The highest efficacy was observed in CP-CML patients harboring a BCR::ABL1 T315I mutation who received ponatinib at 45 mg daily.
Four-year follow-up data from the phase 2 OPTIC trial (NCT02467270) showed sustained efficacy and safety with ponatinib (Iclusig) in patients with chronic-phase chronic myeloid leukemia (CP-CML) with a BCR::ABL1 T315I mutation.1
Data from the post-hoc analysis presented at the 2024 ASCO Annual Meeting showed that the ≤1% BCR:ABL1IS (MR2) response rate by 48 months was highest in the patients who received ponatinib at a highest dose of 45 mg daily and who harbored a BCR::ABL1 T315I mutation. Specifically, in those with a BCR::ABL1 T315I mutation, the response rates were 64%, 25%, and 16% at highest doses of 45 mg (n = 25), 30 mg (n = 20), and 15 mg (n = 19).
In those with a BCR::ABL1 mutation other than T315I, the respective response rates with highest doses of 45 mg (n = 16), 30 mg (n = 15), and 15 mg (n = 18) were 56%, 40%, and 50%. In the group of patients who did not harbor a BCR::ABL1 mutation, the response rates were 60%, 47%, and 45% for highest doses of 45 mg (n = 50), 30 mg (n = 58), and 15 mg (n = 53), respectively.
“[Differences in ≤1% BCR:ABL1IS (MR2) response rates by dose were] less demonstrable in the patients without BCR::ABL1 mutations, and certainly not different in those patients with a mutation other than T315I,” Michael Deininger, MD, PhD, of Versiti Blood Research Institute, in Milwaukee, Wisconsin, said in a presentation of the data. “Bear in mind that the numbers are relatively small, but the signal is relatively clear [for the 45-mg dose] for those patients with the T315I mutation.”
Similar findings were observed with regard to the ≤0.1% BCR::ABLIS (MR3) response rate and the ≤0.0032% BCR::ABL1IS (MR4.5) response rate by 48 months. Superior responses were observed with the 45-mg dose of ponatinib in those who harbored a T315I mutation.
“These results from the post-hoc analysis of the 4-year follow-up of the OPTIC trial support ponatinib’s long-term efficacy and manageable safety profile in patients who are positive for the difficult-to-treat T315I mutation, Deininger said. “Although it’s a post-hoc analysis with small numbers of patients in the mutation and dosing cohorts, the results in patients with CP-CML with the T315I mutation appear consistent with previous analyses of the trial.”
The ongoing, multicenter, randomized OPTIC trial enrolled a total of 283 adult patients with CP-CML who were resistant to 2 or more prior TKIs or who harbored BCR::ABL1 T315I mutations, and who had greater than 1 BCR::ABL1IS.
Study participants were randomly assigned 1:1:1 to receive ponatinib at 45 mg daily, 30 mg daily, or 15 mg daily. Those in the 45- and 30-mg cohorts reduced dosing to 15 mg daily upon achievement of ≤1% BCR::ABL1IS. Those in the 15-mg cohort reduced dosing to 10 mg daily if they experienced adverse effects (AEs). The primary end point of the study was ≤1% BCR::ABL1IS at 12 months.
Results from the primary analysis of the trial showed that ponatinib had “robust efficacy” in the overall population of patients with CP-CML and in the subset of patients who harbored the T315I mutation, according to Deininger.
The key objectives of the post-hoc analysis were to evaluate BCR::ABL1IS response rates, progression-free survival (PFS), overall survival (OS), and safety at 4 years in the subset of patients with the T315I mutation. The data cutoff was May 8, 2023, and the median follow-up for the 45-, 30-, and 15-mg cohorts was 60.6, 63.5, and 60.7 months, respectively.
“The 3 groups were well balanced. You will also note that they are not super large. If you look at the T315I-positive patients, [they accounted for] roughly 25% throughout the 3 dosing cohorts,” Deininger said. No significant differences in other demographics and baseline disease characteristics were noted.
