Editor’s Note: The 65th Annual Meeting of the American Society of Hematology (ASH) recently concluded, with significant contributions in the field of Chronic Myeloid Leukemia (CML) treatment. Professor Jiang Qian and her team from Peking University People’s Hospital presented multiple studies, with abstracts 867 and 869 selected for oral presentations. These reports highlighted the potential of TGRX-678 and Olverembatinib in CML treatment and overcoming drug resistance. “Hematology Frontier” had the privilege of interviewing Professor Jiang Qian on these topics.
1
Background:
TGRX-678 is a novel allosteric inhibitor of ABL kinases, specifically targeting the ABL Myristoyl Pocket (STAMP). In vitro data supports TGRX-678 targeting the most common BCR-ABL mutations, including T315I. Here we report an open-label, first-in-human study to evaluate the safety, preliminary efficacy, and pharmacokinetic properties of orally administered TGRX-678 in patients with resistant/refractory CML.
Methods:
This study included dose escalation and expansion phases. During dose escalation, patients with CML in chronic or accelerated phase (CP or AP) and who had failed ≥3 prior TKIs were enrolled. Patients received orally a single dose, after a 3-5 day observation, continuously daily doses ranging from 10 to 80 mg (BID) or 40 to 240 mg (QD) were given. Dose escalation followed an adaptive Bayesian logistic regression model based on dose-limiting toxicities (DLTs) occurring in cycle 1 (28 Days). Dose-expansion had three cohorts: CML-CP without T315I mutation with ≥2 prior TKIs, CML-CP with T315I with ≥1 prior TKIs, and CML-AP with ≥1 prior TKIs. The eligible patients received continuous treatments until disease progression, intolerant toxicity, consent withdrawal, or death.
Results:
From April 30, 2021 to July11, 2023, 95 (CP n = 58, AP n = 37) patients were treated with TGRX-678 at the BID doses including 10 mg (n = 3), 20 mg (n = 6), 40 mg (n = 5), and 80 mg (n = 3), and QD doses including 40mg (n=18), 80 mg (n = 6), 160mg (n= 4) and 240mg (n=50). 40 (42%) patients were female. The median age was 45 (range 35-52) years and the median interval from diagnosis to initial TGRX-678 treatment was 97 (range 28-136) months. Median treatment duration was 8 (range 6-13) months. At baseline, 93 (98%) patients had received ≥2 lines of prior TKI therapy, among them, 78 (82%) received ≥3 lines of prior TKIs, 44 (46%) received ≥4 lines of prior TKIs. 46 (48%) patients had ≥1 ABL mutation and 28 (30%) had T315I mutation.
Of 58 patients with CML-CP, 16 (89%) achieved complete hematologic responses (CHR), 25 (43%) major cytogenetic responses (MCyR), 19 (33%) complete cytogenetic responses (CCyR), and 11 (19%) major molecular responses (MMR). Of 14 CML-CP patients with T315I mutation, 9 (100%) achieved CHR, 9 (62%) MCyR, 8 (57%) CCyR and 7 (50%) MMR. Of 35 CML-CP patients without any ABL mutations, 12 (100%) achieved CHR, 11 (31%) MCyR, 6 (17%) CCyR and 1 (3%) MMR (Fig. A). Of 9 CML-CP patients with other ABL mutations, 4 (67%) achieved CHR, 5 (56%) MCyR, 5 (56%) CCyR and 3 (33%) MMR (Fig. B). Of 37 CML-AP patients, 31 (84%) had major hematologic response, 13 (35%) MCyR, and 9 (24%) CCyR (Fig. C).
There were 22 CML-CP and 23 CML-AP patients previous received 3rd Gen TKIs (ponatinib or HQP1351) or asciminib. Of 22 CP patients, 21 (95%) achieved CHR, 4 (18%) MCyR and 3 (14%) CCyR. Of 23 CML-AP patients, 17 (74%) achieved CHR, 5 (22%) MCyR and 3 (13%) CCyR.
The PK results suggested that TGRX-678 exposure (Cmax and AUCtau) was dose-proportional within range of 10mg~80mg BID or 40mg~240mg QD. The elimination of TGRX-678 in human plasma is slow, and the half-life (T1/2) of which is about 120 hours. At steady state, the accumulation ratios of Cmax and AUCtau are 3.7-8.0 and 5.4-11.8, respectively. The high accumulation ratio of TGRX-678 resulted in not only an increase of plasma exposure, but also a decrease of the gap between Cmax and Ctrough (Fig. D).
