Nailike (olverembatinib)

P=N/A, N=30, Not yet recruiting, Peking University People's Hospital

P1, N=100, Recruiting, Ascentage Pharma Group Inc. | N=60 --> 100

P2, N=67, Recruiting, Nanfang Hospital, Southern Medical University

Prior therapies included imatinib, dasatinib, nilotinib, olverembatinib, radotinib and ponatinib. Of the 58 patients, only Grade 1 AEs were reported, including diarrhea, rash and eye edema. Conclusion Flumatinib has good efficacy and safety in the treatment of adult patients with resistant or intolerant Chronic-Phase Chronic Myeloid Leukemia, it will be a good choice for second-line or above treatment for CML-CP In clinical practice.

Figure 1. HRQOL profile

Here, we present 6 patients with CD19-positive MPAL that are successfully treated with blinatumomab in combination with venetoclax and/or azacytidine in front line setting...The patient with BCR: : ABL1 received blinatumomab in combination with olverembatinib. Intrathecal (IT) chemotherapy with cytarabine and methotrexate was administered to central nervous system (CNS) as prophylaxis treatment... The results provide preliminary evidence of effective and safe treatment with blinatumomab and venetoclax combination as first-line therapy in MPAL resulting in the achievement of normal bone marrow function with less toxicity than using conventional chemotherapy.

The 15 R/R patients (11, Ph + ALL; 4, CML-BP) received olverembatinib 30 or 40 mg on alternate days combined with VP (vindesine 4 mg once per week for 4 weeks and prednisone 1 mg/kg for 3 weeks and tapered at the fourth)...Among the 16 patients with molecular resistance to TKI-based chemotherapy (imatinib [n = 4]; dasatinib [n = 9]; flumatinib [n = 3]), 2 received olverembatinib monotherapy, 7 olverembatinib plus VP, and 7 hyper-CVAD, of whom 8 received subsequent allogeneic transplantation...Treatment-related nonhematologic severe adverse events were observed in 3 patients, including (each) stable angina pectoris, severe pneumonia, and fatal Klebsiella sepsis. Conclusions Olverembatinib-based chemotherapy is effective and safe in patients with R/R and molecular resistant Ph + ALL or CML-LBP.

As for the 23-year-old female pt with CML-LBP, dasatinib was switched to olverembatinib when T315I, E255K, and E255V mutations were detected...At present, the patient maintained in CR, and blinatumomab will be used for MRD clearance before allo-HSCT...In addition, bridging allo-HSCT after deeper molecular remission could further improve survival. The safety profiles were manageable, but there is still a need to explore the optimal dose in elderly pts.

A similar pattern was also observed when olverembatinib was combined with doxorubicin. ConclusionsOlverembatinib, a novel, third-generation TKI, in combination with chemotherapeutic agents vincristine or doxorubicin decreased MCL-1, BCL-2, and BCL-xL and increased BAX and PUMA in a dose-dependent manner, the combinations have demonstrated synergistic antitumor effects by enhancing apoptosis and antiproliferation in Ph⁺ ALL cells, which may provide an alternative approach for treatment of patients with Ph⁺ ALL.

The Olverembatinib involving regimen included: Olverembatinib and Venetoclax in combination with VP based low intensive chemotherapy (Vindesine /Prednisone), Olverembatinib+Blinatumomab, Olverembatinib + INO. ConclusionThis work suggests that Olverembatinib showed a profound response rate and was well tolerated in MRD clearance prior to allo-HSCT in Ph+ALL with disease recurrence and persistently MRD positive. Larger prospective studies are needed.

Recently, such pts have new hope with the wide application of a novel third-generation TKI Olverembatinib developed in China and Blinatumomab（CD19 antibody,BITE）and INOTUZUMAB OZOGAMICIN(CD22 antibody,Ino. For heavily treated RR ABL1+B ALL pts,including those after treatment with ponatinib and other TKICART and HSCT, Olverembatinib combined with monoclonal antibodies is effective and safe. In my cases, it is particularly noteworthy that one pts ,Ph like ALL with ABL1 FG, received Olverembatinib combination BITE and achieved a surprising response, so Olverembatinib may also be effective and safe for such pts. In addition, venetoclax may be used as a sensitizer for TKI or other antitumor drugs.

Common nonhematologic adverse events included hepatotoxicity, nephrotoxicity, myalgia, arthralgia, rash, and edema, of which most were mild. Conclusion Olverembatinib-based therapies are generally well tolerated and efficacious for patients with Ph/BCR-ABL1-positive acute lymphoblastic leukemia.

P1, N=62, Recruiting, Ascentage Pharma Group Inc. | Trial primary completion date: Jan 2023 --> Jan 2024

Background: In patients (pts) with CML, the BCR::ABL1 T315I gatekeeper mutation confers treatment resistance to all approved ATP-competitive tyrosine kinase inhibitors (TKIs) except ponatinib and olverembatinib; thus pts harboring this mutation have limited treatment options. Asciminib demonstrated effectiveness in pts with CML and the T315I mutation in routine medical practice, including ponatinib pre-treated pts, a population with limited available treatment options. Effectiveness estimates were consistent with those observed in clinical trials. Although the number of pts was small, this global study reports on one of the largest cohorts of pts with CML and the T315I mutation.

