Dose-finding study of ponatinib in chronic phase chronic myeloid leukemia patients

Although most patients with chronic phase chronic myeloid leukemia (CP-CML) have good long-term efficacy after treatment with tyrosine kinase inhibitors (TKIs), a considerable number of patients still suffer from poor efficacy or adverse events (AEs).
The treatment regimen needs to be changed
.

Ponatinib is a third-generation TKI that inhibits BCR-ABL1 with or without kinase domain mutations (including T315I)
.

 The phase II PACE trial evaluated ponatinib 45 mg once daily in patients with CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) (resistant or intolerant to dasatinib or nilotinib, or with T315I mutation), the results showed that regardless of BCR-ABL1 mutation status, ponatinib showed strong clinical activity, with rapid, deep, and durable remission, with good survival (CP-CML The 5-year OS rate was 73%), although 80% of CP-CML patients were resistant to prior therapy
.

However, arterial occlusive events (AOEs) were reported in 84 of 270 CP-CML patients (31%)
.

Post hoc multivariate regression analysis of pooled data from 3 clinical trials of ponatinib in patients with Ph+ leukemia showed that every 15 g/d reduction in mean dose intensity of ponatinib was associated with a 33% lower risk of AOE
.

 To further understand the impact of ponatinib dose on patient safety and efficacy, the investigators conducted the Phase II OPTIC trial to explore a new dose reduction regimen based on response
.

Research methods The inclusion criteria are adult CP-CML patients (age ≥18 years old) who are resistant or intolerant to ≥2 previous TKIs or with T315I mutation
.

Patients with risk factors for AOEs were also eligible, provided comorbidities were controlled at enrollment
.

BCR-ABL1 transcript levels must be >1% measured on an international scale (BCR-ABL1IS) by real-time quantitative polymerase chain reaction
.

 The study included patients from 19 countries (including North America, Europe, Latin America, and Asia Pacific) who were randomly assigned in a 1:1:1 ratio to receive ponatinib 45mg (45mg group), 30 (30mg group) once daily ) or a starting dose of 15 mg (15 mg group)
.

Randomization was stratified by age (≥60 years vs <60 years), history of arterial hypertension, diabetes, and/or hyperlipidemia (yes/no)
.

Patients in the 45 mg and 30 mg groups required a dose reduction to 15 mg once daily when BCR-ABL1IS reached ≤1%
.

There were no response-based dose changes for patients in the 15 mg group
.

 The primary endpoint was BCR-ABL1IS ≤1% at 12 months
.

Secondary efficacy endpoints included molecular, cytogenetic, and hematologic response rates and survival outcomes
.

Safety assessments included the occurrence of AEs, including AOEs, serious AEs, discontinuation, dose reduction and discontinuation due to AEs
.

Findings 1 Patient characteristics data cutoff date was May 31, 2020, and median follow-up (range) was 32 (1-57) months
.

From August 2015 to May 2019, 283 patients were randomized, 282 of whom received at least 1 dose of study drug
.

Of these, 134 (47.
5%) were still receiving treatment and were included in the analysis of this study
.

All patients were evaluable for response
.

Fifty-five percent of patients had received at least 3 prior TKI treatments, and 99% were resistant to at least 1 prior TKI treatment
.

61% of patients had a best response to their last prior therapy with a CHR or worse
.

Thirty-three percent of patients had at least 1 CV risk factor at baseline
.

More than 40% of patients had at least one kinase domain mutation at study entry
.

Of the 282 patients, 204 (72.
3%) were exposed for more than 12 months, and 100 (35.
5%) were exposed for more than 24 months
.

2.
At 12 months, the BCR-ABL1IS≤1% rate (98.
3%CI) of the 45mg, 30mg and 15mg groups were 44.
1% (31.
7-57.
0), 29.
0% (18.
4-41.
6) and 23.
1% ( 13.
4-35.
3) (Figure 1A)
.

