ICLUSIG Film-coated tablet Ref.[9024] Active ingredients: Ponatinib

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors
ATC code: L01EA05

Mechanism of action

Ponatinib is a potent pan BCR-ABL inhibitor with structural elements, including a carbon-carbon triple-bond, that enable high affinity binding to native BCR-ABL and mutant forms of the ABL kinase.

Pharmacodynamic effects

Ponatinib inhibits the tyrosine kinase activity of ABL and T315I mutant ABL with IC₅₀ values of 0.4 and 2.0 nM, respectively. In cellular assays, ponatinib was able to overcome imatinib, dasatinib, and nilotinib resistance mediated by BCR-ABL kinase domain mutations. In preclinical mutagenesis studies, 40 nM was determined as the concentration of ponatinib sufficient to inhibit viability of cells expressing all tested BCR-ABL mutants by >50% (including T315I) and suppress the emergence of mutant clones. In a cell-based accelerated mutagenesis assay, no mutation in BCR-ABL was detected that could confer resistance to 40 nM ponatinib.

Ponatinib elicited tumour shrinkage and prolonged survival in mice bearing tumours expressing native or T315I mutant BCR-ABL.

At doses of 30 mg or greater plasma steady state trough concentrations of ponatinib typically exceed 21 ng/mL (40 nM). At doses of 15 mg or greater, 32 of 34 patients (94%) demonstrated a ≥50% reduction of CRK-like (CRKL) phosphorylation, a biomarker of BCR-ABL inhibition, in peripheral blood mononuclear cells.

Ponatinib inhibits the activity of other clinically relevant kinases with IC₅₀ values below 20 nM and has demonstrated cellular activity against RET, FLT3, and KIT and members of the FGFR, PDGFR, and VEGFR families of kinases.

Cardiac electrophysiology

The QT interval prolongation potential of Iclusig was assessed in 39 patients with leukaemia who received 30 mg, 45 mg, or 60 mg Iclusig once daily. Serial ECGs in triplicate were collected at baseline and at steady state to evaluate the effect of ponatinib on QT intervals. No clinically significant changes in the mean QTc interval (i.e., >20 ms) from baseline were detected in the study. In addition, the pharmacokinetic-pharmacodynamic models show no exposure-effect relationship, with an estimated QTcF mean change of –6.4 ms (upper confidence interval –0.9 ms) at C_max for the 60 mg group.

Clinical efficacy and safety

Patients with CML and Ph+ ALL previously treated with other tyrosine kinase inhibitors (TKIs) or who have the T315I mutation

PACE Trial

The safety and efficacy of Iclusig in CML and Ph+ ALL patients who were resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy were evaluated in a single-arm, open-label, international, multicenter trial. All patients were administered 45 mg of Iclusig once-daily with the possibility of dose de-escalations and dose interruptions followed by dose resumption and re-escalation. Patients were assigned to one of six cohorts based on disease phase (CP-CML; AP-CML; or BPCML/Ph+ ALL), resistance or intolerance (R/I) to dasatinib or nilotinib, and the presence of the T315I mutation. The trial is ongoing.

Resistance in CP-CML was defined as failure to achieve either a complete haematological response (by 3 months), a minor cytogenetic response (by 6 months), or a major cytogenetic response (by 12 months) while on dasatinib or nilotinib. CP-CML patients who experienced a loss of response or development of a kinase domain mutation in the absence of a complete cytogenetic response or progression to AP-CML or BP-CML at any time on dasatinib or nilotinib were also considered resistant. Resistance in AP-CML and BP-CML/Ph+ ALL was defined as failure to achieve either a major haematological response (AP-CML by 3 months, BP-CML/Ph+ ALL by 1 month), loss of major haematological response (at any time), or development of kinase domain mutation in the absence of a major haematological response while on dasatinib or nilotinib.

Intolerance was defined as the discontinuation of dasatinib or nilotinib due to toxicities despite optimal management in the absence of a complete cytogenetic response for CP CML patients or major haematological response for AP CML, BP CML, or Ph+ ALL patients.

The primary efficacy endpoint in CP-CML was major cytogenetic response (MCyR), which included complete and partial cytogenetic responses (CCyR and PCyR) by 12 months. The secondary efficacy endpoints in CP-CML were complete haematological response (CHR) and major molecular response (MMR).

