Olverembatinib Demonstrates Efficacy and Safety in Heavily Pretreated CP-CML

Treatment with olverembatinib (HQP1351) demonstrated preliminary efficacy and was well tolerated in patients with heavily pretreated chronic-phase chronic myeloid leukemia (CP-CML), according to a 1.5-year follow-up data from a phase 1b trial (NCT04260022) shared in a poster presentation at the 2024 ASH Annual Meeting.

In the evaluable population of patients treated with olverembatinib (n = 60), the complete cytogenetic response (CCyR) rate was 58.3%, and the major molecular response (MMR) rate in evaluable patients (n = 64) was 45.3%. When breaking up responses by dose, the CCyR was 57.7% in the 30-mg dose group (n = 26), 57.7% in the 40-mg dose group (n = 26), and 62.5% in the 50-mg dose group (n = 8). The MMR rates were 46.6% for the 30-mg group (n = 28), 46.4% for the 40-mg group (n = 28), and 37.5% for the 50-mg group (n = 8).

When broken down by BCR::ABL1 T315I mutation status, those patients harboring the mutation (n = 18) had a CCyR of 66.7%, and those without the mutation (n = 42) had a CCyR of 54.8%. The MMR rates were 50.0% and 43.35%, respectively

“Olverembatinib showed preliminary efficacy and was well tolerated at doses of up to 50 mg administered every other day in patients with heavily treated CML, including ponatinib [Iclusig]- or asciminib [Scemblix]-resistant or -intolerant disease,” Elias Jabbour, MD, and colleagues wrote in the poster presentation of data. Jabbour is a professor in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston.

Understanding the Investigation of Olverembatinib

Olverembatinib is a novel, potent BCR::ABL1 TKI that has demonstrated antitumor activity in patients with CP-CML.

Adult patients with CP-CML, irrespective of BCR::ABL1 T315I mutation status, were eligible for enrollment on the trial. These patients needed to be resistant or intolerant to 2 or more TKIs, have an ECOG performance score of no more than 2, and have adequate organ function. Patients were not eligible for enrollment if they have certain cardiovascular diseases.

Patients were randomly assigned to olverembatinib at 30 mg, 40 mg, or 50 mg doses every other day in 28-day cycles. The primary end points of the trial evaluated for efficacy, safety, and pharmacokinetics.

All enrolled patients (n = 66) had a median age of 50.5 years (range, 21-80) and a majority of patients were male (56.1%). Furthermore, a total of 51.5% of patients had preexisting cardiovascular comorbidities, and 27.3% harbored BCR::ABL1 T315I mutations.

Patients were previously treated with either 2 (18.2%), 3 (30.3%), or 4 or more (51.5%) TKIs. Forty-seven percent of patients (n = 31) received prior ponatinib, and within this group, 22.6% were intolerant to the agent, and 74.2% were resistant. Prior asciminib was given to 30.3% of patients (n = 20), and within this population, 20% were intolerant, and 75% were resistant.

At the July 1, 2024, data cutoff, the median follow-up of treatment was 73.3 weeks (range, 12-197), and the median duration of treatment was 59.4 weeks (range, 0-191).

Further Exploring Data With Olverembatinib

Investigators evaluated CCyR and MMR in patients with CP-CML who had been pretreated with ponatinib or asciminib. Evaluable patients who were resistant or intolerant to treatment with ponatinib (n = 28) had a CCyR rate of 53.6% and an MMR rate of 40.0%. These respective rates in evaluable patients previously treated with asciminib (n = 16) were 37.5% and 30.0%, respectively.

When looking at responses further broken up, patients who were resistant to ponatinib (n = 23) had a CCyR rate of 52.2%, whereas those who were intolerant to ponatinib (n = 4) had a CCyR rate of 75.0%. Those who were resistant to ponatinib (n = 23) had an MMR rate of 47.8%, and those who were intolerant (n = 6) had an MMR rate of 16.7%. In patients who were asciminib-resistant and -intolerant (n = 13; n = 2), the CCyR rates were 30.8% and 50%, respectively, whereas the MMR rates in patients who were asciminib-resistant and -intolerant (n = 15; n = 4) was 26.7% and 25.0%, respectively.

A total of 93.9% of patients enrolled on the study (n = 66) experienced a treatment-emergent adverse effect (TEAE) at any grade, and 66.7% experienced a grade 3 or higher TEAE. The most common all-grade TEAEs included increased blood creatine phosphokinase levels (48.5%), thrombocytopenia (30.3%), increased lipase levels (28.8%), increased alanine aminotransferase levels (27.3%), increased aspartate aminotransferase levels (25.8%), fatigue (25.8%), vomiting (25.8%), constipation (24.2%), myalgia (24.2%), and nausea (24.2%).

The most common grade 3 or higher TEAEs included thrombocytopenia (19.7%), increased blood creatine phosphokinase levels (13.6%), neutropenia (13.6%), increased AST levels (9.1%), fatigue (6.1%), vomiting (4.5%), nausea (4.5%), increased ALT levels (3.0%), and anemia (3.0%).

Serious TEAEs (45.5%) included intestinal obstruction (4.5%), noncardiac chest pain (4.5%), anemia (3.0%), atrial fibrillation (3.0%), COVID-19 (3.0%), embolism (3.0%), febrile neutropenia (3.0%), pain in extremity (3.0%), pneumonia (3.0%), increased troponin levels (3.0%), and urinary tract infection (3.0%); however, intestinal obstruction, noncardiac chest pain, COVID-19, pain in extremity, pneumonia, and urinary tract infection were not related with olverembatinib.

No treatment-related AEs led to death. No significant exposure-safety relationship for grade 3 or higher treatment-related AEs (TRAEs) or TEAEs, serious TEAEs, serious TRAEs, or neutropenia were reported.

“Based on these and other findings, a global randomized phase 3 registrational study [called] POLARIS-2 [NCT06423911] of olverembatinib in patients with CP-CML was initiated and is in progress,” Jabbour concluded.

The POLARIS-2 study is active and is continuing to recruit patients.

Reference

Jabbour E, Jamy O, Koller PB, et al. Olverembatinib (HQP1351) overcomes resistance/intolerance to asciminib and ponatinib in patients (pts) with heavily pretreated chronic-phase chronic myeloid leukemia (CP‑CML): a 1.5-year follow-up update with comprehensive exposure-response (E-R) analyses. Blood. 2024;144(suppl 1):3151. doi:10.1182/blood-2024-207139