Efficacy of tgrx-678, a potent BCR::ABL1 allosteric inhibitor, in CML-CP and CML-AP patients harboring T315I mutation: Results from a phase 1 study

Abstract Background: TGRX-678 is a novel allosteric inhibitor of ABL kinases that specifically targets the Myristoyl Pocket (STAMP) of ABL. Previous results showed TGRX-678 was well tolerated and demonstrated activity in patients (pts) with CML- chronic phase (CP) or accelerated phase (AP) who are resistant/intolerant to prior TKIs (Jiang,et al. Blood (2024) 144 (Supplement 1): 477). The T315Imutation is common resistant in CML pts after multiple lines of TKI therapy. Here, we present updated data from phase 1 study in patients harboring the T315I mutation (NCT05434312). Methods: We included all the pts in CP or AP with T315I mutation detected by Sanger sequencing in phase 1 study, a single-arm study evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy of TGRX-678 CML. Results: As of June 17, 2025, 53 T315I-mutated CML pts (32 CP and 21 AP) were enrolled. 11 (21%) pts had additional ABL1 mutations. Doses of TGRX-678 included 40 mg/d (4 CP, 3 AP), 80 mg/d (6 CP, 4 AP), 160 mg/d (2 CP, 2 AP), and 240 mg/d (20 CP, 12 AP). 36 (68%) pts were male. Median age was 44 (IQR, 35-51) years. Median interval from CML diagnosis to starting TGRX-678 was 68 (IQR 29-149) months. 35(66%) pts received ≥ 3 prior TKIs; 24(45%) pts previously received ponatinib, olverembatinib, asciminib, and/or HS-10382 (STAMP inhibitor). 44 (83%) pts had BCR::ABL1 >10% at baseline. At the data cut-off, median TGRX-678 treatment duration was 17 months (range 8-28), treatment was ongoing in 19 (59%) CP and 11 (52%) AP pts. 23 pts discontinued treatment due to physician's decision (n = 10), consent withdrawal (n = 6), disease progression (n =5), treatment related adverse events (TRAEs, n =1), and drug-unrelated death (n =1). In efficacy-evaluable pts, 81% CP pts and 80% AP achieved complete hematological response (CHR) and major hematological response (MaHR), respectively. The 2-year cumulative incidences of complete cytogenetic response (CCyR) and major molecular response (MMR) were 48% (95%CI 33-61%) and 33% (20-46%), respectively. The corresponding 2-year duration of response (DOR) rates were 80% (95%CI 58-91%) for CCyR and 84% (95%CI, 59-95%) for MMR, respectively. The 2-year probabilities of progression free survival (PFS) and survival were 89% (95%CI 76-96%) and 89% (95%CI, 74-94%). Efficacy outcomes were comparable across T315I mutation status (single vs. compound mutations) and TGRX-678 dose levels (≤160 mg/d vs. 240 mg/d), with all p-values ranging from 0.258 to 0.547. The 2-year cumulative incidences of CCyR and MMR were significantly higher in the CP cohort compared to the AP cohort (59% [95%CI, 39–75%] vs. 29% [95%CI, 11–50%], P = 0.030; and 45% [95%CI, 26–62%] vs. 15% [95%CI, 3–34%], P = 0.040, respectively). Among patients with prior exposure to ponatinib, olverembatinib, asciminib, or HS-10382, the cumulative incidences of CCyR and MMR were significantly lower than in those without such exposure (26% [95%CI, 10–45%] vs. 66% [95%CI, 44–81%], P = 0.002; and 9% [95%CI, 1–25%] vs. 53% [95%CI, 32–70%], P = 0.002, respectively). However, duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were comparable between groups. Grade 3/4 hematological TRAEs included neutropenia (28%), thrombocytopenia (25%), leukopenia (17%) and anemia (15%). Common (≥5%) non-hematological TRAEs were Common non-hematological TRAEs (all grade, mainly grade 1 - 2) were hypertriglyceridemia (42%), hypercholesterolemia (30%), alanine aminotransferase increase (26%), aspartate aminotransferase increase (23%), hyperuricemia (23%),γ-glutamyltransferase increase (21%), lipase increase (17%) and hyperglycemia (13%) Safety profiles were comparable across dose groups. Conclusion: Our study demonstrated that TGRX-678 achieved strong efficacy in patients with T315I-mutated CML in chronic or accelerated phase, with no clear dose–response relationship observed. These results suggest that lower doses of TGRX-678 may offer comparable efficacy with potentially improved safety, particularly in heavily pretreated patients harboring T315I mutations.