Results of a phase 1 clinical trial showed that approximately 66% of patients with chronic-phase chronic myeloid leukemia (CML) had a major cytogenetic response (MCyR) to the novel oral BCR-ABL1 tyrosine kinase inhibitor (TKI) vodobatinib, regardless of whether they previously received ponatinib therapy. Jorge E. Cortes, MD, Director, Georgia Cancer Center, Augusta University, presented the results at ASH 2020.
“We have seen efficacy in a heavily pretreated patient population, and the efficacy seems to be comparable for ponatinib-naïve and ponatinib-treated patients. Responses are present and are durable, despite a number of prior therapies, including prior TKIs,” Dr Cortes said. “The findings merit further study of vodobatinib as a potential new agent for the treatment of previously treated chronic-phase CML,” he added.
Vodobatinib is a novel third-generation TKI that has shown efficacy against wild-type CML and CML with BCR-ABL1 mutations. “It was designed to be potent and selective,” Dr Cortes explained.
Study Design
This phase 1 clinical trial was a multicenter dose-escalation study of vodobatinib in patients with chronic-phase CML who received ≥3 previous TKIs. The investigators focused on comparing vodobatinib’s activity in patients who did versus those who did not receive previous ponatinib therapy.
Patients received escalating doses of vodobatinib once daily in 28-day cycles, with doses between 12 mg and 240 mg evaluated in 31 patients, including 15 ponatinib-naïve patients and 16 ponatinib-treated patients.
The patients in the ponatinib-treated group were more likely to have received at least 3 TKIs, as well as omacetaxine and interferon or peginterferon, and to have cardiovascular comorbidities. The patients in the ponatinib-naïve group were more likely to have mutations at baseline, although double mutations were more common in the ponatinib-treated group.
At study entry, the majority of patients in both cohorts had a complete cytogenetic response (CCyR), and approximately 40% in each cohort had a partial CCyR. Molecular responses were rare, and approximately 60% in each cohort had >10% transcripts at baseline.
The maximum tolerated dose was 204 mg, and the recommended dose was 174 mg. An expansion phase 2 study will evaluate patients who receive 174 mg.
Response by Ponatinib Treatment Status
Across all doses, MCyR to vodobatinib was observed in 21 of the 31 (68%) evaluable patients with chronic-phase CML. The efficacy according to previous ponatinib treatment was similar, Dr Cortes reported.
In the ponatinib-naïve cohort, 9 of the patients did not achieve MCyR at study entry. Treatment with vodobatinib led to MCyR in 10 of the 15 (67%) patients in that group. This included 3 patients who maintained CCyR since baseline, and 7 patients who achieved CCyR with vodobatinib.
In the patients who had received ponatinib treatment, 11 patients had MCyR after treatment with vodobatinib. This included 4 patients who maintained a response from baseline and an additional 7 patients who had a complete or a partial response to vodobatinib.
Molecular responses deepened over time, with a trend for better responses in patients who received the optimal dose of ≥174 mg. Responses were achieved in both cohorts. Many of the responses are durable, with the majority of patients in both cohorts continuing vodobatinib therapy to 18 cycles and beyond.
Safety Profile
“A well-tolerated safety profile was seen in both treatment groups,” said Dr Cortes. The most common hematologic treatment-related adverse events were thrombocytopenia (10%), neutropenia (10%), and anemia (6%), which were grade 3 or 4.
Other adverse events included constitutional symptoms, gastrointestinal symptoms, pruritus, rhinitis, dizziness, and headache. In addition, 4 nonserious cardiovascular events were reported in 3 patients, mostly arrhythmias and palpitations, which were deemed unrelated to the study drug.
A total of 3 serious adverse events were related to vodobatinib, including fatal intracranial hemorrhage, back pain, and worsening amnesia. A total of 3 deaths occurred during the study, 2 because of disease progression and 1 caused by pneumonia believed to be related to COVID-19 disease.
A multinational phase 2 clinical trial is now ongoing in patients who have not responded to or are intolerant of ponatinib therapy.