7 DLTs were observed, one case of elevated alanine aminotransferase at 20 mg BID and five cases of thrombocytopenia at 40mg QD (1), 40mg BID (2) and 80mg QD (2) and one hepatic function abnormal at 240 mg QD. However, MTD was not reached according to protocol criteria. Most treatment-related adverse events (TRAEs) were grade 1-2. AEs ≥ grade 3 that happened more than 5% were thrombocytopenia (50%), neutropenia (42%), anemia (24%) and hypertriglyceridemia (9%). In total 15 patients discontinued the study due to disease progression (5, all APs), intolerance (2), physician’s decision (2), consent withdrawal (6). There was one death occurred which was not drug related.
Research Conclusion: Clinical activity of TGRX-678 was seen in all cohorts and across TKI-resistant mutations including T315I, providing a promising treatment option for CML CP/AP patients, including those who failed ponatinib or asciminib. Its unique PK properties might bring additional benefit to patients. TGRX-678 was well tolerated in heavily pretreated CML patients. Currently two doses were selected to optimize the RP2D.
2
Introduction：
This was a multicenter, randomized, registrational phase 2 study to assess the efficacy and safety of olverembatinib compared with BAT in pts with CML-CP who were resistant and/or intolerant to 3 TKIs (imatinib [I], dasatinib [D], nilotinib [N]) in China.
Methods：
Eligible adult CML-CP pts were resistant and/or intolerant to 3 TKIs, were in ECOG PS 0-2, and had adequate organ function. Pts were randomized 2:1 to investigational olverembatinib (40 mg QOD) or the BAT arm, which could be one of the following per investigator choice: TKIs (I, D, or N), interferon (IFN), hydroxyurea (HU), and homoharringtonine (HHT). The primary endpoint was event-free survival (EFS), including time from randomization to AP or BP progression); all-cause mortality; relapse; treatment failure (no complete remission [CR] within 3 cycles); loss of complete hematologic response (CHR); and treatment intolerance as per investigator and study sponsor. Efficacy was analyzed in the intention-to-treat (ITT) efficacy population and safety in pts receiving ≥1 dose of olverembatinib.
Results：
As of April 30, 2023, a total of 144 pts (96, olverembatinib; 48, BAT) were enrolled, including 69.4% male and 30.6% female, with a median (range) age of 49.0 (18-77) years. A total of 129 pts (89.6%) were previously treated with ≥ 3 TKIs (I, D, N). 15 pts (10.5%) with T315I mutation received ≥1 TKIs, of whom 9 (6.3%) received 2. Median (range) follow-up was 12.67 (0.0-40.9) and 2.94 (0.0-40.4) months in the olverembatinib and BAT arms, respectively. A total of 66 (45.8%) pts had ≥1 BCR::ABL1 mutation and 39 (27.1%) BCR::ABL1T315I. A total of 97 pts discontinued therapies (56 [58.3%] olverembatinib, 41 [85.4%] BAT) due to disease progression/treatment failure, AE, consent withdrawal, poor compliance, or death. In the safety population, 82/96 (85.4%) pts receiving olverembatinib and 31/46 (67.4%) BAT experienced a grade ≥ 3 AE. Any-grade AEs (> 20% incidence) included thrombocytopenia; leukopenia; anemia; neutropenia; elevated CPK, ALT, and AST; and hypertriglyceridemia. Serious AEs (SAEs) (>5%) included thrombocytopenia. A total of 7 SAEs were possibly related to olverembatinib: 1 acute myocardial infarction, 3 coronary heart disease cases, 2 cerebral infarctions, and 1 congestive heart failure. Common AEs (≥10%) leading to discontinuation, dose reduction, or treatment withdrawal were thrombocytopenia, neutropenia, and leukopenia.
Median (range) EFS was 21.22 (95% CI, 10.15-NR) months in the olverembatinib arm and 2.86 (95% CI 2.53-4.73) months in the BAT arm (P < .001; HR, 0.352; 95% CI, 0.228-0.545). Compared with the BAT control arm, olverembatinib reduced the event risk 65%. In the olverembatinib arm, estimated EFS at 6, 12, and 24 months was 73% (95% CI, 62.5-81.0), 58.7% (95% CI, 47.5-68.2), and 46.9% (95% CI, 35.9-57.2), respectively. In the BAT group, it was 32.6% (95% CI, 19.7-46.2), 26.1% (95% CI, 14.5-39.3), and 16.9% (95% CI, 7.7-29.2), respectively. Median OS was NR in either group (P = .41). Up to data cutoff, 34 (71%) pts in the BAT control arm were crossed-over to be treated with olverembatinib after EFS endpoint was reached. In the ITT efficacy group, among those treated with olverembatinib, 51/60 (85%) pts achieved a CHR; 42/88 (47.7%) MCyR; 32/88 (36.4%) CCyR; and 24/88 (27.3%) MMR. In the BAT group, 8/23 (34.8%) pts achieved a CR, 11/37 (29.7%) MCyR, 6/37 (16.2%) CCyR, and 3/37 (8.1%) MMR.
