|Year : 2019 | Volume
| Issue : 2 | Page : 190-196
Ponatinib: A drug review
Hasmukh Jain, Jayashree Thorat, Manju Sengar, Abha Dubey
Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
|Date of Web Publication||20-Dec-2019|
Tata Memorial Centre, Homi Bhabha National Institute, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
The discovery of Philadelphia (Ph) chromosome in 1959 was a landmark moment in the history of targeted therapies for cancer. The BCR-ABL fusion gene formed as a result of this translocation is the key pathogenetic event of chronic myeloid leukemia (CML) and Ph-positive acute lymphoblastic leukemia (ALL). Currently, there are five tyrosine kinase inhibitors (TKIs) available in the clinic to target the BCR-ABL kinase. The last one to be added to the list is ponatinib. Ponatinib is highly effective even in the presence of mutations such as T315I that render all other TKIs ineffective. The initial enthusiasm following the impressive results from the Ponatinib Ph-positive ALL and CML Evaluation (PACE) trial was dampened by the emergence of arterial occlusive events. With a dose-adapted strategy, the drug seems to be ready for a comeback. We review the drug ponatinib, including the history, chemistry, mechanism of action, pharmacokinetics, clinical trial data, ongoing clinical trials, and adverse events.
Keywords: Chronic myeloid leukemia, Philadelphia-positive acute lymphoblastic leukemia, ponatinib, tyrosine kinase inhibitor, CML, ALL, T315I
|How to cite this article:|
Jain H, Thorat J, Sengar M, Dubey A. Ponatinib: A drug review. Cancer Res Stat Treat 2019;2:190-6
| History|| |
A balanced reciprocal translocation between chromosomes 9 and 22 leads to a shortened chromosome 22, which is designated as the Philadelphia (Ph) chromosome. This is the key pathogenetic event of chronic myeloid leukemia (CML) and Ph-positive acute lymphoblastic leukemia (ALL). The ABL gene fuses with the BCR gene as a result of the translocation, which leads to constitutive activation of the ABL kinase. Imatinib was the first Bcr-Abl kinase inhibitor, approved for use in 2001. It changed the management of CML, converting it into a chronic manageable illness. The long-term data from the IRIS trial have confirmed the safety and efficacy of imatinib. While imatinib was very successful, up to 20% of chronic-phase (CP) patients would progress due to the emergence of mutations involving the tyrosine kinase domain. The second-generation tyrosine kinase inhibitors (TKIs) such as dasatinib and nilotinib are effective against some of these resistant cases. However, in the presence of a resistance mutation like T315I, these TKIs are ineffective. In addition, the difficult-to-treat cases such as CML in accelerated or blast crisis phase and the Ph-positive ALL patients have only modest responses with the available TKIs. Ponatinib was developed with a computation and structure-based drug design platform specifically to overcome the T315I-mutant BCR-ABL by Ariad Pharmaceuticals.
| Chemistry and Mechanism of Action|| |
The chemical name of ponatinib is 3-(Imidazo [1,2-b] pyridazine 3-ylethynyl)-4-methyl-N-19 benzamide hydrochloride. Ponatinib (AP24534) has a unique structure that allows it to bind to BCR-ABL even in the presence of T315I mutation.
It has a purine-based scaffold with a carbon–carbon triple bond linkage that is able to bind to the adenosine triphosphate-binding pocket even in the presence of a T315I mutation [Figure 1].
|Figure 1: The structure of Ponatinib (Reproduced with permission from Dr. O'Hare)|
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The preclinical activity of ponatinib was demonstrated by O'Hare et al., in theirin vitro studies on Ba/F3 cell lines, with wild-type BCR/ABL and T315I-mutant BCR-ABL. The inhibitory concentration 50 (IC50) of ponatinib ranged from 0.37 to 2nM. The drug was also found to be selective for the CML cell lines, with an IC50 that was approximately 500-fold lower compared to the normal cells. Ponatinib was effective in cell lines with other BCR-ABL mutations as well.
The results were confirmed in animal studies with Ba/F3 expressing mouse models. The drug used at a dose of 2.5 mg/kg or 5 mg/kg was effective compared to no treatment.
| Other Targets|| |
Ponatinib demonstrated activity against other targets as well, such as the FLT3, KIT, FGFR1, PDGFR, and RET oncoproteins.
| Pharmacokinetics|| |
The drug is effective at a dose level ranging from 15 to 60 mg per day. The oral bioavailability is uncertain. The peak levels are attained at 6 hours. There is no interaction with food. Increased gastric pH decreases the oral bioavailability.