The primary efficacy endpoint in AP-CML and BP-CML/Ph+ ALL was major haematological response (MaHR), defined as either a complete haematological response (CHR) or no evidence of leukaemia (NEL). The secondary efficacy endpoints in AP-CML and BP-CML/Ph+ ALL were MCyR and MMR.

For all patients, additional secondary efficacy endpoints included: confirmed MCyR, time to response, duration of response, progression free survival, and overall survival. Also, post-hoc analyses to assess the relationship of shorter-term cytogenetic (MCyR) and molecular (MMR) response outcomes with longer-term outcomes of PFS and OS, maintenance of response (MCyR and MMR) after dose reductions, and PFS and OS by Arterial Occlusive Event status were conducted.

The trial enrolled 449 patients of which 444 were eligible for analysis: 267 CP-CML patients (R/I Cohort: n=203, T315I Cohort: n=64), 83 AP-CML patients (R/I Cohort: n=65, T315I Cohort: n=18), 62 BP-CML (R/I Cohort: n=38, T315I Cohort: n=24), and 32 Ph+ ALL patients (R/I Cohort: n=10, T315I Cohort: n=22). A prior MCyR or better (MCyR, MMR, or CMR) to dasatinib or nilotinib was only achieved in 26% patients with CP-CML and a prior MaHR or better (MaHR, MCyR, MMR, or CMR) was only achieved in 21%, and 24% of AP-CML, and BP-CML/Ph+ALL patients, respectively. Baseline demographic characteristics are described in Table 12 below.

Table 12. Demographics and disease characteristics for the PACE trial:

^a* of 427 patients reporting prior TKI therapy with dasatinib or nilotinib
^b Of the patients with one or more BCR-ABL kinase domain mutations detected at entry, 37 unique mutations were detected.

Overall, 55% of patients had one or more BCR-ABL kinase domain mutation at entry with the most frequent being: T315I (29%), F317L (8%), E255K (4%) and F359V (4%). In 67% of CP-CML patients in the R/I cohort, no mutations were detected at study entry.

Efficacy results are summarized in Table 13, Table 14, and Table 15.

Table 13. Efficacy of Iclusig in resistant or intolerant chronic phase CML patients:

^a Primary endpoint for CP-CML Cohorts was MCyR, which combines both complete (No detectable Ph+ cells) and partial (1% to 35% Ph+ cells) cytogenetic responses.
^b Measured in peripheral blood. Defined as a ≤0.1% ratio of BCR-ABL to ABL transcripts on the International Scale (IS) (ie, ≤0.1% BCR-ABLIS; patients must have the b2a2/b3a2 (p210) transcript), in peripheral blood measured by quantitative reverse transcriptase polymerase chain reaction (qRT PCR).
Database cutoff date 06 February 2017.

CP-CML patients who received fewer prior TKIs attained higher cytogenetic, haematological, and molecular responses. Of the CP-CML patients previously treated with one, two, three or four prior TKIs, 75% (12/16), 68% (66/97), 44% (63/142), and 58% (7/12)) achieved a MCyR while on Iclusig, respectively. The median dose intensity was 28 mg/day or, 63% of the expected 45 mg dose.

Of the CP-CML patients with no mutation detected at entry, 49% (66/136) achieved a MCyR.

For every BCR-ABL mutation detected in more than one CP-CML patient at entry, a MCyR was achieved following treatment with Iclusig.

In CP-CML patients who achieved MCyR, the median time to MCyR was 2.8 months (range: 1.6 to 11.3 months) and in patients who achieved MMR, the median time to MMR was 5.5 months (range: 1.8 to 55.5 months). At the time of updated reporting with minimum follow-up for all ongoing patients of 64 months, the median durations of MCyR and MMR had not yet been reached. Based on the Kaplan-Meier estimates, 82% (95% CI: [74%–88%]) of CP-CML (median duration of treatment: 32.2 months) patients who achieved a MCyR are projected to maintain that response at 48 months and 61% (95% CI: [51%-70%]) of CP-CML patients who achieved a MMR are projected to maintain that response at 36 months. The probability of all patients with CP-CML maintaining MCyR and MMR did not change further when the analysis was extended out to 5 years.

With a minimum follow-up of 64 months, 3.4% (9/267) of CP-CML patients experienced transformation of their disease to AP-CML or BP-CML.

For CP-CML patients overall (N=267), as well as for CP-CML R/I Cohort A patients (N=203) and T315I Cohort B patients (N=64), the median OS has not yet been reached. For the overall CP-CML disease group, the probability of survival at 2, 3, 4, and 5 years is estimated as 86.0%, 81.2%, 76.9%, and 73.3%, respectively, as shown in Figure 1.