17 (30.4%) patients were pretreated with third-generation TKI (ponatinib). As of the data cutoff date, 37 (66.1%) patients continued on treatment and 19(33.9%) discontinued because of disease progression, intolerance, loss to follow-up or death. Conclusion Olverembatinib-based therapy showed strong efficacy and tolerable toxicity in advanced Ph+ leukemia.

Purposes Study safety and efficacy of olverembatinib or ponatinib and azacitidine (AZA) in this setting. KRAS and TP53 mutations and PFKFB3::LINC02649 fusions had predictive impact on outcomes. Determining whether adding azacitidine to a 3rd-generation TKI requires a randomized controlled trial.

The upfront use of third generation TKI ponatinib has improved the frequency of complete molecular response (CMR) and the overall survival rate to a greater extent...They received three cycles of OVP regimen(for 28 days each cycle :olverembatinib 40mg qod d1-28,Vindesine 4mg d1,8,15,22,Prednisone1mg/Kg/d d1-21,0.5mg/kg/dd22-28). Twelve intrathecal injections of cytarabine alternating with methotrexate were designed as central nervous system prophylaxis in the following therapy after the diagnosis...The trial is ongoing. we need more time to observe.

Furthermore, through analyzing patients who received TKI treatment, we observed that 3G TKIs like olverembatinib exhibited advantages in prognosis, including achieving deep molecular response, rapid remission reduction, and decreased relapse probability, for both newly diagnosed and relapsed Ph+ ALL patients...The promising outcomes observed with 3G TKIs suggest their potential as a treatment option for both newly diagnosed and relapsed Ph+ ALL patients, offering advantages in terms of molecular response depth, rapid remission, and reduced relapse risk. Further investigations are warranted to explore the clinical significance of unreported ABL1 KD mutations and validate the effectiveness of 3G TKIs against them.

There were 22 CML-CP and 23 CML-AP patients previous received 3rd Gen TKIs (ponatinib or HQP1351) or asciminib. 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.

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...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)...Olverembatinib was observed to be better tolerated and more effective than BAT in treating these pts. Internal study (CT.gov) numbers: HQP1351CC203 (NCT04126681).

Pts were treated with a combination of venetoclax (100 mg d1, 200 mg d2, 400 mg d3-28), olverembatinib 40 mg once every continuously other day, vincristine 1.4 mg/m2 (maximum dose 2 mg) on day 1, 8, 15, 22, and prednisone 60 mg/m2 on day 1-14; 40 mg/m2 on day 15-28 in cycle 1...Routine triple intrathecal injection (methotrexate 10 mg, cytarabine 50 mg, and dexamethasone 10 mg) was performed to prevent central nervous system involvement...Conclusion The combination of olverembatinib and venetoclax with reduced-intensity chemotherapy is a safe and effective regimen in patients with newly diagnosed Ph+ ALL. The regimen results in high rates of CMR in the absence of intensive chemotherapy or immunotherapy.

Prophylactic oral levofloxacin and posaconazole were administered from day 8 through whole myelosuppression period of every cycles. MVHO therapy was effective and reasonably well tolerated in pediatric patients with refractory or relapsed AML, suggesting that it may comprise a suitable first-line treatment option for pediatric AML patients.

In the combination cohort, pts with Ph+ B-cell precursor (BCP) ALL or lymphoid CML-BP (CML-LBP) resistant to at least 1 TKI were enrolled and received olverembatinib (30 or 40 mg) QOD in combination with blinatumomab. Internal study identifier: HQP1351-CU101. Clinicaltrials.gov identifier: NCT04260022.

Background The combination of dasatinib and blinatumomab represented a chemotherapy-free treatment approach, which had been employed in the management of newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). A recent study demonstrated that combination therapy of ponatinib with blinatumomab may achieve better efficacy, with a complete molecular response (CMR) rate of 87%...However, further clinical trials are needed to definitively establish the efficacy of this treatment approach and validate the potential benefits. This research was supported by the National Natural Science Foundation of China(NFSC82170163, 81970147), Clinical Study of Nanfang Hospital(LC2016ZD009/2019CR012).

P1, N=60, Recruiting, Ascentage Pharma Group Inc. | Trial completion date: Mar 2024 --> Dec 2026 | Trial primary completion date: Sep 2023 --> Dec 2024

P1/2, N=30, Recruiting, Xijing Hospital

P2, N=60, Recruiting, Institute of Hematology & Blood Diseases Hospital, China | N=30 --> 60

This budget impact analysis suggests that the introduction of olverembatinib in national insurance result in cost saving in the first two years mainly and a moderate increase in the third year.

