11 endovascular procedures, resulting in blindness and maxillectomy on the affected side. These interventions failed to slow the growth of the arteriovenous malformation, and he required opioids for severe pain and antibiotics for recurrent cellulitis. He also experienced recurrent hemorrhages.

The patient enrolled in the MAV-RAPA clinical trial and received sirolimus, an mTOR inhibitor, for a duration of 6 months, but discontinued treatment due to lack of efficacy and adverse events. With his condition deteriorating in the absence of further treatment options, the man was offered sotorasib. Follow-up MRI showed a sustained reduction in the volume of the vascular malformation over the course of 24 months. The patient experienced no drug-related adverse events during the treatment period.

Patient 2 Case Study

The second patient was a 45-year-old woman with a vascular malformation involving the oral cavity — especially the tongue — with extension to the right eustachian tube, leading to chronic dysfunction and recurrent middle ear infections. Despite 20 endovascular and surgical procedures, she experienced progressive growth of the arteriovenous malformation, resulting in pain, deafness in the right ear, dysphagia, and slurred speech.

After starting sotorasib therapy, she experienced rapid clinical improvement, including deafness correction, the disappearance of pain, and reduced facial and jaw infiltration. While her sotorasib dose was reduced to 720 mg per day due to the development of grade 1 diarrhea, no other drug-related adverse events were reported. Imaging at 6 months showed a 19. 8% reduction of the vascular infiltration in the right mastoid cells surrounding her vestibulocochlear system.

Conclusion

Canaud and colleagues concluded that “targeting KRAS G12C appears to be a promising therapeutic approach for patients with KRAS G12C-related vascular malformations.” Sotorasib is a KRAS G12C inhibitor, which has been tested in clinical trials for lung cancer. This study shows the importance of genetic testing in vascular malformations to provide targeted therapy. These promising results need to be confirmed in further studies. The study opens up new perspectives for treating patients in whom surgery is not an option or has failed to manage an arteriovenous malformation.

Originally Post From https://www.medpagetoday.com/dermatology/generaldermatology/111154

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