The drug is highly (99%) protein bound. It is metabolized by the CYP3A4 enzyme and to a certain extent by other CYP enzymes (2C8, 2D6, and 3A5). The terminal elimination half-life is 24 hours, and it is eliminated via feces, with negligible renal elimination.
| Drug Interactions|| |
- Drugs that raise gastric pH such as proton pump inhibitors and H2 receptor blockers can interfere with absorption. These drugs should be preferably avoided
- CYP3A4 inhibitors such as azoles (posaconazole, ketoconazole, itraconazole, and voriconazole), protease inhibitors (ritonavir and indinavir), macrolides, and grapefruit juice can increase the drug levels. The recommended starting dose of ponatinib in such cases is 30 mg
- CYP3A4 inducers such as carbamazepine, phenytoin, and rifampicin can reduce the efficacy of ponatinib. These drugs should be avoided unless their benefits outweigh the risk of reduced ponatinib drug level
- Substrates of p-glycoprotein (P-gp) or ABCG2 transporter systems - ponatinib inhibits these transporter systems. There is a potential interaction between ponatinib and drugs that are substrates of these transporter systems such as digoxin, imatinib, methotrexate, and rosuvastatin.
| Special Situations|| |
Not studied, probably increased drug exposure can occur in the presence of hepatic impairment. The drug should be avoided in Child-Pugh Class B and C unless the benefits clearly outweigh the risks.
Not studied, probably moderate-to-severe impairment has an impact.
Not mutagenic in cell assays.
Animal studies have demonstrated that ponatinib can impair fertility.
| Clinical Trial Data|| |
Phase I trial
A dose finding study of ponatinib was conducted in 81 patients with resistant hematological cancers. The most common side effects were rash and constitutional symptoms. Pancreatitis was identified as the dose-limiting toxicity. Ponatinib at a dose of 45 mg was identified as the maximum tolerated dose. The desired trough concentration of 40nM was achieved at a dose of 30 mg. The drug was also found to be effective in this cohort of patients with resistant disease.
Ponatinib Ph-positive acute lymphoblastic leukemia and chronic myeloid leukemia evaluation (PACE) trial study
The PACE trial was a Phase II multicentric trial that tested the activity of ponatinib at 45 mg dose. Four hundred and forty-nine pretreated patients of CML (all phases) and Ph-positive ALL were included if they were resistant/intolerant to nilotinib or dasatinib or with a T315I mutation. The primary endpoints were major cytogenetic response (MCyR) at 12 months for CP and major hematological response at 6 months for the other patients. The initial data were presented with a median follow-up of 15 months [Table 1].
|Table 1: Results of the ponatinib Philadelphia-positive acute lymphoblastic leukemia and chronic myelogenous leukemia evaluation (PACE) trial|
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Arterial occlusive events (AOEs) occurred in 27% patients. Fifty-five percent of the patients had a cardiovascular (CV) risk factor. Twelve percent of patients discontinued treatment. No resistant mutations emerged while on ponatinib.
The drug was granted accelerated approval by the Food and Drug Administration (FDA) in December 2012, and was granted orphan drug designation, for use in adult patients with CP, accelerated-phase (AP), and blast-phase (BP) CML, for whom no other TKI therapy was indicated, patients with T315I-positive CML, and in T315I-positive Ph-positive ALL. However, due to the reports of increased AOEs, the dose was preemptively reduced.
The long-term results were reported with a 5-year median follow-up. The dose was reduced to 15 mg in CML-CP patients with a MCyR and to 30 mg in others. Patients with CML-CP had a durable response, with 82% of patients maintaining MCyR at 5 years. The responses deepened over time, with 24% of patients achieving molecular response (MR) 4.5 at some point of time. The 5-year progression-free survival and overall survival were 53% and 73%, respectively. Interestingly, the cumulative incidence of AOEs was approximately 24%. Even though the PACE trial demonstrated rapid and deep responses compared to the results with other 2nd-generation TKIs, this came at the cost of increased toxicities. Better patient selection and dose-adaptation need to be tested.
Evaluation of ponatinib versus imatinib in chronic myeloid leukemia (EPIC) study
The EPIC trial was a Phase III open-label multicenter study to test the efficacy of ponatinib at 45 mg orally daily versus imatinib at 400 mg orally daily in CML-CP. The primary endpoint was the major molecular response at 12 months. The study accrued 307 patients (data available for 306 patients) between August 2012 and October 2013. In light of the AOEs reported from the PACE trial, the study was terminated in October 2013. Only 23 patients were evaluable for the primary endpoint. However, at 3 months, BCR-ABL transcripts <10% were achieved in 94% (103/109 patients) on the ponatinib arm versus 68% (77/114 patients) on imatinib. There were 11 AOEs reported in 154 patients (7%) on the ponatinib arm versus 3 in 152 patients (2%) on the imatinib arm.
