Approximately two-thirds of patients with chronic-phase chronic myeloid leukemia (CML) achieved a major cytogenetic response to the novel oral BCR-ABL1 tyrosine kinase inhibitor (TKI) vodobatinib, regardless of whether they had received previous treatment with ponatinib (Iclusig), according to findings from a recent phase 1 clinical trial.
“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,” said Jorge E. Cortes, MD, Director, Georgia Cancer Center, Augusta University, who presented results from this study at the virtual 2020 ASH Annual Meeting.
“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 and mutated BCR-ABL1 (and the majority of relevant mutations) with limited off-target activity, in patients with CML. “It was designed to be potent and selective,” Dr Cortes noted.
Clinical Trial Design
In the phase 1 multicenter dose-escalation study of vodobatinib in patients with chronic-phase CML who had failed at least 3 previous TKIs (or less, if ineligible for other approved third-generation TKIs), investigators compared the drug’s activity in patients with and without previous treatment with ponatinib. Patients received escalating doses of vodobatinib once daily in 28-day cycles, with doses of 12 mg to 240 mg evaluated in a total of 40 patients.
Patients in the ponatinib-treated group were more likely to have received at least 3 TKIs as well as omacetaxine (Synribo) and interferon/peginterferon in addition to TKIs, and to have cardiovascular comorbidities. Patients in the ponatinib-naïve group, however, were more likely to have mutations at baseline, although double mutations were more common in the ponatinib-treated group.
The majority of patients in both cohorts had achieved a complete hematologic response and approximately 40% in each cohort had achieved a partial or complete cytogenetic response at the time of enrollment in the study. Molecular responses were rare, and approximately 60% of patients in each cohort had >10% transcripts at baseline.
The maximum tolerated dose of ponatinib was determined to be 204 mg, and the recommended phase 2 dose is 174 mg. An expansion phase will evaluate patients receiving a 174-mg dose.
Across all doses, a major cytogenetic response to vodobatinib was observed in 21 of 31 (68%) evaluable patients with chronic-phase CML. Efficacy according to previous ponatinib treatment was similar, Dr Cortes said.
Although none of the 9 ponatinib-naïve patients had achieved a cytogenetic response at the time of study entry, treatment with vodobatinib led to major cytogenetic responses in 10 of 15 (67%) patients. This included 3 patients who maintained the complete cytogenetic response they had at baseline, and 7 who achieved one with vodobatinib, he said.
In the ponatinib-treated group, 10 of 16 patients entered the study without a cytogenetic response, and 11 achieved a major cytogenetic response after treatment with vodobatinib. This included 4 who maintained a response from baseline and an additional 7 who achieved a complete or partial response to vodobatinib.
Molecular responses deepened over time, with a trend for better responses in patients treated with the optimal dose of ≥174 mg. Responses were achieved in both cohorts.
Many of the responses have been durable, with the majority of both cohorts continuing on therapy to 18 cycles and beyond.
“A well-tolerated safety profile was seen in both treatment groups,” said Dr Cortes, who noted that the most common hematologic treatment-related adverse events were thrombocytopenia, neutropenia, and anemia, which were grade ≥3 in 10%, 10%, and 6%, respectively.
Other treatment-related adverse events included constitutional symptoms, gastrointestinal symptoms, pruritis, rhinitis, dizziness, and headache. There were 4 “non-serious” cardiovascular events in 3 patients, mostly arrhythmias and palpitations deemed unrelated to study drug.
Three serious adverse events were related to vodobatinib—fatal intracranial hemorrhage, back pain, and worsening amnesia. Three deaths occurred; 2 were attributed to disease progression and 1 to pneumonia believed to be related to COVID-19.
A multinational phase 2 study is ongoing in patients who have progressed on, or are intolerant to, ponatinib therapy.