Dosing adjustments of ponatinib based on responses increased tolerability in patients with chronic myeloid leukemia according to OPTIC.
Reducing ponatinib (Iclusig) doses upon patients achieving a response resulted in optimal long-term risk benefits in third-line chronic-phase chronic myeloid leukemia (CML) according to 5-year follow-up data from the phase 2 OPTIC trial (NCT02467270) published in Leukemia.1
Data from the trial showed that in the intention-to-treat population 60% of patients who received ponatinib daily at 45 mg (n = 94), 30 mg (n = 95), and 15 mg (n = 94) achieved BCR::ABL1 responses of at least 1% at rates of 60%, 41%, and 40%, respectively. Median time to responses were 6.0 months (range, 2.9-21.1), 3.1 months (range, 2.9-45.0), and 6.2 months (range, 2.9-33.1) in each of the respective dosing cohorts. At 5-years, 68.8% (95% CI, 53.9%-79.8%) of patients in the 45-mg cohort maintained their response, 74.4% (95% CI, 56.3%-85.8%) did so in the 30-mg cohort, and 84.3% (95% CI, 65.9%-93.2%) in the 15-mg cohort.
Notably, those who received 45-mg and 30-mg daily doses of ponatinib had their doses reduced to 15 mg upon achieving a response.
“[These] data confirmed that ponatinib is a safe drug in the optimized dose schedule… [Ponatinib] should be considered in patients who have failed [on a] second-generation TKI, particularly if they have resistant disease,” Hagop M. Kantarjian, MD, said in an exclusive interview with OncLive®.
Kantarjian is a professor in the Department of Leukemia and the Samsung Distinguished Leukemia Chair in Cancer Medicine at The University of Texas MD Anderson Cancer Center; as well as a non-resident fellow in health policy at the Rice University Baker Institute, both in Houston.
In terms of safety, 100% of patients in the 45-mg cohort experienced any-grade treatment-emergent adverse effects (TEAEs), compared with 97.9% in the 30-mg and 15-mg cohort. Grade 3 or 4 TEAEs were experienced by 70.2%, 66.0%, and 68.1% of patients in each of the respective cohorts. Additionally, serious TEAEs were experienced by 40.4% of patients in the 45-mg cohort, 35.1% in the 30 mg cohort, and 41.5% in the 15 mg cohort. Treatment discontinuations due to TEAEs occurred in 24.5%, 19.1%, and 20.2% of patients in each cohort.
“The study showed several things,” Kantarjian added. “The first thing it showed is that this optimization of the ponatinib dose schedule made the drug much safer.”
The open label trial enrolled patients who were at least 18 years of age with disease that was resistant to at least 2 TKIs or a BCR::ABL1 T315I mutation. Patients also needed to have an ECOG performance status of 2 or less, adequate renal and hepatic function, and normal pancreatic status.2
If patients had received approved TKIs, investigational agent, interferon, cytarabine, or immunotherapy within the prior 2 weeks, undergone autologous or allogeneic stem cell transplant within the prior 60 days of their first dose, or had previously received ponatinib they were not included in the trial.
Patients were randomly assigned to receive daily doses of ponatinib either at 45 mg, 30 mg, or 15 mg.1 Those in the 45-mg and 30-mg cohorts had their doses reduced to 15 mg upon achieving a BCR::ABL1 response of at least 1%. Dose reductions to 10 mg were permitted for AEs, and dose re-escalation was also permitted if patients lost their BCR::ABL1 response of at least 1% in across 2 consecutive assessments.
“Ponatinib was developed around 2006, and the initial studies were done at the dose schedule of 45 mg daily. [Initial studies] showed that ponatinib is probably one of the most potent BCR::ABL1 TKIs, but it also has toxicities at 45-mg daily. The OPTIC trial came back with later follow-up to address the issue of the adverse effects [AEs] of ponatinib, and to see whether we can use safer schedules that will be equally effective,” Kantarjian explained.
BCR::ABL1 responses of at least 1% at 12 months was the primary end point of the trial. Secondary end points included BCR::ABL1 responses of at least 0.1%, progression-free survival (PFS), overall survival (OS), and safety and tolerability.
Baseline characteristics revealed that patients in the 45-mg cohort had a median age of 46 years (range, 19-81), 51 years (range, 21-77) in the 30-mg cohort, and 49 years (range, 18-81) in the 15-mg cohort. Most patients in the 45-mg and 15-mg cohorts were male (53%; 56%) whereas most were female in the 30 mg cohort (60%). BCR::ABL1 mutations at baseline were found in 44%, 37%, and 42% of patients from each of the respective dosing cohorts.
The median PFS was not evaluable (NE) both 45-mg (95% CI, 63.5-NE) and 15-mg (95% CI, 45.8-NE) cohorts compared with 75 months (95% CI, 45-NE) for the 30-mg cohort. Five-year PFS rates for 45-mg, 30-mg, and 15-mg cohorts were 63.1% (95% CI, 51.2%-72.8%), 57% (95% CI, 43.0%-68.8%), and 60.1% (95% CI, 47.0%-71.0%), respectively.
Median OS for patients from each dosing cohort were all NE (95% CI, NE-NE). The 5-year OS rates were 85.1% (95% CI, 75.8%-91.1%), 83.3% (95% CI, 73.4%-89.8%), and 86.4% (95% CI, 77.3%-92.0%) in the 45-mg, 30-mg, and 15-mg cohorts, respectively. Regarding patients with BCR::ABL1 T315I mutations at baseline, 5-year OS rates were 86.3% (95% CI, 63.2%-95.4%), 61.7%% (95% CI, 37.7%-78.7%), and 31% (95% CI, 44.1%-85%) in the 45-mg, 30-mg, and 15-mg cohorts, respectively. Additionally, for patients with BCR::ABL1 mutations other than T315I at baseline, these respective rates were 79.8% (95% CI, 49.4%-93.0%), 92.3% (95% CI, 56.6%-98.9%), and 81.6% (95% CI, 53.0%-93.7%).
“[The OPTIC trial] also shows, which was very important, an improvement in the survival in patients with T315I mutation. The 5-year survival was 86%, which is high and amazing,” Kantarjian explained. “What do [these data] tell me? It tells me that in patients with BCR::ABL1 T315I mutations, it's very important to start at 45 mg and reduce the dose schedule. In patients with other mutations or no mutations, we can always start with 30 mg and reduce the dose to 15 mg.”
BCR::ABL1 responses of at least 1% for patients with mutations other than T315I were 56% for the 45-mg cohort, 40% for the 30-mg cohort, and 50% for the 15-mg cohort. These rates for patients with BCR::ABL1 T315I mutations were 64%, 25%, and 16%.
The most common any-grade hematologic TEAEs that patients from each cohort experienced was thrombocytopenia, occurring at respective rates of 43.6%, 38.3%, and 38.3%. The most common any-grade nonhematologic TEAE was hypertension which occurred at respective rates of 33%, 41.5%, and 29.8% in each cohort.
“The optimization of the ponatinib dose schedule made the drug much safer. We saw a much lower incidence of arterial occlusive events, veno-occlusive events, and also a lower incidence of hypertension and skin rashes. [Ponatinib] was a much safer drug at the lower dose schedules,” Kantarjian concluded.
