AYVAKYT is the first therapy to use the mIWG-MRT-ECNM criteria as the primary endpoint to evaluate efficacy in an Advanced SM registration trial1,2
PATHFINDER
PATHFINDER is an ongoing multicentre, open-label, single-arm, phase 2 registration trial of AYVAKYT 200 mg once daily in adult patients with a centrally confirmed diagnosis of Advanced SM1
The efficacy and safety of AYVAKYT were evaluated in 62 patients with Advanced SM1
PATHFINDER trial of AYVAKYT in Advanced SM1
With evaluable population who had received at least one prior systemic therapy
Enrolled (N=62)
Central review
AYVAKYT at a starting dose of 200 mg once daily (both cohorts)a
Cohort 1, efficacy evaluable (n=52)
Advanced SM patients with an evaluable baseline C-finding
Cohort 2, efficacy non-evaluable (n=10)
Advanced SM patients without an evaluable baseline C-findingb
Prespecified interim analysis
Performed when 32 patients in cohort 1 had sufficient follow-up for response evaluation
Key inclusion criteria:
- Confirmed diagnosis of Advanced SM
- ≥18 years of age
- ECOG PS 0–3
Key exclusion criteria:
- Baseline platelet count <50 x 109/L
Patient characteristics:
- Had received at least one prior systemic therapy
a2 patients started at 100 mg once daily.
bPatients without an evaluable C-finding could not be assessed for efficacy, with the exception of patients with MCL who, as per mIWG-MRT-ECNM criteria, were enrolled into cohort 1 and evaluated for reductions in disease burden.3
Primary endpoint (cohort 1)
- Overall response rate (ORR) as per mlWG-MRT-ECNM response criteria
Secondary endpoints (both cohorts)
- Mean change from baseline in patient-reported total symptom score (TSS) and quality of life
- Time to response
- Duration of response
- Progression-free survival (PFS)
- Overall survival (OS)
- Changes in mast cell burden
- Safety
- Confirmed diagnosis of Advanced SM per WHO criteria
- Deemed evaluable by mIWG-MRT-ECNM criteria at baseline
- Had received at least 1 dose of AYVAKYT
- Had at least 2 post-baseline bone marrow examinations
- Had been in the study for at least 24 weeks or completed an end-of-study visit
The response-evaluable population (n=47) comprised different subtypes, including ASM (n=8), SM-AHN (n=29) and MCL (n=10), who had received at least one prior systemic therapy:4
Baseline demographic characteristics of response-evaluable patients (n=47)4
| Median age, years (range) | 69 (31–86) |
| Male/female, n (%) | 33 (70)/14 (30) |
| ECOG PS, n (%) | |
| 0–1 | 31 (66) |
| 2–3 | 16 (34) |
| Advanced SM subtype, n (%) | |
| ASM | 8 (17) |
| SM-AHN | 29 (62) |
| MCL | 10 (21) |
| Positive KIT D816V mutation status in peripheral blood, n (%) | 42 (89) |
| Median KIT D816V MAF in blood, % | 26.2 |
| Prior systemic therapy, n (%) | |
| Midostaurin | 37 (78.7) |
| Cladribine | 8 (17.0) |
| Interferon alpha | 7 (14.9) |
| Hydroxycarbamide | 5 (10.6) |
| Azacytidine | 3 (6.4) |
| Median bone marrow mast cell infiltrate, % | 70 |
| Median serum tryptase level, ng/mL | 325 |
Efficacy was based on ORR per mIWG-MRT-ECNM response criteria across all evaluable patients (n=47), who received at least one prior systemic therapy and a starting dose of 200 mg AYVAKYT once daily. The median follow-up period was 12 months4
The mIWG-MRT-ECNM criteria validate the efficacy of AYVAKYT, as it was developed by expert consensus to overcome the limitations of prior response criteria and is recognised to be the most comprehensive system for adjudicating treatment response in SM2,3
The efficacy of AYVAKYT was tested by updated, clinically meaningful criteria1–3
The mIWG-MRT-ECNM criteria evaluates ORR by:2,3
≥12 weeks
response duration
Resolution of ≥1 findings
of non-haematological and haematological organ damage (‘C’-findings)*
≥50% reduction in biomarker response
(bone marrow mast cell aggregates and serum tryptase)**
*’C’-findings:
• Bone marrow dysfunction that manifests in one or more cytopenia (ANC <1 x 109/L, Hb <10 g/dL or platelets <100 x 109/L)
• Palpable hepatomegaly with impairment of liver function, ascites and/or portal hypertension
• Skeletal involvement with large osteolytic lesions and/or pathological fractures
• Palpable splenomegaly with hypersplenism
• Malabsorption with weight loss due to gastrointestinal tract mast cell infiltrates
**Serum tryptase must be <20 ng/mL if the baseline value was ≥40 ng/mL for CR or CRh.
ANC=absolute neutrophil count; CR=complete response; CRh=complete remission with partial haematological recovery; ECOG PS=Eastern Cooperative Oncology Group performance status; Hb=haemoglobin; MAF=mutant allele fraction; mlWG-MRT-ECNM=modified International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis; PR=partial response; WHO=World Health Organization
