Olverembatinib for heavily pretreated BCR::ABL1-positive leukemia, including resistance or intolerance to ponatinib and/or asciminib

The prognosis of patients with chronic myeloid leukemia (CML) improved dramatically with the introduction of the tyrosine kinase inhibitor (TKI) imatinib in 2001. Subsequent development of second-generation TKIs has meant that many patients no longer experience disease progression, and in developed countries, life expectancy is now similar to that of people without CML (1). In the past, the goal of CML treatment was to prevent the transformation to blast phase, but now that deep remission and long-term survival can be achieved in many cases, the goal of treatment has shifted to achieving long-term treatment-free remission (TFR) (2,3). The prognosis of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) has also been improving with the addition of TKIs to conventional chemotherapy (4-6). However, resistance or intolerance to TKIs remains a challenge. In particular, ponatinib, a third-generation TKI, is effective against the T315I variant, which is the most common variant occurring in approximately 20% of TKI-resistant CML cases and is resistant to first- and second-generation TKIs (7,8), but there are limited treatment options for patients who become resistant or intolerant to ponatinib. Unlike ABL-TKIs, which target the adenosine triphosphate (ATP) binding site, asciminib is a drug that shows an antitumor effect by binding to the myristoyl pocket, which regulates ABL activity (9), and it has been reported that its therapeutic effect in the third-line treatment of CML and beyond is similar to that of ponatinib (10,11). However, in patients who received asciminib treatment, the progression-free survival (PFS) rate at 12 months for ponatinib pre-treated patients was significantly lower than for ponatinib-naive patients (12). In addition, another study has shown that it is difficult to achieve a deeper therapeutic effect using asciminib in patients with CML who are resistant to TKIs, including those resistant to ponatinib (13). Therefore, patients who are resistant to ponatinib or who are resistant or intolerant to asciminib need further therapeutic options.

Olverembatinib is a new third-generation TKI that is currently approved and marketed in China for the treatment of adult patients with chronic phase CML (CP-CML) who are resistant to TKIs or with the T315I variant (14). Olverembatinib was designed using scaffold-hopping strategies that create extensive donor-acceptor hydrogen bond networks, and by adding one hydrogen bond, olverembatinib bind more tightly to non-phosphorylated (DFG-out) BCR::ABL1, including the T315I variant, than ponatinib; it is also able to bind to phosphorylated BCR::ABL1 with a DFG-in conformation (14,15). Olverembatinib shows more potent activity than all other TKIs including ponatinib and asciminib in the growth inhibition assay of BCR::ABL1-positive cells expressing various variants including T315I and compound variants in vitro (16). In phase I/II clinical trials in China, a total of 165 patients with CP-CML or accelerated phase (AP)-CML were treated with olverembatinib, 62% had a single T315I variant, and 82% had ≥2 TKIs. In patients with CP-CML, 3-year cumulative incidences of complete cytogenetic response (CCyR) and the major molecular response (MMR) rate were 69% and 56%, respectively. In patients with AP-CML, 3-year cumulative incidences of CCyR and the MMR rate were 47% and 45%, respectively. The Phase II study included only patients with T315I variants. In CP-CML, the estimated 3-year PFS and overall survival (OS) were 92% and 94%, respectively. In AP-CML, the estimated 3-year PFS and OS were 60% and 71%, respectively (17). These results suggest that the efficacy of olverembatinib is comparable to that of ponatinib or asciminib (7,9). However, the main limitations of this study were that it only included data from Chinese patients, and it did not include patients who had ponatinib failure or asciminib failure.

In the recent article in JAMA Oncology entitled “Olverembatinib After Failure of Tyrosine Kinase Inhibitors, Including Ponatinib or Asciminib: A Phase 1b Randomized Clinical Trial”, Jabbour et al. reported the pharmacokinetic profile, tolerability and strong antileukemic activity of olverembatinib in non-Chinese patients with heavily pretreated BCR::ABL1-positive leukemia (18).

