Ponatinib is a BCR-ABL1 inhibitor that has demonstrated activity against the native and mutated BCR-ABL1 proteins and is the only tyrosine kinase inhibitor (TKI) effective against the T315I mutation. Ponatinib initially received accelerated approval by the US FDA for the treatment of chronic myeloid leukaemia (CML) in adults with resistance or intolerance to prior TKI therapy but subsequently after reports of vascular complications, including arterial and venous thromboses and embolic events (>27%) this approval was modified to narrow indications to treatment of adults with T315I-positive CML and for adults with CML where no other TKI is indicated.
The initial phase I dose escalation study of ponatinib included 65 patients with relapsed or resistant Philadelphia (Ph) positive leukemia, including 43 patients with CML in chronic phase (CP-CML).r In these patients 98% had received two prior TKIs, 63% had received three prior TKIs, and 29% had a known T315I mutation. At a median follow-up of 66 weeks the rates of complete hematologic response (CHR), major cytogenetic response (MCR), and complete cytogenetic response (CCR) were 98, 72, and 63%, respectively. The median time to MCR was 12 weeks (range, 8-72). The median duration of MCR was not reached (range, 8-117). Of those who attained a MCR, 89% (95% CI 69-96%) were estimated to remain on therapy at one year. Of the 12 patients with T315I mutation, all attained a CHR and MCR, CCR, and major molecular response (MMR) were seen in 11, 9, and 8 patients, respectively.
The phase II PACE trial of ponatinib included 449 heavily pre-treated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the T315I mutation.r This trial reported MCR in 51% of the 203 patients with CP CML and in 70% of the 64 patients in CP with T315I mutations. The median time to MCR was 2.8 months and 91% were sustained at one year. No specific mutations appeared to confer resistance. In the 83 patients with accelerated phase CML including patients with T315I mutations, MHR was observed in 55%. Median time to MHR and median duration of MHR were 21 days and 12 months, respectively. MCR, CCR, and MMR were attained in 39, 24, and 16%, respectively. The median time to MCR was 3.7 months and 73% maintained this response at one year. In the 62 patients with CML in blast crisis (myeloid or lymphoid) including patients with T315I mutations, MHR was achieved in 31%. Median time to MHR and median duration of MHR were 4 and 5 months, respectively. At 12 months, 42% had a sustained response. MCR and CCR were attained in 23 and 18%, respectively. Estimated progression-free and overall survival rates at one year were 55 and 84%, respectively.
The MD Anderson group conducted a single arm phase II study of ponatinib first line in 51 patients with CP-CML.r The primary endpoint was the proportion of patients who achieved CCR by 6 months. Median follow-up was 20.9 months. Initially 43 patients were started on 45 mg ponatinib daily but because of tolerability issues subsequently eight patients were started on 30 mg daily. 43 (94%) of 46 evaluable patients achieved CCR at 6 months. The study was terminated early at the recommendation of the FDA due to concern about the increased risk of thromboembolic disease. Similarly the EPIC study, which was an international multicentre randomised, open-label, phase III trial designed to assess the efficacy and safety of ponatinib, compared with imatinib, in newly diagnosed patients with CP-CML was terminated early following these safety concerns, which limited the assessment of the primary endpoint.r Although ponatinib first line is efficacious, due to adverse events (particularly arterial occlusive events) it is not recommended nor reimbursed in this setting.
The OPTIC trial is the first prospective randomized clinical trial to evaluate different dosing regimens for CP-CML patients resistant or intolerant to at least 2 previous TKIs, or had T315I mutation.r A total of 283 patients were randomly assigned 1:1:1 to 3 cohorts receiving 45 mg, 30 mg or 15 mg ponatinib once daily, with the primary endpoint of response of BCR-ABL1 ≤ 1% at 12 months. In patients who received 45 mg or 30 mg ponatinib daily, the dose was reduced to 15mg daily on achievement of BCR-ABL1 ≤1%. The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) of patients who received 45 mg daily, 29.0% (18.4-41.6) of patients receiving 30 mg daily, and 23.1% (13.4-35.3) for patients receiving 15 mg daily. Independently confirmed grade 3 or above treatment-emergent arterial occlusive events occurred in 5, 5, and 3 patients in the 45-, 30-, and 15 mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit/risk outcomes occurred with the 45 mg starting dose, which was decreased to 15 mg upon achievement of a response.
