Bezuclastinib in non-advanced systemic mastocytosis: Insights from the Phase 2 Summit trial

Q. What is the clinical burden of non-advanced systemic mastocytosis for patients?

The clinical burden of NonAdvSM is encompassed by 4 different symptom domains, including fatigue, skin, neurocognitive, and a fourth umbrella domain, which includes gastrointestinal and pain symptoms. The main patient reported outcome measure of the Summit trial is known as the Mastocytosis Symptom Severity Daily Diary (MS2D2) total symptom score. This score essentially captures 11 potential symptoms within these four domains that patients may have on a day-to-day basis.

There are several other disease manifestations to think about, for example approximately half of patients with NonAdvSM will have fixed skin lesions on sun shielded areas of their body that can be sparse or dense, and depending on the person and on the density, can negatively affect a person’s quality of life. In addition to chronic symptoms and skin lesions that you can see with the naked eye, there are also challenges with bone health, including reduced bone mineral density that can lead to fractures, which we think affects somewhere between 25–50% of patients. Also, around half of patients with NonAdvSM may experience severe anaphylaxis once or more in their lifetime. Anaphylaxis in patients with SM is usually more severe than patients who do not have SM. Finally, there is also the chance of progression to a more advanced form of SM.

Q. What is the mechanism of action of bezuclastinib, and what was the rationale for investigating it in this indication?

NonAdvSM is caused by a driver mutation in the gene called KIT, which causes an amino acid substitution at codon 816, resulting in the mutated protein known as KIT D816V. Bezuclastinib is a highly selective tyrosine kinase inhibitor that specifically targets the mutated KIT D816V protein that is found in NonAdvSM, and it does not inhibit closely related proteins, which some of the other KIT inhibitors do. For instance, avapritinib can inhibit related proteins called PDGFR-alpha and -beta.

The rationale for investigating bezuclastinib in this indication was ultimately the potential to use higher and more effective doses of a KIT D816V inhibitor and still maintain safety and tolerability; essentially maximizing efficacy and maximizing safety. Bezuclastinib provides a very precise way of targeting the mutated KIT D816V protein that is the underlying cause of the neoplasm in nearly every patient with SM.

Q. Could you describe the aims, design and enrollment criteria of the Phase 2 Summit trial?

The pivotal portion of the Summit trial was a double-blind, placebo-controlled trial over 6 four-week cycles and, after that, participants went into an open-label extension. In terms of enrollment criteria, the patients had to have a centrally adjudicated diagnosis of an NonAdvSM subtype, which could include bone marrow mastocytosis, indolent systemic mastocytosis, or smoldering systemic mastocytosis. The central review of SM diagnoses has been a really important part of the study.

In terms of the aims and what the intent was, the study was designed in a way very similar to the Pioneer study, which investigated avapritinib. The primary endpoint was related to comparing the change in the total symptom score between those treated with bezuclastinib and those treated with placebo, and seeing if there was a difference over 24 weeks. Regarding symptom-related secondary endpoints, there were 2 related to the total symptom score: ≥30% improvement in total symptom score and then a higher threshold of ≥50% improvement in total symptom score.

Then, there were 3 additional key secondary endpoint assessed at week 24 including: (1) a ≥50% reduction in bone marrow neoplastic mast cell burden; (2) a ≥50% reduction in serum tryptase; and (3) a ≥50% reduction in KIT p.D816V variant allele frequency.

Q. How well were the primary and secondary endpoints met in the study?

The primary and all secondary endpoints were met in this trial. Notably, patients reported improvement in each individual symptom across all four domains which demonstrates that symptom improvement is not limited to one symptom or one symptom domain. Moreover, at the end of the pivotal portion of the trial (cycle 7, day 1) when the main assessments were made, 55% of patients in the bezuclastinib group no longer met diagnostic criteria for the neoplasm, compared to less than 5% in the placebo group. From my personal experience, this is a huge achievement. For more than half of the patients treated with bezuclastinib, a hematopathologist can no longer clearly see the neoplasm in their bone marrow. There also appears to be a correlation between bone marrow pathological and laboratory remission with the magnitude of symptom improvement.

On top of that, there are several other observations. First, from personal experience with trial subjects, we are seeing complete resolution of their skin lesions. Second, at the AAAAI meeting, I presented a poster on the bone health findings, and we are seeing very promising results in terms of increasing bone mineral density, in particular in the lumbar spine, at cycle 7 day 1. Overall, improvements in bone health, resolution of skin lesions, as well as improvements in symptoms overall and individually across symptom domains suggests we are going in a positive direction.

Q. How significant are these findings for non-advanced systemic mastocytosis?