This trial involved 80 patients with CML or Ph-positive ALL resistant or intolerant to at least 2 TKIs, of whom 65 (81%) had received ≥3 TKIs. A total of 25 patients (31%) had a T315I variant, and there was no restriction on the number of prior treatments for patients with the T315I variant. Ponatinib and asciminib were administered to 46 (58%) and 25 (31%) patients, respectively, and 11 patients (14%) were refractory to both ponatinib and asciminib. A total of 62 patients with CP-CML were enrolled, of whom 18 patients (29%) had the T315I variant. A total of 18 (29%) and 32 (51.6%) patients had received 3 or ≥4 TKIs, respectively. Of the 31 (50%) patients treated with ponatinib, 21 (33.9%) were resistant, with 7 (11.3%) intolerant and 3 (4.8%) other. In 17 (27.4%) patients treated with asciminib, 12 (19.4%) were resistant, with 3 (4.8%) intolerant and 2 (3.2%) other. Pharmacokinetic studies of olverembatinib showed that the systemic exposure increased in proportion to the dose when administered every other day, that the absorption was slow, with a mean terminal elimination half-life of about 20 hours, and that it was suitable for alternative-day administration. After a median follow-up duration of 48 weeks (range, 0–166 weeks), 31 of 51 (61%) evaluable patients with CP-CML achieved CCyR, and 42% achieved MMR. Similar response rates were observed regardless of T315I variant status, with CCyR achieved by 56% of patients with the T315I variant and 64% without it, and MMR was achieved by 44% and 42%, respectively (Table 1). Of 26 evaluable patients with ponatinib-failed CP-CML, 15 (58%) achieved CCyR, including 53% with ponatinib resistance and 75% with intolerance. Among 30 evaluable patients previously treated with ponatinib, 11 (37%) achieved MMR, including 43% with prior resistance and 17% with intolerance. Most cases of ponatinib resistance that responded to olverembatinib had the T315I variant. In evaluable patients with asciminib resistance, 4 of 8 patients (50%) achieved CCyR, and 33% achieved MMR. The MMR rate of patients who were resistant to both ponatinib and asciminib was 27%. The median duration of olverembatinib treatment was 48 weeks, 53 patients (66%) were able to continue treatment, and there were no fatal treatment-related adverse events (TRAE). Of the 15 cases where treatment was discontinued, 4 (27%) were due to adverse events. Thrombocytopenia was the most frequent hematologic treatment-emergent adverse events (TEAEs) (29%; grade 3–4: 18%), followed by neutropenia (19%; grade 3–4: 13%) and anemia (10%; grade 3–4: 6%). The most commonly reported non-hematologic TEAEs (≥20%) were elevated blood creatine phosphokinase, nausea, fatigue, and elevations in transaminase levels. Treatment-related arterial occlusive events (AOEs) were observed in 2 cases (3%) of grade 1 or 2. These results suggest that olverembatinib is generally safe and has a strong anti-leukemic effect, even in CP-CML patients refractory to ponatinib and/or asciminib.

Although the exact mechanism by which olverembatinib overcomes ponatinib resistance is unknown, the following inferences can be made based on its characteristics. By adding one hydrogen bond, olverembatinib bind to both non-phosphorylated and phosphorylated BCR::ABL1 (14). On the other hand, ponatinib can only bind to non-phosphorylated BCR::ABL1 (19). The T315I variant is known to stabilize the active ABL kinase conformation (DFG-in), and this may be the reason why olverembatinib, which can also bind to phosphorylated ABL1, is effective in cases of T315I variant that are resistant to ponatinib. The median follow-up period was 48 weeks, which is a short period, so early safety and adverse events are acceptable, but the safety of long-term use is unknown. In particular, it has been reported that AOEs may occur as early as 12 months with TKIs (20), but even taken into account, the follow-up period in this trial was short. Close monitoring with longer follow-up is necessary to assess the therapeutic efficacy, safety and adverse events associated with long-term use. In the near future, it is expected that the number of cases in which asciminib is used as first-line treatment will increase. The results of this study in patients pretreated with asciminib (resistant cases) suggest that the therapeutic effect of olverembatinib on such cases is promising. A randomized, phase III trial comparing olverembatinib with bosutinib in patients with CP-CML who failed at least 2 prior TKI therapies (POLARIS-2 trial) is currently underway, and it will clarify the efficacy and safety of olverembatinib in T315I variant-positive CML. It is desirable to conduct a clinical trial with a larger number of cases to verify the efficacy of olverembatinib in CML patients who failed ponatinib and/or asciminib.

The study also included 18 patients with advanced leukemia, of whom 3 had Ph-positive ALL. The number of ALL cases is too small to make a reliable evaluation, and the authors state that this is a limitation. Liu et al. retrospectively analyzed efficacy and safety in 31 relapsed/refractory (R/R) Ph-positive ALL (including 24 with the T315I variant) cases that received olverembatinib. In this study, approximately 40% of patients achieved minimal residual disease (MRD) negativity with olverembatinib in combination with chemotherapy (21). The report has documented 2 cases of R/R T315I-mutated Ph-positive ALL treated with olverembatinib and blinatumomab (22). In both cases, MRD became negative early after one course, but because allogeneic transplantation was performed afterwards, the long-term efficacy of this chemotherapy-free regimen is unknown. However, it may be a promising treatment for R/R Ph-positive ALL, along with blinatumomab plus ponatinib therapy, which has been reported to have a very high response rate (23).

In conclusion, the study by Jabbour et al. showed that the pharmacokinetics and tolerability of olverembatinib in non-Chinese patients with CP-CML were comparable to the data from the Chinese clinical trial. In addition, olverembatinib also showed promising efficacy in heavily pretreated patients who were resistant or intolerant to ponatinib or asciminib, indicating the potential to address unmet clinical needs. However, it is most important to confirm the safety and therapeutic effects after longer-term use. Although many of the toxicities seem to be relatively manageable in the short term, the number of cases is small, so it is hoped that this will become clear through larger-scale studies in the future. Further investigation is warranted to elucidate the mechanism by which olverembatinib may overcome resistance to ponatinib and asciminib. Well-designed clinical trials will also be necessary.

Acknowledgments

I thank FORTE Science Communications (https://www.forte-science.co.jp/) for English language editing.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine. The article has undergone external peer review.

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Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-25-28/coif). The author has no conflicts of interest to declare.

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