The 45 mg group met the prespecified statistical endpoint (P<0.
017)
.

The median time to response (range) was 6.
0 (2.
9-18.
0), 3.
0 (2.
9-15.
3), and 6.
0 (2.
9-31.
9) months for the 45 mg, 30 mg, and 15 mg groups, respectively
.

Cumulative responses increased over time in all groups (6 months, 12 months, and 24 months), with the 45 mg group showing the most rapid increase (Figure 1B)
.

Figure 1: The once-daily ponatinib response study also calculated the cumulative rate of BCR-ABL1IS ≤1% at 12 months in each subgroup of patients
.

In the 45 mg group, the incidence of BCR-ABL1IS ≤ 1% at 12 months was high in patients with or without the T315I mutation at baseline (60.
0% and 48.
5%, respectively)
.

In the low-dose group, patients with a T315I mutation had a lower incidence of BCR-ABL1IS ≤1% compared with patients without the T315I mutation
.

This difference was more pronounced among patients in the 15 mg group (10.
5% vs 29.
6%) than in the 30 mg group (25.
0% vs 38.
4%)
.

In the 45mg, 30mg and 15mg groups, the response rates for patients without mutations at baseline were 46.
0%, 37.
9% and 28.
3%, respectively
.

In the 45, 30, and 15 mg groups, the overall major molecular response rates were 34.
4%, 24.
7%, and 23.
1%, respectively; the overall major cytogenetic response (MCyR) rates were 50.
5%, 33.
3%, and 43.
8%, respectively
.

3Disease progression and survival during the study period, 11%-12% and 1%-3% of patients in the 3 arms progressed to accelerated-phase CML and acute-phase CML, respectively
.

Median PFS was not reached (NR) in the 45 mg and 30 mg groups and was 45.
6 months in the 15 mg group (Figure 2A); the estimated 24-month PFS rates were 80%, 76%, and 78% for the 3 groups, respectively
.

The median OS for all groups was NR (Figure 2B); the estimated 24-month OS rates were over 90%
.

Figure 2: Survival Analysis PFS (A) vs.
OS (B) 4 Safety and Tolerability Table 1 summarizes “treatment period” adverse events (TEAEs) and dose adjustments for TEAEs
.

The most common non-hematologic TEAEs in all groups were arterial hypertension (28%), headache (18%), and increased lipase (17%); most were grade 1 or 2
.

The most common hematologic TEAEs were thrombocytopenia (40%), neutropenia (26%), and anemia (19%)
.

There were 4 deaths related to AEs (2 sudden deaths in the 45mg group in these patients with CV risk factors at baseline and 2 deaths from pneumonia in the 15mg group)
.

Table 1: Summary of AEs Profile 5 Dose Dynamics Overall median (range) dose intensity (mg/day) was 27.
7 (10.
5-45.
0) in the 45mg group, 23.
0 (5.
1-30.
0) in the 30mg group, and It was 14.
7 (6.
0-15.
0) in the 15 mg group, and 75 (79.
8%), 58 (61.
7%), and 33 (35.
1%) patients in the 45 mg, 30 mg, and 15 mg groups, respectively, had dose reductions
.

The median (range) time to reduction was the shortest in the 45 mg group at 3.
4 (0.
1-41.
9) months, compared with 7.
1 (0.
1-40.
5) and 11.
4 (0.
2-46.
6) months in the 30-mg and 15-mg groups, respectively
.

CONCLUSIONS: The OPTIC study showed that ponatinib benefited most (99%) patients with drug-resistant CP-CML with 3 starting dose regimens, with the best benefit/risk outcome occurring in the 45 mg starting dose group , reduced to 15 mg when a response was obtained (BCR-ABL1IS ≤ 1%)
.

Reference source: Jorge Cortes, Jane Apperley, Elza Lomaia et.
al Blood (2021) 138 (21): 2042–2050.
https://doi.
org/10.
1182/blood.
2021012082.
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