P3, N=350, Recruiting, Ascentage Pharma Group Inc. | Not yet recruiting --> Recruiting

P3, N=350, Not yet recruiting, Ascentage Pharma Group Inc.

Introduction Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) was historically associated with poor outcomes when treated with chemotherapy followed by allogeneic stem cell transplantation (ASCT).1 Four different BCR::ABL1 tyrosine kinase inhibitors (TKIs) have been combined with chemotherapy in patients with Ph-positive ALL, leading to improved outcomes: imatinib, dasatinib, nilotinib, and ponatinib...Future studies combining asciminib or olverembatinib with blinatumomab in the frontline setting are warranted...These strategies have reduced the incidence of toxicities and mitigated the need for ASCT. The incorporation of NGS for the detection of MRD can help select patients who may be candidates for TKI discontinuation.

No abstract available

In particular, the only previously available treatments for patients with CML-CP with the T315I mutation were ponatinib, olverembatinib (exclusively approved for use in China at the time of this writing), omacetaxine, and hematopoietic stem cell transplantation. While asciminib may overcome unmet needs for patients with CML-CP and continues to be studied in other novel settings, guidance on how to integrate asciminib in treatment algorithms is needed. This review focuses on clinical data and how asciminib can overcome current unmet needs, discusses how to individualize patient selection, and highlights future directions to investigate asciminib in earlier lines of therapy and in children and adolescents.

Treatment outcomes for children with Philadelphia chromosome-positive (Ph) acute lymphoblastic leukemia (ALL) remained poor despite the use of intensive chemotherapy, imatinib or dasatinib, and consolidative allogeneic hematopoietic cell transplantation. Safety profile in 6 evaluable patients was excellent with grade 2 extremity pain occurred in 2 patients and grade 2 myopathy of lower extremity and grade 3 fever in 1 patient each. Olverembatinib appeared to be safe and effective in children with relapsed Ph ALL.

P2, N=22, Not yet recruiting, The First Affiliated Hospital of Soochow University

No abstract available

Recently approved by FDA, the first-of-its-kind STAMP inhibitor asciminib has proven safe and effective, obtaining deep and stable molecular responses even in heavily pretreated patients and with T315I mutation...Among these, novel agents such as vodobatinib and olverembatinib have provided promising result in clinical trials, representing valuable therapeutic possibilities in intolerant or refractory patients. Therefore, a more complex therapeutic paradigm is expected in the near future.

Previous studied showed that ponatinib, combined with Hyper-CVAD, result in modest rates of complete molecular response (CMR) of 75% in three months. The results of olverembatinib combined with PDT-ALL-2016 pediatric-inspired protocol continue to demonstrate excellent outcome results and acceptable safety data, indicating that this strategy maybe another standard of care approach in frontline Ph-positive ALL and further clinical trial is needed to conduct. (This work was supported by National Natural Science Foundation of China [81770170, 81970147, 82170163], Science and Technology Planning Project of Guangdong [2017A030313601], Clinical Trial Funding of SMU [2016A020215112], Clinical Trial Funding of Nanfang Hospital [LC2016ZD009/2019CR012])

In this exploratory study, adult Ph/BCR-ABL1+ ALL pts with T315I mutation or disease progression were treated with olverembatinib monotherapy (40mg, every 2 days) or in combination with VP based low intensive chemotherapy (Vincristine/Prednisone). The novel third-generation TKI Olverembatinib is effective and safe in Chinese adult Ph/BCR-ABL1+ ALL with molecular or hematological R/R disease, especially in pts with T315I mutation. In addition, bridging allo-HSCT after MRD clearance could be a better choice to improve PFS and OS. These results laid an essential foundation for subsequent prospective clinical trials.

In the frontline therapy of CML in the chronic phase (CML-CP), imatinib and the three second-generation TKIs (bosutinib, dasatinib and nilotinib) are associated with comparable survival results...The TKI dosing is more flexible than has been described in the registration trials, and dose adjustments can be considered both in the frontline and later-line settings (e.g., dasatinib 50 mg frontline therapy; dose adjusted schedules of bosutinib and ponatinib), as well as during an ongoing TKI therapy to manage toxicities, before considering changing the TKI...Asciminib is a third-generation TKI with possibly a better toxicity profile, but lesser activity in T315I-mutated CML. Olverembatinib is another potent third-generation TKI with early promising results.

In recent years, TKIs, including axitinib, lenvatinib, and cabozantinib, plus immunotherapy have been approved to treat advanced RCC...Taken together, these data suggest that combining olverembatinib with a CPI confers synergistic antitumor effects in an RCC cancer mouse model by targeting tumor growth, angiogenesis, and immune regulation. This novel combination may provide an alternative approach to enhance treatment effects with CPIs in renal cancers.

Our results demonstrate that olverembatinib and BCL-2 inhibitor lisaftoclax have additive antitumor effects in imatinib-resistant GIST. This novel dual approach may have the potential for treating patients with GISTs whose disease has progressed after treatment with TKIs.