Additional efficacy data showed that in the 45-mg cohort, the median PFS was not yet reached (NE) in those who harbored a T315I mutation (95% CI, 55.2-NE) or those without a BCR::ABL1 mutation (95% CI, NE-NE). “This translates into survival differences as far as PFS is concerned,” Deininger said. “Those patients with a 45-mg starting dose do significantly better than the other 2 groups.”
He added, “Does this translate into OS? The answer is no. It doesn’t look like that; it’s very clear from the graphs. But again, let’s bear in mind that the numbers are relatively small. [They do] suggest that maybe unlike what we’ve always thought in the past, a lot of patients who become resistant have effective salvage options or maybe the post-ponatinib TKIs such as asciminib [Scemblix] play a role in this setting.”
Of those who achieved response at any time but subsequently lost response, the majority of patients regained ≤1% BCR::ABLIS after dose re-escalation. Specifically, in the 45-mg cohort, 64% of patients (n = 16/25) achieved ≤1% BCR::ABLIS at any time; 60% of patients (n = 9) lost that response, 89% (n = 8) dose re-escalated after loss of response, and 75% (n = 6) regained response. In the 30-mg cohort, 25% (n = 5/20) achieved ≤1% BCR::ABLIS at any time, 60% (n = 3) lost response, 67% (n = 2) dose re-escalated, and 50% (n = 1) regained response.
“All in all, that suggests that this dosing reduction that is built in is safe and effective,” Deininger noted.
Deininger noted that the incidence of treatment-emergent AEs (TEAEs) was comparable across the dosing cohorts and irrespective of mutation status.
Specifically, for patients harboring T315I mutations, any-grade TEAEs occurred in all evaluable patients in the 45-mg cohort (n = 25), 95% of those in the 30-mg cohort (n = 21), and 95% of those in the 15-mg cohort (n = 21); these effects were grade 3 or 4 for 52%, 33%, and 29% of patients, respectively. Serious AEs occurred in 36%, 33%, and 29% of patients, respectively, and grade 5 AEs occurred in 8%, 5%, and 10% of patients, respectively.
In the 45-mg cohort, 48% of patients harboring T315I mutations required dose reduction due to TEAEs, 64% required dose interruption, and 8% required discontinuation. These respective rates in the 30-mg cohort were 24%, 48%, and 14%; in the 15-mg cohort, these respective rates were 5%, 38%, and 5%.
The most common hematologic grade 3 or higher TEAEs across the dosing cohorts of patients with T315I mutations were thrombocytopenia, neutropenia, and anemia, he added. Thrombocytopenia occurred in 20%, 14%, and 5% of patients in the 45-, 30-, and 15-mg cohorts, respectively; neutropenia occurred in 16%, 5%, and 5% of patients, respectively; and anemia was reported in 4%, 5%, and 0% of patients, respectively.
An AE of special interest was treatment-emergent arterial occlusive events (TE-AOEs). Notably, rates of TE-AOEs were generally low across the cohorts and irrespective of mutation status.
In patients with T315I mutations, any-grade TEAOEs were reported in 8% of those in the 45-mg cohort, 14% of those in the 30-mg cohort, and 5% of those in the 15-mg cohort; these effects were grade 3 or 4 for 4%, 14%, and 5% of patients, respectively. No grade 5 TE-AOEs were reported.
“In particular, the 45-mg initial dosing seems to be safe in terms of cardiovascular toxicity. Now, this is different from what we have seen in the past or what was published a number of years ago in the initial [phase 2] PACE study [NCT01207440],” Deininger said.
Exposure-adjusted AOEs were 2.37 (95% CI, 0.00-5.74), 7.32 (95% CI, 0.00-15.64), and 2.83 (95% CI, 0.00-7.99) in the 45-, 30-, and 15-mg cohorts, respectively.
“This is a study that used a very novel design of inbuilt dose reduction, that in my mind, should be considered in other TKI [trials,] as well,” Deininger concluded.
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