Novel TKI Shows Promise in Resistant Chronic Myeloid Leukemia

Investigational vodobatinib turned in respectable results in patient with chronic myeloid leukemia (CML) who were refractory to previous treatment with other tyrosine kinase inhibitors (TKIs), according to a phase I/II trial.

The global trial enrolled adults with Ph-positive CML or acute lymphoblastic leukemia (the latter were only allowed in phase I) and an ECOG performance status ≤2. Phase I had patients who had gotten at least three TKIs previously, or who had no other treatment options due to their country’s regulatory access,restrictive comorbid conditions, or insufficient insurance. Phase II called for patients to have treatment resistance or intolerance (or both) with loss of response to at least three TKIs and earlier ponatinib use, explained Jorge E. Cortes, MD of the Georgia Cancer Center-Augusta University, and co-authors.

Patients self-administered oral vodobatinib (dose ranging from 12-240 mg) once daily for each 28-day treatment cycle and for up to 60 months "unless patient discontinuation due to adverse events [AEs], progressive disease, lost to follow-up, or death," they wrote in the Lancet Haematology. "The primary endpoints were to determine the maximum tolerated dose (based on dose-limiting toxicities in phase I) and antileukemic activity of vodobatinib (ie, major cytogenetic response for chronic-phase and major hematological response for accelerated-phase or blast-phase in phase II). Assessment of vodobatinib safety, activity, and pharmacokinetics were determined based on the pooled analysis of data from the phase I and II studies."

In total, 78 patients were enrolled (n=58 in phase I; n=20 in phase II), with the trial phases running 2017-2023 and 2020-2023; phase II enrollment shut down early in summer 2023 because of "recruitment-related challenge," the authors reported. Median follow-up was about 22 months. The authors reported that:

• Based on two patient with dose-limiting toxicities while on the maximum vodobatinib dose, 204 mg was set as the maximum tolerated dose.
• At data cutoff, major cytogenetic response was observed in 70% of 63 patients with chronic-phase CML: 75% of 16 in that group had major cytogenetic response in phase II.
• At data cutoff, among patients with accelerated-phase CML, 86% of seven patients had a major hematological response with a median duration of 17.8 months; major hematological response was seen in three evaluable patients in phase II.
• Major hematological response was 50% of four patients with blast-phase CML with a median duration of response of 6.2 months; no blast-phase patients were enrolled in phase II.

The study was presented at the 2022 American Society of Hematology meeting. That same year at the John Goldman Conference on Chronic Myeloid Leukemia (ESH CML), Cortes told VJOncology that vodabatinib does not have value in patients with the Thr315Ile mutation, so they were excluded from the trial, but that the studied selective BCR::ABL1 fusiononcoprotein TKI does have "a very nice safety profile."

Regarding AEs, the authors reported that 94% patients had ≥1 treatment-emergent AEs, mostly hematological or gastrointestinal, and they were grade ≤2, in terms of severity, the authors noted. Grade ≥3 TRAEs occurred in 60% patients, predominantly thrombocytopenia (18%) followed by neutropenia (13%), anemia (12%), and increased lipase (10%).

They emphasized the relatively low toxicity rate with the agent, stating that "[v]odobatinib had a tolerable safety profile across all doses and [CML] phases, which is noteworthy for patients who were predominantly intolerant to previous TKIs at baseline…Most adverse events were non­serious…and reversible with treatment modifications."

In a comment accompanying the current study, Henrik Hjorth-Hansen, MD, of St Olavs Hospital-Norwegian University of Science and Technology in Trondheim, asked if another TKI is really needed in CML? "Vodabatinib… is structurally similar to ponatinib, the most potent TKI for treatment of patients with" CML," he wrote.

But he also conceded that the ongoing trial — estimated study completion date is June 2026 — held its ground despite some considerable obstacles, such as the Covid-19 pandemic and the competing phase III ASCEMBL trial (asciminib versus bosutinib in pre-treated CML)

"[V]odobatinib showed promising activity and safety, which is the main value of this study and impetus for further development of vodobatinib," Hjorth-Hansen said.

However, he seemed to take some issue with the trial’s dosing scheme. Cortes and co-authors said that phase I included an accelerated titration dose escalation of vodobatinib (12-48 mg), followed by a standard 3 + 3 design of vodobatinib (48-240 mg), and then dose expansion at 174 mg. Phase II evaluated the safety and antileukemic activity of vodobatinib 174 mg.

Hjorth-Hansen suggested that in the future "the patients and funder should allow experienced physicians more freedom in dosing than conventionally done in trials. If toxic effects were to occur at the chosen initial dose, the strategy should be to reduce the dose substantially (eg, by 50%) and then increase the dose according to tolerance, and not a rigid stepwise pausing and rechallenge method." The authors highlighted that, at least for any-grade transient amylase elevations and lipase elevations, which occurred in 9% and 15%, respectively, "most events resolved with temporary treatment interruptions and did not recur upon rechallenge."

Still, Hjorth-Hansen’s guided the authors to ASEMBL and the BYOND trial (bosutinib) for alternate dosing approaches.

Overall, 9% of the patients died during the study, from causes such as intracranial hemorrhage (deemed related to treatment), lung infection suspected as being related to Covid-19, fungal infection, septic shock, disease progression, pericardial effusion with severe post­anoxic encephalopathy, and sudden death.

Again, Cortes’ group were keen to emphasize the safety of vodobatinib, pointing out that hematological AEs were common, but that’s not unusual for TKIs in general, and that AEs "related to vodobatinib were generally consistent with those observed in an advanced patient population" with CML and "multiple comorbidities," mostly cardiovascular (CV) disorders. The most common grade ≥3 CV AE was worsening of cardiac failure.

The trial was done at 28 sites in 10 countries. The majority of patients (85%) had chronic-phase CML. More than half were male with a median age 59 years. At least three-fourths had received ≥3 TKIs. Study limitations included the single-arm design "and a high rate of patients ineligible on screening due to stringent eligibility criteria," the authors noted. Recruitment was a problem, which did not surprise Hjorth-Hansen. CML "is often easy to manage with one or two TKIs, hence the patients included in this study are difficult to find," he wrote.

The trial was funded by Sun Pharma Advanced Research Company (SPARC)/Sun Pharmaceutical Industries (Sun Pharma), and supported by Red Nucleus. Some co-authors are SPARC or Sun Pharma employees.

Cortes reported relationships with, and/or support from, AbbVie, Biopath Holdings, Bristol Myers Squibb, Forma Therapeutic, Gilead Sciences, Novartis, Pfizer, Sun Pharma, Tern Pharma, Takeda, Ascentage, and Kartos. Co-authors reported support from the UK National Institute for Health and Cancer (NIHR)/Imperial College NIHR Biomedical Research Centre, and relationships with multiple entities including Sun Pharma.

Hjorth-Hansen reported no relationships relevant to the contents of this paper to disclose.

Cortes JE, et al "Vodobatinib for patients with Philadelphia chromosome-positive chronic myeloid leukaemia resistant or intolerant to multiple lines of previous therapy: an open-label, multicentre, phase 1/2 trial" Lancet Haematol 2025;12:e201-213; DOI: 10.1016/S2352-3026(24)00354-5.

Hjorth-Hansen H "Do we need another TKI for chronic myeloid leukaemia?" Lancet Haematol 2025;12: e167-e168.