Jason Gotlib, MD, leader of the Stanford Cancer Institute Hematology Clinical Research Group, led a study that paved the way for FDA approval of avapritinib, a first-of-its-kind treatment for a rare blood cancer called indolent systemic mastocytosis (ISM). The study was published in May 2023 in The New England Journal of Medicine Evidence. At the time of publishing, there were no FDA-approved treatments for ISM.
ISM is a subtype of systemic mastocytosis (SM), which occurs when mast cells, a type of white blood cell, accumulate in the body. ISM makes up the majority of SM cases, with patients often experiencing lifelong debilitating skin, gastrointestinal, cognitive, musculoskeletal, and systemic symptoms, such as anaphylaxis. These symptoms negatively impact patients’ daily functioning, ability to work, and quality of life.
Until avapritinib’s approval, ISM treatments were not targeted specifically for the disease. Instead, anti-inflammatory medications that block mast cell activation were used to reduce symptoms.
Gotlib says, “For most patients, the medications that have been available to treat them aren’t highly or consistently effective and may produce unpleasant gastrointestinal and cognitive side effects. Increasing doses and different types of medications may be required over time, resulting in polypharmacy [simultaneous use of multiple medications for treatment] in some individuals, where disease versus drug side effects become difficult to distinguish.”
A therapeutic breakthrough for systemic mastocytosis
KIT D816V, a mutated protein on the surface of mast cells that causes them to grow and multiply uncontrollably, is the primary driver of ISM and is found in approximately 95% of patients. Avapritinib selectively targets KIT D816V and disrupts the signaling pathways that drive the growth and accumulation of abnormal mast cells.
Avapritinib was FDA approved in June 2021 for advanced systemic mastocytosis, a more serious form of SM that causes organ damage and is associated with decreased survival. Two multi-center clinical trials proved the treatment safe and successful, with patients demonstrating that biomarkers of mast cell burden were markedly reduced, and SM-related organ damage improved in a large proportion of patients.
The PIONEER study and FDA approval
Gotlib led a study named PIONEER to investigate the safety and efficacy of avapritinib for treating ISM. Part 1 of the study evaluated the medication’s safety and effective treatment dose, which was determined to be 25 mg daily.
Part 2 tested the medication against a placebo over a 24-week period. The study enrolled 212 patients with ISM with moderate to severe symptom scores across several centers and randomized them to the treatment or placebo group. Patients in the treatment group received 25 mg of avapritinib once a day and traditional ISM symptom management medications, while the control group received symptom management medications and a placebo. The trial was double-blind, meaning neither the patients nor the investigators knew which treatment the patients received.
Investigators looked at the change in severity of patients’ ISM symptoms, measured as a total symptom score (TSS), quality-of-life measures, and biomarkers of mast cell disease burden, including bone marrow mast cell burden, protein levels in blood, and KIT D816V mutation burden. The study found that the avapritinib group had significantly improved TSS and ISM biomarkers, highlighting avapritinib’s ability to reduce the load of abnormal mast cells in the body, which had not been feasible with conventional supportive care options.
Gotlib says, “In the aggregate, the results really were striking. However, when seeing the changes in individual patients, one gets a more real-world sense of how the medication can impact the unique circumstances of an individual and provide them with an opportunity to get through each day with fewer symptoms and pain and the associated psychological toll that accompanies mast cell disease.”
The medication was well-tolerated and had a favorable safety profile. Most adverse reactions were mild in severity, with the most common being dizziness, flushing, swelling around the eye, and tissue swelling in the hands, legs, and feet. Serious adverse reactions and the need to stop treatment due to adverse reactions occurred in less than 1% of patients.
Due to its efficacy and safety, the medication received FDA approval to treat ISM patients in June 2023, a month after Gotlib and his colleagues published their findings.
Part 3 of the trial is currently ongoing and will evaluate the safety and efficacy of avapritinib 25 mg once daily for up to five years. All patients, including those who received the placebo during part 2, receive avapritinib during part 3 of the study.
To have a new therapy that can effectively manage a broad range of symptoms gives patients with ISM a renewed sense of hope."
Gotlib says, “Having treated patients with this disease for many years, I’ve seen how debilitating the symptoms can be and how frustrated patients and their physicians have become with the historical therapeutic armamentarium. To have a new therapy that can effectively manage a broad range of symptoms gives patients with ISM a renewed sense of hope.”