Figure 1. Kaplan-Meier estimates for overall survival in the CP-CML population (Treated Population):

CP-CML patients who achieved MCyR or MMR response within the first year of treatment had statistically significantly improved progression-free (PFS) and overall survival (OS) compared to those patients who did not meet the treatment milestones. A MCyR at the 3-month landmark correlated strongly and statistically significantly with PFS and OS (p < 0.0001 and p = 0.0006, respectively). Statistical significance was achieved in the correlation of PFS and OS with a MCyR at the 12-month landmark (p = <0.0001 and p = 0.0012, respectively).

Table 14. Efficacy of Iclusig in resistant or intolerant advanced phase CML patients:

^a Primary endpoint for AP-CML and BP-CML/Ph+ ALL Cohorts was MaHR, which combines complete haematological responses and no evidence of leukaemia.
^b CHR: WBC ≤ institutional ULN, ANC ≥ 1 000/mm³, platelets ≥ 100 000/mm³, no blasts or promyelocytes in peripheral blood, bone marrow blasts ≤ 5%, < 5% myelocytes plus metamyelocytes in peripheral blood, basophils < 5% in peripheral blood, No extramedullary involvement (including no hepatomegaly or splenomegaly).
^c MCyR combines both complete (No detectable Ph+ cells) and partial (1% to 35% Ph+ cells) cytogenetic responses.
Database cutoff date 06 February 2017

The median dose intensity was 32 mg/day in the AP-CML patients.

Table 15. Efficacy of Iclusig in resistant or intolerant Ph+ ALL patients:

^a Primary endpoint for AP-CML and BP-CML/Ph+ ALL Cohorts was MaHR, which combines complete haematological responses and no evidence of leukaemia.
^b CHR: WBC ≤ institutional ULN, ANC ≥ 1 000/mm³, platelets ≥ 100 000/mm³, no blasts or promyelocytes in peripheral blood, bone marrow blasts ≤ 5%, < 5% myelocytes plus metamyelocytes in peripheral blood, basophils < 5% in peripheral blood, No extramedullary involvement (including no hepatomegaly or splenomegaly).
^c MCyR combines both complete (No detectable Ph+ cells) and partial (1% to 35% Ph+ cells) cytogenetic responses.
Database cutoff date 06 February 2017

The median dose intensity was 44 mg/day in the BP CML/Ph+ ALL patients.

The median time to MaHR in patients with AP-CML, BP-CML, and Ph+ ALL was 0.7 months (range: 0.4 to 5.8 months), 1.0 months (range: 0.4 to 3.7 months), and 0.7 months (range: 0.4 to 5.5 months), respectively. At the time of updated reporting with minimum follow-up for all ongoing patients of 64 months, the median duration of MaHR for AP-CML (median duration of treatment: 19.4 months) BP-CML (median duration of treatment: 2.9 months), and Ph+ ALL (median duration of treatment: 2.7 months) patients was estimated as 12.9 months (range: 1.2 to 68.4 months), 6.0 months (range: 1.8 to 59.6 months), and 3.2 months (range: 1.8 to 12.8 months), respectively.

For all patients in the PACE phase 2 trial, the dose intensity-safety relationship indicated that there are significant increases in grade ≥ 3 adverse events (cardiac failure, arterial thrombosis, hypertension, thrombocytopenia, pancreatitis, neutropenia, rash, ALT increase, AST increase, lipase increase, myelosuppression, arthralgia) over the dose range of 15 to 45 mg once-daily.

The analysis of the dose intensity-safety relationship in the PACE phase 2 trial concluded that after adjusting for covariates, the overall dose intensity is significantly associated with an increased risk of arterial occlusion, with an odds ratio of approximately 1.6 for each 15 mg increase. In addition, results from logistic regression analyses of data from patients in the phase 1 trial, suggest a relationship between systemic exposure (AUC) and occurrence of arterial thrombotic events. A reduction in dose is therefore expected to reduce the risk of vascular occlusive events, however, the analysis suggested that there may be a 'carry over' effect of higher doses such that it might take up to several months before a dose reduction manifests in risk reduction. Other covariates that show a statistically significant association with the occurrence of vascular occlusive events in this analysis are medical history of ischemia and age.