Conclusions：
This study represents the largest population of pts with CML-CP resistant or intolerant to both 1G and 2G TKIs. Olverembatinib was observed to be better tolerated and more effective than BAT in treating these pts. Internal study (CT.gov) numbers: HQP1351CC203 (NCT04126681)..
Expert Interview
“Hematology Frontier”: Could you discuss the issue of drug resistance in CML treatment and the progress in this field?
Professor Jiang Qian: In the treatment of chronic myeloid leukemia (CML), a small proportion of patients face the challenge of drug resistance. Although the percentage of such patients is not high, in China with its large population, drug-resistant CML is not uncommon. Therefore, there is a significant unmet clinical need. In China, two new drugs have been approved for marketing, namely Olverembatinib and Tgrx-678. Olverembatinib has gained approval for a new indication, specifically for treating chronic-phase CML patients resistant and/or intolerant to first- and second-generation tyrosine kinase inhibitors (TKIs). This brings new hope for patients with drug-resistant CML. Tgrx-678 is a novel ABL kinase conformation inhibitor that targets the BCR-ABL fusion gene’s conformational sites, providing a new therapeutic option for CML patients resistant or intolerant to existing drugs, including those with T315I mutation resistance. It demonstrates excellent efficacy in overcoming drug resistance with minimal side effects.
“Hematology Frontier”: Could you interpret the efficacy and safety of BCR-ABL conformation inhibitor Tgrx-678 in refractory/relapsed chronic myeloid leukemia (R/R-CML)?
Professor Jiang Qian: Most previous TKIs primarily exert their anti-tumor effects by competitively binding to the adenosine triphosphate (ATP)-binding site of the kinase domain, inhibiting or reducing tyrosine kinase phosphorylation. Tgrx-678’s mechanism of action is similar to Asciminib, but with structural improvements and optimization, resulting in stronger anti-tumor activity. It specifically targets the Src-homology 3 (SH3) and 2 (SH2) domains in the BCR-ABL1 fusion protein, thereby treating CML with high specificity, minimal toxicity, and providing a new selective mechanism to overcome drug resistance.
“Hematology Frontier”: Could you discuss the value of Olverembatinib in CML treatment?
Professor Jiang Qian: In fact, Olverembatinib has made its sixth appearance at the ASH conference, with new research data presented and disclosed each time. It has entered a registered randomized phase II study, showing confident efficacy and safety data. For CML patients with the T315I mutation, Olverembatinib demonstrates remarkable effectiveness. Even in foreign CML patients who have failed ponatinib treatment, it exhibits good efficacy, providing encouraging results.
Medical Doctor, Chief Physician, Professor, Doctoral Supervisor
National Clinical Medical Research Center for Hematologic Diseases
Peking University Institute of Hematology
Deputy Chief of Hematology Department, Peking University People’s Hospital
Research Interests: Acute and Chronic Leukemias, Myeloproliferative Neoplasms, and other hematologic diseases; profound expertise in clinical research on Chronic Myeloid Leukemia (CML)
Member of the National Representative Committee of the International CML Foundation (iCMLf)
Member of the Hematology Branch of the Chinese Medical Association, Deputy Head of the Leukemia-Lymphoma Group
Vice Chairman of the Hematology Branch of the Beijing Medical Association
Vice Chairman of the Hematology Specialty Committee of the China Association of Chinese Medicine
Deputy Chairman of the Hematology Professional Committee of the China Association of Medical Education
Deputy Chairman and Chief Committee Member of the Leukemia Academic Working Committee of the Hematology Branch of the Chinese Society of Geriatrics
Editorial Board Member of Leukemia Research, Chinese Journal of Hematology, Chinese Journal of Experimental Hematology, and Journal of Clinical Hematology
Principal Investigator for multiple National Natural Science Foundation projects; published over 100 articles in Chinese and English journals such as Blood, Leukemia, and American Journal of Hematology.
