Olverembatinib: A Game Changer in CML and Ph+ ALL Treatment
Thursday, Nov 21, 2024 9:24 pm ET
4min read The battle against chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) has taken a significant turn with the emergence of olverembatinib. This novel BCR::ABL1 tyrosine kinase inhibitor (TKI) has demonstrated remarkable potential in overcoming resistance to ponatinib and asciminib, two previously approved TKIs, while maintaining a well-tolerated safety profile. A recent report published in JAMA Oncology highlights the promising results of a phase Ib multicenter clinical trial (NCT04260022) that evaluated the efficacy and safety of olverembatinib in heavily pretreated patients with CML and Ph+ ALL.
The trial enrolled 80 patients, with approximately 57% having chronic-phase CML (CP-CML) and 43% having advanced Ph+ leukemia. The median age was 54 years, and 56.6% of the patients were male. The study population was heavily pretreated, with 18% having received two prior TKIs, 28% three, and 54% at least four. Notably, 46 patients (57.5%) had received ponatinib, 25 (31.3%) asciminib, and 11 (13.8%) both medications.
The primary objective of the trial was to determine the recommended phase 2 dose of olverembatinib. Patients were randomized to receive oral olverembatinib 30, 40, or 50 mg on alternate days. The study found that olverembatinib was well tolerated, with leading treatment-emergent adverse events including elevated blood creatine phosphokinase and thrombocytopenia, typically mild or moderate. There were no fatal treatment-related adverse events, and treatment-related arterial occlusive events were infrequent (3%) and mild or moderate.
The trial demonstrated that olverembatinib showed sustained antileukemic activity in patients with CML and Ph+ ALL. Among evaluable patients with CP-CML, the complete cytogenetic response (CCyR) rate was approximately 61%, and the major molecular response (MMR) rate was around 42%. Notably, olverembatinib's efficacy was similar in patients with or without the T315I mutation, which confers resistance against imatinib and other second-generation TKIs. The drug also showed activity in patients who had previously failed ponatinib or asciminib therapy, with CCyR rates of 58% and 50%, respectively.
The broad mutational coverage of olverembatinib, spanning the pan-BCR::ABL1-kinase domain, contributes to its ability to overcome ponatinib and asciminib resistance. This is particularly evident in patients with compound mutations, where olverembatinib demonstrates greater sensitivity and clinical benefit compared to other approved TKIs and the STAMP inhibitor asciminib. By addressing critical unmet clinical needs related to TKI treatment resistance and intolerance, olverembatinib may help alleviate humanistic and economic burdens, especially in heavily pretreated patients with suboptimal outcomes.
In conclusion, the recent report in JAMA Oncology highlights the potential of olverembatinib as a valuable addition to the treatment landscape for CML and Ph+ ALL. Its broad mutational coverage, ability to overcome resistance to other TKIs, and well-tolerated safety profile make it an attractive option for patients with limited alternatives. As olverembatinib advances through clinical trials, it may become a crucial treatment option for patients with CML and Ph+ ALL, particularly those who have failed previous therapies.
The trial enrolled 80 patients, with approximately 57% having chronic-phase CML (CP-CML) and 43% having advanced Ph+ leukemia. The median age was 54 years, and 56.6% of the patients were male. The study population was heavily pretreated, with 18% having received two prior TKIs, 28% three, and 54% at least four. Notably, 46 patients (57.5%) had received ponatinib, 25 (31.3%) asciminib, and 11 (13.8%) both medications.
The primary objective of the trial was to determine the recommended phase 2 dose of olverembatinib. Patients were randomized to receive oral olverembatinib 30, 40, or 50 mg on alternate days. The study found that olverembatinib was well tolerated, with leading treatment-emergent adverse events including elevated blood creatine phosphokinase and thrombocytopenia, typically mild or moderate. There were no fatal treatment-related adverse events, and treatment-related arterial occlusive events were infrequent (3%) and mild or moderate.
The trial demonstrated that olverembatinib showed sustained antileukemic activity in patients with CML and Ph+ ALL. Among evaluable patients with CP-CML, the complete cytogenetic response (CCyR) rate was approximately 61%, and the major molecular response (MMR) rate was around 42%. Notably, olverembatinib's efficacy was similar in patients with or without the T315I mutation, which confers resistance against imatinib and other second-generation TKIs. The drug also showed activity in patients who had previously failed ponatinib or asciminib therapy, with CCyR rates of 58% and 50%, respectively.
The broad mutational coverage of olverembatinib, spanning the pan-BCR::ABL1-kinase domain, contributes to its ability to overcome ponatinib and asciminib resistance. This is particularly evident in patients with compound mutations, where olverembatinib demonstrates greater sensitivity and clinical benefit compared to other approved TKIs and the STAMP inhibitor asciminib. By addressing critical unmet clinical needs related to TKI treatment resistance and intolerance, olverembatinib may help alleviate humanistic and economic burdens, especially in heavily pretreated patients with suboptimal outcomes.
In conclusion, the recent report in JAMA Oncology highlights the potential of olverembatinib as a valuable addition to the treatment landscape for CML and Ph+ ALL. Its broad mutational coverage, ability to overcome resistance to other TKIs, and well-tolerated safety profile make it an attractive option for patients with limited alternatives. As olverembatinib advances through clinical trials, it may become a crucial treatment option for patients with CML and Ph+ ALL, particularly those who have failed previous therapies.
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