Profile
General Information
Iclusig (ponatinib) is a small-molecule dual Abl/Src protein inhibitor.
Iclusig is specifically indicated:
- for the treatment of adult patients with chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.
- as a first-line treatment for patients with newly diagnosed Ph+ALL in combination with chemotherapy. This indication is approved under accelerated approval based on minimal residual disease (MRD)-negative complete remission (CR) at the end of induction.
Dosing/Administration
Iclusig is supplied as a tablet for oral administration. Treatment should be continued until evidence of disease progression or unacceptable toxicity. Dose modifications should be considered for myelosuppression, non-hematologic adverse reactions, and use with strong CYP3A inhibitors. See drug label for appropriate dose modifications.
Recommended Dosage in Newly Diagnosed Ph+ ALL: Starting dose is 30 mg orally once daily in combination with chemotherapy, with a reduction to 15 mg once daily upon achievement of MRD-negative (≤0.01% BCR::ABL1/ABL1) CR at the end of induction.
Recommended Dosage in Monotherapy for Ph+ ALL for Whom No Other Kinase Inhibitors are Indicated or T315I-positive Ph+ ALL: Starting dose is 45 mg orally once daily.
Recommended Dosage in CP-CML: Starting dose is 45 mg orally once daily with a reduction to 15 mg once daily upon achievement of ≤1% BCR::ABL1IS.
Recommended Dosage in AP-CML and BP-CML: Starting dose is 45 mg orally once daily.
Mechanism of Action
Ponatinib is a kinase inhibitor. Ponatinib inhibited the in vitro tyrosine kinase activity of ABL and T315I mutant ABL with IC50 concentrations of 0.4 and 2.0 nM, respectively. Ponatinib inhibited the in vitro activity of additional kinases with IC50 concentrations between 0.1 and 20 nM, including members of the VEGFR, PDGFR, FGFR, EPH receptors and SRC families of kinases, and KIT, RET, TIE2, and FLT3. Ponatinib inhibited the in vitro viability of cells expressing native or mutant BCR-ABL, including T315I. In mice, treatment with ponatinib reduced the size of tumors expressing native or T315I mutant BCR-ABL when compared to controls.
Side Effects
Adverse events associated with the use of Iclusig may include, but are not limited to, the following:
Use as a single agent:
rash and related conditions, arthralgia, abdominal pain, headache, constipation, dry skin, hypertension, fatigue, fluid retention and edema, pyrexia, nausea, pancreatitis/lipase elevation, hemorrhage, anemia, hepatic dysfunction and AOEs. The most common Grade 3 or 4 laboratory abnormalities (>20%) are platelet count decreased, neutrophil cell count decreased, and white blood cell decreased
Use in combination with chemotherapy:
hepatic dysfunction, arthralgia, rash and related conditions, headache, pyrexia, abdominal pain, constipation, fatigue, nausea, oral mucositis, hypertension, pancreatitis/lipase elevation, neuropathy peripheral, hemorrhage, febrile neutropenia, fluid retention and edema, vomiting, paresthesia, and cardiac arrhythmias. The most common Grade 3 or 4 laboratory abnormalities (>20%) are decreased white blood cell count, decreased neutrophil cell count, decreased platelet count, decreased lymphocyte cell count, decreased hemoglobin, increased lipase, and increased alanine aminotransferase
The Iclusig drug label comes with the following Black Box Warning:
- Arterial occlusive events (AOEs), including fatalities, have occurred in Iclusig treated patients. AOEs included fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Monitor for evidence of AOEs. Interrupt or discontinue Iclusig based on severity. Consider benefit-risk to guide a decision to restart Iclusig.
- Venous thromboembolic events (VTEs) have occurred in Iclusig treated patients. Monitor for evidence of VTEs. Interrupt or discontinue Iclusig based on severity.
- Heart failure, including fatalities, occurred in Iclusig treated patients. Monitor for heart failure and manage patients as clinically indicated. Interrupt or discontinue Iclusig for new or worsening heart failure.
- Hepatotoxicity, liver failure and death have occurred in Iclusig treated patients. Monitor liver function tests. Interrupt or discontinue Iclusig based on severity
Clinical Trial Results
The FDA approval of Iclusig was based on a single-arm, open-label, international, multicenter trial in 449 subjects with CML and Ph+ALL whose disease was considered to be resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy. Subjects were assigned to one of six cohorts based on disease phase (chronic phase CML [CP-CML]; accelerated phase CML [AP-CML]; or blast phase CML [BP-CML]/Ph+ALL), resistance or intolerance (R/I) to prior TKI therapy, and the presence of the T315I mutation. All subjects were administered a starting dose of 45 mg of Iclusig once daily. 444 subjects eligible for efficacy analysis: 267 subjects with CP-CML (R/I Cohort: n=203, T315I: n=64), 83 with AP-CML, 62 subjects with BP-CML, and 32 with Ph+ALL. Five subjects were not eligible for efficacy analysis due to lack of confirmation of T315I mutation status. The primary efficacy endpoint in CP-CML was major cytogenetic response (MCyR), which included complete and partial cytogenetic responses (CCyR and PCyR); this was reached by 54% of the population. The median time to MCyR was 84 days. At the time of analysis, the median durations of MCyR had not yet been reached. The primary efficacy endpoint in AP-CML, BP-CML, and Ph+ALL was major hematologic response (MaHR), defined as either a complete hematologic response (CHR) or no evidence of leukemia (NEL); this was reached by 52% of the AP-CML population, 31% of the BP-CML population and 41% of the Ph+ ALL population. The median time to MaHR in patients with AP-CML, BP-CML, and Ph+ALL was 21 days, 29 days and 20 days, respectively. The median duration of MaHR for patients with AP-CML, BP-CML, and Ph+ALL was 9.5 months, 4.7 months and 3.2 months, respectively.
The FDA approved Iclusig for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy under accelerated approval based on minimal residual disease (MRD)-negative complete remission (CR) at the end of induction. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.