Hyper-Cyclophosphamide, vincristine, doxorubicin and dexamethasone (CVAD) with ponatinib in Ph + acute lymphoblastic leukemia
This was a phase II single-center study reported from the MD Anderson Cancer Center in Texas, USA. Ph + ALL patients were treated with eight cycles of hyper-CVAD (fractionated courses of cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine) and ponatinib in the first-line setting. Ponatinib was given at a dose of 45 mg orally once daily for 14 days in cycle 1. Subsequently, a continuous dosing was used. After 37 patients were enrolled, an amendment was made to reduce the dose to 30 mg orally once daily and to 15 mg in those who had achieved a complete molecular response (CMR). A CMR was achieved in 63 (83%) patients. Fifteen patients underwent allogeneic stem cell transplant. Common Grade 3/4 adverse events included infections, pancreatitis, hypertension, and bleeding. There were six deaths; two patients died due to myocardial infarction. Five patients had AOEs and ten patients had venous thromboembolic events.
Ongoing clinical trials
Ponatinib was initially identified to inhibit BCR-ABL and Proto-oncogene tyrosine-protein kinase Src kinases. However, it was further discovered to have multitargeted action against FGFR, RET, ERK1/2, KIT, MEKK2, and other kinases. Therefore, it is being tested in several cancers including thyroid, breast, lung, and ovarian cancers as well as neuroblastoma, rhabdoid tumors, and in myeloproliferative disorders.
[Table 2] and [Table 3] include a summary of the ongoing clinical trials.
|Table 2: Ongoing trials investigating the use of ponatinib in patients with chronic myeloid leukemia or Philadelphia-positive acute lymphoblastic leukemia|
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|Table 3: Ongoing trials investigating the use of ponatinib in patients with non-hematological cancers|
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The following are FDA-approved indications for the use of ponatinib:
- Adult patients with CP, AP, or BP CML that is resistant to or intolerant to prior TKI therapy
- Ph-positive ALL that is resistant or intolerant to prior TKI therapy.
| Adverse Events|| |
The following adverse reactions have been reported in >10% patients in at least one ponatinib trial:
- CV – hypertension (53%–71%), AOEs and cardiac failure (4%)
- Gastrointestinal (GI) – abdominal pain (34%–49%), constipation (24%–47%), diarrhea (13%–26%), oral mucositis (9%–23%), and GI bleed (2%–11%)
- Infections – febrile neutropenia (1%–25%) and pneumonia (3%–13%)
- Central nervous system – headache (25%–39%), peripheral neuropathy (6%–13%), and dizziness (3%–11%)
- Respiratory – pleural effusion (3%–19%), cough (6%–18%), and dyspnea (7%–21%)
- Skin – rash (34%–54%) and dry skin (24%–39%)
- Musculoskeletal – arthralgia (13%–31%), myalgia (6%–22%), and spasms (5%–13%)
- Others – fatigue (31%–39%), decreased appetite (8%–31%), edema (13%–22%), weight loss (5%–13%), and insomnia (7%–12%)
- CV, pulmonary, and metabolic toxicities (hyperlipidemia and hyperglycemia) – the drug was withdrawn after initial approval due to the concern regarding the development of VOEs.
A spectrum of adverse effects has been reported with the use of ponatinib.
This has been seen in 8% of patients. It is recommended to assess for CV risk factors at baseline and then at regular intervals. An electrocardiogram and two-dimensional echocardiogram can be performed as clinically indicated. The treatment follows the standard guidelines for the management of cardiac failure.
Corrected QT interval prolongation
This is reported rarely with ponatinib. It is recommended to check the concurrent medications, monitor electrolytes and check the electrocardiogram when clinically indicated.
This complication is related to the inhibition of vascular endothelial growth factor, depletion of nitrous oxide and interference with the glomerular function. In a study in 449 patients, hypertension was reported in 67% patients, and as a serious adverse event in 2% of the patients. An assessment for risk factors and regular monitoring of blood pressure is warranted. ACE-inhibitors, angiotensin receptor blockers, and dihydropyridine calcium-channel blockers are preferred for the management.
It was reported in 5% of the patients. There was no correlation with the dose intensity. Low molecular weight heparin for longer than 6 months is preferred as therapy over vitamin K antagonists. In patients who develop venous thrombosis, the dose of ponatinib needs to be reduced or discontinued.