Dose reduction in CP-CML patients

In the PACE phase 2 trial, dose reductions were recommended following adverse events. Additional recommendations for prospective dose reduction in all CP-CML patients in the absence of adverse events were introduced in this trial with the aim of reducing the risk of vascular occlusive events. With a minimum follow-up of 48 months, and approximately 2 years after the recommendation for prospective dose reduction, there were 110 CP-CML patients ongoing. A majority of these ongoing patients (82/110 patients; 75%) were reported to be receiving 15 mg at the last dose, while 24/110 patients (22%) were receiving 30 mg, and 4/110 (4%) were receiving 45 mg. At the time of study closure initiation (minimum follow-up of 64 months, and more than 3 years after the recommendation for prospective dose reduction), 99 CP-CML patients were ongoing and 77 (78%) of these patients received 15 mg as their last dose on study.

Safety

In the phase 2 trial, 86 CP-CML patients achieved MCyR at a dose of 45 mg, 45 CP-CML patients achieved MCyR after a dose reduction to 30 mg, mostly for adverse events. Vascular occlusive events occurred in 44 of these 131 patients. Most of these events occurred at the dose at which the patient achieved MCyR; fewer events occurred after dose reduction.

Table 16. Vascular occlusive first adverse events in CP-CML patients who achieved MCyR at 45 mg or 30 mg (data extraction 7 April 2014):

The median time to onset of the first cardiovascular, cerebrovascular, and peripheral vascular arterial occlusive events was 351, 611, and 605 days, respectively. When adjusted for exposure, the incidence of first arterial occlusive events was greatest in the first two years of follow-up and declined with decreasing daily dose intensity (following recommendation for prospective dose reduction). Factors other than dose may also contribute to this risk of arterial occlusion.

Efficacy

Data from the PACE phase 2 trial are available for the maintenance of response (MCyR and MMR) in all CP-CML patients who underwent dose reduction for any reason. Table 17 shows these data for patients who achieved MCyR and MMR at 45 mg; similar data are available for patients who achieved MCyR and MMR at 30 mg.

The majority of patients who underwent a dose reduction maintained response (MCyR and MMR) for the duration of currently available follow-up. A proportion of patients did not undergo any dose reduction, based on an individual benefit-risk assessment.

Table 17. Maintenance of response in CP-CML patients who achieved MCyR or MMR at 45 mg dose (data extraction 6 February 2017):

The anti-leukaemic activity of Iclusig was also evaluated in a phase 1 dose escalation study that included 65 CML and Ph+ ALL patients; the study is completed. Of 43 CP-CML patients, 31 CP-CML patients achieved a MCyR with a median duration of follow-up of 55.5 months (range: 1.7 to 91.4 months). At the time of reporting, 25 CP-CML patients were in MCyR (median duration of MCyR had not been reached).

OPTIC open-label randomized Phase 2 Trial

The safety and efficacy of Iclusig was evaluated in the OPTIC phase 2 trial, a dose-optimization trial. Eligible patients had CP-CML whose disease was considered to be resistant to at least 2 prior kinase inhibitors or who have the T315I mutation. Resistance in CP-CML while on a prior kinase inhibitor was defined as failure to achieve either a complete hematologic response (by 3 months), a minor cytogenetic response (by 6 months), or a major cytogenetic response (by 12 months), or development of a new BCR-ABL1 kinase domain mutation or new clonal evolution. Patients were required to have > 1% BCR-ABL1IS (by real-time polymerase chain reaction) at trial entry. Patients received one of three starting dosages: 45 mg orally once daily, 30 mg orally once daily, or 15 mg orally once daily.

Patients who received a starting dose of 45 mg or 30 mg had a mandatory dose reduction to 15 mg once daily upon achieving ≤ 1% BCR-ABL1IS. The primary efficacy endpoint was a molecular response based on the achievement of ≤ 1% BCR-ABL1IS at 12 months. All patients reached the 12-month time point (primary endpoint) by the primary analysis data cut-off. The median duration of follow-up for the 45 mg cohort (N=94) was 77.9 months (95% CI: 72.4, 84.0). Only the efficacy results for the recommended starting dose of 45 mg are described below. A total of 282 patients received Iclusig: 94 received a starting dose of 45 mg, 94 received a starting dose of 30 mg, and 94 received a starting dose of 15 mg. Baseline demographic characteristics are described in Table 18 for patients who received a starting dose of 45 mg.

