Efficacy Produced from Olverembatinib in Ponatinib-Resistant, T25I-Mutant CML, and Ph-Positive ALL

Results from a phase 1 trial (NCT04260022) were found to have increased responses and durability when olverembatinib was given to patients with chronic myeloid leukemia (CML), Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL), and those with CML whose tumors have a T315I mutation, compared with ponatinib (Iclusig), according to a presentation from the 2022 American Society of Hematology (ASH) Annual Meeting.¹

At a median follow-up of 9 months, results showed that in 23 evaluable patients with resistant CML, 77.8% of patients achieved a complete cytogenetic response (CCyR) and 43.5% of patients achieved a major molecular response (MMR) with olverembatinib. Response rates were similar regardless of whether patients received olverembatinib at 30 mg every other day or 40 mg every other day.

In patients who had previously failed on ponatinib, the CCyR rate was 83.3% and the MMR rate was 42.9%. In those with BCR-ABL T315I-mutant tumors, the CCyR rate was 87.5% and the MMR rate was 55.6%. These rates were 70% and 35.7%, respectively, in those who did not harbor the T315I mutation.

Seven of 13 patients with Ph-positive ALL were evaluable for responses, and 2 responded. Here, the MCyr was 42.9%, the CCyR was 28.6% achieved a CCyR, and the MMR was 28.6%.

The 2 responders did not have a T315I mutation and had received prior ponatinib.

“Olverembatinib has a favorable pharmacokinetics [PK] profile and will provide similar [data] to what was reported already [with the agent] in a Chinese patient population,” lead study author, Elias Jabbour, MD, a professor of medicine in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, in Houston, Texas, said in a presentation on the data. “The treatment has been shown to be effective and safe, particularly in patients who had resistance to ponatinib with a T315I mutation.”

The utilization of the novel, third-generation TKI olverembatinib previously provided promising preliminary data, including a favorable safety profile, in a Chinese patient population with CML and Ph-positive ALL.² These data led to the rationale of this pharmacokinetic-driven, bridging phase 1 trial, which evaluated a similar patient population in the United States.

To be eligible for enrollment, patients aged 18 years or older had either CML-chronic phase (CP), or Ph–positive ALL in accelerated phase or blast phase. Patients must have failed on and been resistant or intolerant to 2 prior BCR-ABL1 inhibitors. Additionally, patients were required to have an ECOG performance score of 0 or 1 and have adequate cardiac, hepatic, and renal function. The phase 1 trial excluded those with CML-CP if they had already achieved a CCyR on previous therapy.

Investigators randomized 51 patients 3:3:2 to 30 mg of olverembatinib once daily (n = 21), 40 mg of olverembatinib once daily (n = 18), and 50 mg of olverembatinib once daily (n = 10). Each cycle lasted for 28 days.

Patients were stratified by leukemia phases and their T315I mutation status at baseline.

The primary end point was pharmacokinetics, primarily looking at maximum plasma concentration and systemic exposure of area under plasma concentration: time curve. Secondary end points include efficacy and safety.

Regarding baseline characteristics, 38 patients had CML and 13 patients had Ph-positive ALL. The overall median age was 51 years old (range, 21-79), and more than half of patients were male (54.9%) and most were White (80.4%). Additionally, 41.2% of patients had an ECOG score of 0, 27.5% had a score of 1, and 3.9% had a score of 2.

A total of 54.9% of patients had a cardiovascular comorbidity, while 35.3% of patients had hypertension.

“More than half of patients had comorbidities, mainly cardiovascular risk factors that can include dyslipidemia, carotid disease, and obesity, etc.,” Jabbour added.

The majority were in their second salvage line of therapy and beyond, as nearly 77% of the patient population had already failed 2 or more TKIs. In the overall patient population 54.9% of patients had failed prior ponatinib, 75% of whom were resistant to the TKI. A total 37.3% of patients had a T315I mutation.

Pharmacokinetic data showed that was an approximate dose proportional increase in systemic exposure from 30 mg to 50 mg of olverembatinib every other day. These data were aligned with pharmacokinetic findings with the Chinese population, Jabbour said.

Eleven patients discontinued treatment due to adverse events (AEs; n = 2), thrombocytopenia and leukopenia (n = 1), worsening vascular issues (n = 1), disease progression (n = 3), and other (n = 6).

Regarding safety, grade 3/4 non-hematologic AEs included increased blood creatine phosphokinase (13.5%), increased lipase (5.4%), increased alanine aminotransferase (5.4%), increased aspartate aminotransferase (5.4%), arthralgia (2.7%), abdominal pain (2.7%), and increased Troponin T (2.7%).

Grade 3/4 hematologic AEs included thrombocytopenia, neutropenia, and leukopenia occurred in 18.9% and 16.2% of patients, respectively.

Eight serious AEs were reported in 6 patients, including blood creatine phosphokinase increase (n = 2), troponin I increase, obstructive pancreatitis, generalized edema, atrial fibrillation, sinus tachycardia, and neutropenia (n = 1 each). None of these led to treatment discontinuation.

Most patients who had previously failed ponatinib for intolerance were able to tolerate olverembatinib, Jabbour explained, adding that 1 patient withdrew from treatment due to an increased infection rate.

Artery occlusive events that were possibly linked to olverembatinib included 1 any-grade angina pectoris at the 40 mg dose level and 1 cardiac failure at the 50 mg dose level.

“The treatment was well tolerated. Although we have seen thrombocytopenia, neutropenia, and leukopenia, these were half the rate of what was reported already in patients in China,” Jabbour said on the rate of AEs in American patients.

References

1. Jabbour E, Koller PB, Oehler VG, et al. Olverembatinib (HQP1351) overcomes ponatinib resistance in patients with heavily pretreated/refractory chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ALL). Blood. 2022;140(suppl 1):200-202. doi:10.1182/blood-2022-162387
2. Jiang Q, Chen Zi, Niu Q, et al. Updated results of pivotal phase 2 trials of olverembatinib (HQP1351) in patients (pts) with tyrosine kinase inhibitor (TKI)-resistant chronic- and accelerated-phase chronic myeloid leukemia (CML-CP and CML-AP) with T315I mutation. Blood. 2022;140(suppl 1):203-204. doi:10.1182/blood-2022-170698