AUTHORS
Qian Jiang Jr, MD, Xiaoshuai Zhang, PhD2, Yue Chen3, Yanli Zhang, MD4, Weiming Li, PhD5, Qiang WANG, MD6, Suning Chen, MD, PhD7, Jianyu Weng, MD, PhD8, Bingcheng LIU, MD9, Xin Du, MD10, Jie Jin, MD11, Zhuogang Liu12, Zhenfang Liu, DO13, Xielan Zhao14, Li Meng, MD15, Lie Lin16, Jingrong Cao17, Hanying Bao, MD, PhD18
AFFILIATIONS
1 Peking University Institute of Hematology, Beijing, China
2 Peking University Institute of Hematology, Beijing, China
3 Peking University Institute of Hematology, Beijing, China
4 Henan Cancer Hospital, Henan, China
5 Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
6 Nanfang Hospital, Southern Medical University, Department of Hematology, Guangzhou, China
7 The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, National Clinical Research Center of Hematologic Diseases, Suzhou, China
8 Guangdong Provincial People’s Hospital, Guangzhou, China
9 National Clinical Research Center for Blood Diseases, State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
10 Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
11 The First Affiliated Hospital, Zhejiang University School of Medicine, Department of Hematology, Hangzhou, China
12 Shengjing Hospital of China Medical University, Department of Hematology, Shenyang, China
13 The First Affiliated Hospital of Guangxi Medical University, Department of Hematology, Nanning, China
14 Xiangya Hospital of Central South University, Changsha, China
15 Tongji Hospital Tongji Medical College of HUST, Wuhan, China
16 Department of Hematology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Hainan, China
17 Shenzhen TargetRx Inc., Shenzhen, China
18 Shenzhen TargetRx Inc., Shenzhen, China
ABSTRACT
Background
TGRX-678 is a novel allosteric ABL kinase inhibitor targeting the myristoyl pocket (STAMP). The phase 1, first-in-human, open-label trial TGRX-678-1001 (NCT05434312) evaluated its safety and efficacy in TKI-resistant/intolerant patients (pts) with CML-CP or CML-AP. Here, we present the updated data and a preliminary exploratory analyses of biomarkers.
Methods
In dose escalation, pts received TGRX-678 at 10–80 mg BID or 40–240 mg QD. In dose expansion, four cohorts were enrolled: (1) CML-CP without T315I, ≥2 prior TKIs; (2) CML-CP with T315I, ≥1 prior TKI; (3) CML-AP, ≥1 prior TKI; (4) CML-CP, 1 prior TKI. Dosing was 80 mg or 240 mg QD. Primary endpoint: MTD. Secondary endpoints: safety and efficacy (MaHR, CHR, MCyR, CCyR, MMR). ABL1 muts were assessed by Sanger sequencing. Targeted DNA sequencing of baseline samples from 91 patients explored associations between non-ABL1 somatic muts and outcomes—analyzed at gene and pathway levels.
Results
MTD was not reached. As of July 16, 2026, 180 patients (127 CML-CP, 53 CML-AP) received treatment. Median age: 46 years (IQR, 35–56); 62% male; median time from CML diagnosis to TGRX-678: 69 months (IQR, 27–147). Prior TKI exposure: 55% of CP and 87% of AP patients had ≥3 TKIs; 33% of CP and 72% of AP had received ponatinib, olverembatinib, asciminib, or HS-10382. T315I muts: single in 19% (CP) and 34% (AP); T315I + other in 6% (CP) and 6% (AP); other ABL1 muts in 17% (CP) and 26% (AP).
Median treatment duration: 28 months (IQR, 8–39). At cutoff, treatment continued in 67% of CP and 43% of AP patients. Discontinuations: unfavorable response (21%), disease progression (8%), AEs (7%), consent withdrawal (2%), other (1%).
≥ Grade 3 hematologic TRAEs: thrombocytopenia (44%), neutropenia (42%), anemia (26%). Most common non-hematologic TRAEs (mostly Grade 1–2): hypertriglyceridemia (36%), hypercholesterolemia (35%), ALT increase (28%), AST increase (23%).
In the evaluable CP pts, 46/54 (85.2%) achieved CHR by 3 cycles. 3-year (3-y) cumulative incidences (CIs) of CCyR, and MMR were 53%, and 39%; in those with a single T315I mut, 3-y CIs of CCyR, and MMR were 71%, and 63%. In those receiving prior 3G-TKI or STAMP inhibitors, 3-y CIs of MCyR, CCyR and MMR were 53%, 33% and 10%. 3-y probabilities of PFS and OS were 93% (95% CI: 82; 97) and 94% (86; 98).
In the evaluable AP pts, 37/48 (77%) achieved MaHR by 3 cycles. 3-y CIs of MCyR, CCyR, and MMR were 40%, 28%, and 23%; in those with a single T315I mut, 33%, 28%, and 22%. In those receiving prior 3G-TKI or STAMP inhibitors, 3-y CIs of MCyR, CCyR and MMR were 25%, 16% and 9%. 3-y probabilities of PFS and OS were 81% (67; 90) and 80% (65; 89).
Clinically meaningful responses were observed in several pts with M244V: one with M244V (AP-CML) achieved MaHR; one with M244V/G250E/L387M (CP-CML) achieved MCyR. One with F359C achieved durable CHR, MCyR, and MMR. Sustained BCR::ABL1 transcript reductions occurred in those harboring baseline M244V, F359C, F359I, or F359V.
Among the 91 patients (CP 72, AP 19) with DNA sequencing data, 45 (49%) harbored ABL1 muts, and 73 (80%) harbored at least 1 non-ABL1 somatic mut, with a median number of 2 (IQR, 1 - 3). Non-ABL1 somatic muts involved chromatin-modifying genes (63%), cell-signaling genes (41%), transcription factor-related genes (27%), DNA-methylation genes (11%) and tumor suppressor genes (10%). The most frequent ABL1 muts included T315I (30%), E255V/K (11%) and Y253H (6%).
The most frequent non-ABL1 somatic muts were ASXL1 (48%), RUNX1 (11%), SETD1B (8%), KMT2D (7%), GNAS (6%), and DNMT3A (6%). After adjustment for clinical co-variates, T315I and E255K/V muts were significantly associated with higher rates of cytogenetic and molecular responses, whereas no ABL1 mut status was independently associated with inferior therapy responses. RUNX1 muts were significantly associated with inferior PFS and OS. Muts involving transcription factor-related genes and pathway-level alterations in TP53 signaling, cell-cycle signaling, and JAK-STAT signaling were also independent adverse co-variates for PFS and/or OS.
Conclusions
TGRX-678 demonstrates a favorable safety profile and robust efficacy in heavily pretreated CML-CP and CML-AP—including patients with T315I or prior 3G-TKI/STAMP inhibitor failure. Exploratory genomic profiling identified RUNX1 muts and selected pathway-level alterations as potential adverse biomarkers beyond ABL1 mut status, supporting further validation for risk stratification.
DISCLOSURES
Qian Jiang Jr, MD: No relevant conflicts of interest to declare.