Arterial occlusive events
Thirty-five percent of the patients experienced AOE, beginning at <2 months of therapy. There was a correlation between the occurrence of AOEs with age, CV risk factors, and dose. Peripheral arterial occlusive disease was reported in 12% patients. In a study of ponatinib in heavily pretreated patients, after a median follow-up of 28 months, arterial thrombotic events were reported in 19% of 449 patients and were serious in 14% patients, including CV (10%), cerebrovascular (7%), and peripheral vascular events (4%). It is important to assess the risk, measure ankle–brachial index, manage the risk factors aggressively and use low-dose aspirin.,
Owing to the toxicity profile of ponatinib, the US FDA created a specific warning box including the risk of CV events and liver toxicity related to this drug. For this reason, the starting recommended dose has now been suggested at lower than 45 mg/day. However, to date, there are no standardized guidelines recommending the initial dose of ponatinib in particular CML cases or dose modifications during the treatment, and it is difficult to define a common therapeutic strategy for all patients with CML. Each patient needs a personalized treatment according to resistance or intolerance previously developed to other TKIs, considering comorbidities, CV risk assessment, the response to the initial dose of ponatinib, and side effects during treatment. Unless benefit–risk analysis justifies treatment with a higher dose, the following dose reductions are recommended:
- 15 mg once daily for CP-CML patients with MCyR
- 30 mg once daily for CP-CML patients without MCyR, AP-CML patients, and BP-CML patients.
Ponatinib has to be administered orally with or without food at approximately the same time each day. The tablet has to be taken as a whole without crushing or dissolving. In case a dose is missed, the next dose has to be taken on time. Care should be taken not to take two tablets together to make up for the missed dose.
| Dose Modifications|| |
Dose modifications for myelosuppression
The dose modifications for neutropenia (absolute neutrophil count <1.0 × 109/L) and thrombocytopenia (platelet <50 × 109/L) that are not due to leukemia are summarized in [Table 4].
Dose modifications for non-hematologic adverse reactions
The general guideline in the case of a non-hematological adverse event is to modify the dose or interrupt treatment. For a serious adverse event (including an ischemic event), ponatinib is restarted only after the event has resolved, if the benefit of therapy outweighs the risk of recurrent occlusions and other treatment options are not available. The recommended modifications for hepatic toxicity are summarized in [Table 5].
Recommended modifications for pancreatic adverse reactions are summarized in [Table 6].
|Table 6: Recommended dose modifications for pancreatitis and elevation of lipase|
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| Monitoring|| |
Patients on ponatinib should have the following monitored:
- CV: CV status/function; evidence of arterial and vascular occlusion; signs/symptoms of heart failure; QT (at baseline); blood pressure (every clinic visit); thromboembolism
- GI: Serum lipase (every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated)
- General: Major or complete hematological/cytogenetic response to therapy
- Hematologic: Complete blood count (every 2 weeks for the first 3 months and then monthly or as clinically indicated)
- Hepatic: Liver function tests (at baseline, then at least monthly or as clinically indicated)
- Metabolic: Fluid retention
- Nervous system: Symptoms of neuropathy
- Ocular: Ocular toxicities (conduct comprehensive eye exams at baseline and periodically during treatment).
| Ponatinib Resistance|| |
Very little is known about the mechanism of resistance to ponatinib. Lu et al. demonstrated that in the setting of prior TKI exposure, mutations are likely to be a primary form of kinase domain-mediated ponatinib resistance while in the TKI-naïve setting, BCR-ABL-independent modes of resistance may be more likely. In another study by Mitchell et al., BCR-ABL-independent mTOR pathway activation in ponatinib resistance was demonstrated, and role of catalytic mTOR inhibitor was explored.
Since the exact mechanism still remains to be elucidated, steps to overcome the same are experimental. Asciminib, an allosteric inhibitor targeting the myristoyl-binding pocket of BCR-ABL1, when given in combination with ponatinib was found to overcome resistance in the compound mutant group.
Although additional data are needed about the risks and benefits of allogeneic stem cell transplant in this setting, it remains a reasonable option and is also recommended as per the European Leukemia Net guidelines. Omacetaxine is currently approved in some countries for use in the setting of prior treatment with at least two TKIs or in patients with T315I mutation. However, the response rates are modest.
| Conclusion|| |
Ponatinib is an efficacious drug for use in the setting of resistance or intolerance to other TKIs and provides benefits in terms of cytogenetic and MRs. However, a thorough analysis of the baseline risk factors as well as indication of therapy must be done to establish an optimal initial dose, and every effort must be made to step down to lower doses in particular subset of patients based on the results achieved and the safety profile. Further studies are needed to establish mechanism of action of ponatinib resistance as well as develop drugs to overcome the same.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]