PATHFINDER was the first Advanced SM trial to use SM-specific criteria to assess improvement in organ function1–3
PATHFINDER
PATHFINDER is a 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 SM1,4
Enrolled patients (safety population; N=107)1
≥1 prior systemic therapy1
1-year prespecified analysis: Response evaluable (n=47)1
Data cut: 20 April 20215
4-year followup: Response evaluable (n=53)6
Data cut: 13 March 20256
Discontinued treatment/end-of-study (n=75)6*
Enrolled patients (safety population; N=107)1
≥1 prior systemic therapy1
1-year prespecified analysis: Response evaluable (n=47)1
Data cut: 20 April 20215
4-year followup: Response evaluable (n=53)6
Data cut: 13 March 20256
Discontinued treatment/end-of-study (n=75)6*
PATHFINDER was a single-arm study, with no formal hypothesis testing against a comparator group4
Results from patients at the 4-year cut-off are descriptive only, and not part of the prespecified hypothesis test4
*At the end of the 4-year cut-off, 75 patients were not on treatment due to disease progression, adverse event, withdrew consent, investigator decision, non-compliance, or other reasons.6
Key inclusion criteria:1,4
- ECOG PS 0–3
- Palliative and supportive care medications allowed
Key exclusion criteria:1,4
- Baseline platelet count <50 × 109/L
- High- and very high-risk AHNs such as AML or high-risk MDS
- Philadelphia chromosome-positive malignancies
Selected inclusion and exclusion criteria are shown.
Primary endpoint1,4
- Overall response rate (ORR) as per mIWG-MRT-ECNM response criteria
Secondary efficacy endpoints4
- Time to any response
- Duration of response (DOR)
- Progression-free survival (PFS)
- Overall survival (OS)
- Mean percentage change from baseline in measures of bone marrow mast cell burden, serum tryptase level, blood KIT D816V VAF, and spleen volume
Selected endpoints are shown.
- 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
Baseline demographic characteristics of response-evaluable patients (n=47)1
| 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 at 1-year interim data cut was 12 months1
Overall response rate (ORR) evaluates the improvement in organ function from baseline in Advanced SM2,3
Resolution sustained for 12 weeks:
Complete response (CR)
Resolution of organ damage (C-findings), including biomarker normalisation‡
Partial response (PR)
≥50% improvement in ≥1 C-finding (organ damage), with supportive biomarker improvement†
Clinical improvement
Resolution of ≥1 C-finding**
**Clinical improvement requires improvement of at least one C-finding, such as cytopenias due to bone marrow dysfunction, hepatic dysfunction with ascites and/or portal hypertension, large osteolytic lesions and/or pathological fractures, splenomegaly with hypersplenism, or gastrointestinal malabsorption.2,3
†PR requires improvement of disease-related organ damage (C-findings), ≥50% reduction in mast cell infiltrates, ≥50% reduction in serum tryptase from baseline, and no progression of any C-findings.2,3
‡CR requires normalisation of peripheral blood counts (ANC ≥1 × 109/L, haemoglobin ≥11 g/dL, platelets ≥100 × 109/L), serum tryptase <20 ng/mL, complete clearance of mast cell aggregates, and resolution of all C-findings (organ damage).2,3
ANC=absolute neutrophil count; ASM=aggressive systemic mastocytosis; ECOG PS=Eastern Cooperative Oncology Group performance status; MAF=mutant allele fraction; MCL, mast cell leukaemia; mlWG-MRT-ECNM=modified International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis; SM-AHN=systemic mastocytosis with an associated haematological neoplasm; WHO=World Health Organization