The expert reference panel supported publication of the protocol on the basis of the information summarised below. The committee was most strongly influenced by the study by Cortes et al.r and Jain et al.r
Source |
Study & Year Published |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase I trial |
Cortes et al. 2012r |
Yes |
Yes |
Doses ranged from 2 to 60 mg ONCE daily |
Phase II trials |
Cortes et al. 2013r |
Yes |
Yes |
- |
|
Jain et al. 2015r |
Yes |
Yes |
First-line ponatinib in CP-CML. Patients enrolled before 25/07/13 were started on a dose of 45 mg ONCE daily. Patients enrolled after this date were started on 30 mg ONCE daily due to tolerability issue. |
|
Cortes et al. 2021r |
Yes |
Yes |
Ponatinib in CP-CML after failure ≥ 2 prior TKIs or presence of T315I mutation. Optimal benefit/risk outcome occurred with 45 mg ONCE daily starting dose which was reduced to 15 mg ONCE daily after achievement of BCR-ABL1 ≤1%. |
Guidelines |
Date published/revised |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
NCCN |
CML 2022 V.3 |
Yes |
Yes |
- |
BCCA |
June 2021 |
Yes |
Yes |
- |
CCO |
Sep 2020 |
Yes |
Yes |
- |
Efficacy
Figure 1. Efficacy of ponatinib in chronic-phase CML (CP-CML) - overall, patients resistant or intolerant to previous treatment with dasatinib or nilotinib, and patients with the BCR-ABL1T315I mutationr
© Blood 2018
Figure 2. Efficacy in advanced disease (accelerated-phase CML (AP-CML) and blast-phase CML (BP-CML)) - overall, patients resistant or intolerant to previous treatment with dasatinib or nilotinib, and patients with the BCR-ABL1T315I mutationr
Adapted from © Blood 2018
Toxicity
In the phase 1 study the most common non-hematologic toxicities were typically mild to moderate and included skin changes (rash, dry skin, acneiform dermatitis) and constitutional symptoms (arthralgia, fatigue, nausea).r Pancreatitis, ranging from mild to severe, was seen in approximately 14%. Severe (grade 3 or 4) thrombocytopenia, neutropenia, and anaemia occurred in 28, 14, and 2% respectively.
In the phase II PACE study the most common toxicities (all grades) were thrombocytopenia (41%), rash (40%), dry skin (39%), abdominal pain (27%), and headache (23%).r In this report, cardiovascular, cerebrovascular, and peripheral vascular events were described in 7, 4, and 5% of patients, respectively. The majority of patients with vascular events had at least one vascular risk factor (e.g. hypertension, diabetes, hypercholesterolaemia, obesity). Of the patients who continued ponatinib after a vascular event, 36% had subsequent events. Overall, severe adverse events led to the discontinuation of therapy in 13% of patients. Five patients died with two deaths were potentially related to treatment (pneumonia, acute myocardial infarction).
In the MD Anderson first line ponatinib study the most frequent toxicities included skin-related effects (n=35; 69%) and elevated lipase (n=32; 63%).r Cardiovascular events (mainly hypertension) occurred in 25 (49%) patients. Grade 3 or 4 myelosuppression occurred in 15 (29%) patients. Five (10%) patients developed cerebrovascular or vaso-occlusive disease. 43 (85%) patients required treatment interruptions and 45 (88%) required dose reductions.
Table 1. Treatment-related adverse eventsr
© New England Journal of Medicine 2013
In the OPTIC study, 33% of all patients had at least one cardiovascular risk factor, and the 2 sudden deaths in the 45 mg ponatinib cohort occurred in patients with cardiovascular risk factors.r The overall rate of arterial occlusive events (AOEs) was 6%, with exposure-adjusted treatment-emergent AOEs of 5.6% in those on 45 mg ponatinib. A starting dose of 45 mg with response-related dose reduction was associated with an estimated 6.4 percentage-point increase in the rate of arterial occlusive events compared with 15 mg. However, this was offset by a 26.3 percentage-point improvement in the response rate by 12 months. This benefit-to-risk data is informative when considering that optimal antileukemic effects should be maintained whilst minimizing the risk of adverse events (see Figure 3).
The mechanism by which ponatinib interacts with the endothelium and pre-existing arteriosclerotic plaques is unknown.r
Figure 3. Summary of relationship between efficacy and treatment-emergent arterial occlusive event (TE-AOE) rate (by starting dose)r
© Blood 2021