Table 18. Demographic and disease characteristics for the OPTIC trial:

Efficacy results are summarised in Table 19.

The primary endpoint was met in patients who received a starting dose of 45 mg.

Overall, 44% of patients had one or more BCR-ABL kinase domain mutations at study entry with the most frequent being T315I (27%). The subgroup analysis based on baseline T315I mutation status showed similar ≤ 1% BCR-ABL1IS rates at 2 months in patients with and without T315I (see Table 19 below). No mutations were detected at study entry for 54% of the patients who received the starting dose of 45 mg.

With a median follow up of 6.5 years among patients with CP-CML, the proportion of patients experiencing transformation of their disease to either AP-CML or BP-CML was 11.7% and 3.2% respectively.

Table 19. Efficacy results in patients with CP-CML who received Iclusig at starting dose of 45 mg in the OPTIC phase 2 trial:

^a ITT population (N=93) defined as patients who had b2a2/b3a2 BCR ABL1 transcripts.
^b Primary endpoint was ≤1% BCR-ABL1IS rate at 12 months. Defined as a ≤1% ratio of BCR ABL to ABL transcripts on the International Scale (IS) (i.e., ≤1% BCR-ABLIS; patients must have the b2a2/b3a2 (p210) transcript), in peripheral blood measured by quantitative reverse transcriptase polymerase chain reaction (qRT PCR).
^c 98.3% CI is calculated using the binomial exact (Clopper-Pearson) method.
^d Of the 93 patients, two patients did not have a baseline mutation assessment and were excluded from the response by mutation analysis.
^e Secondary endpoint was MCyR by 12 months which combines both complete (no detectable Ph+ cells) and partial (1% to 35% Ph+ cells in at least 20 metaphases) cytogenetic responses.
^f Analysis is based on ITT cytogenetic population (N=91) defined as patients who had a cytogenetic assessment at baseline with at least 20 metaphases examined. One patient who had a complete cytogenetic response at baseline was excluded from the analysis.
^g Of the 91 patients, one patient did not have a baseline mutation assessment and was excluded from the response by mutation analysis.

The secondary efficacy endpoints included complete cytogenetic response (CCyR) at 12 months, major molecular response (MMR) at 12 and 24 months, complete hematologic response at 3 months, time to response, duration of response, maintenance of response, progression free survival (PFS), and overall survival (OS). Additional assessment included the rates of molecular response at each patient visit at 3-month intervals for 36 months based on the achievement of ≤1% BCR-ABL1IS.

• At 12 months, 34% (32/93) and 17% (16/93) of patients achieved CCyR, and MMR, respectively. At 24 months, 34% (18/75) of patients achieved MMR. The median duration of MMR had not yet been reached.
• The median duration of ponatinib treatment was 31 months.
• Of the 45 patients who had a dose reduction from 45 mg to 15 mg after achieving ≤1% BCR-ABL1IS, 25 patients (55.6%) maintained their response at the reduced dose for at least one year. Of these 25 patients, 16 patients (64%) maintained the response at 15 mg for greater than 60 months. Median duration of response (MR2) was not reached. The probabilities of maintaining MR2 at 60 months was 68.8% (95% CI, 53.9, 79.8).
• The molecular response rates (≤1% BCR-ABLIS) by 60 months was 64.0% (95% CI 42.5, 82.0) in patients with T315I mutation and 59.1% (95% CI, 46.3, 71.0) in patients without T315I mutation.
• The molecular response rates (≤1% BCR-ABL1IS) at 12 months were lower among patients who had received treatment with ≤2 prior TKIs compared with patients who had received ≥3 prior TKIs (40% vs 48%), respectively).

Patients with newly diagnosed Ph+ ALL

PhALLCON Trial

The efficacy of Iclusig in combination with reduced-intensity chemotherapy followed by continued treatment with Iclusig as a single agent was evaluated in PhALLCON, a randomized, active controlled, multicenter, open label trial.

Eligible patients had newly diagnosed Ph+ALL. Randomization was stratified by age at the time of induction therapy (18 to <45 years; ≥45 to <60 years; and ≥60 years). Patients were randomized (2:1) to receive either Iclusig 30 mg orally once daily or imatinib 600 mg orally once daily in combination with 20 cycles of the chemotherapy regimen, followed by Iclusig or imatinib as monotherapy. The Iclusig dose was reduced to 15 mg once daily after completion of the induction phase and achievement of MRD negative CR. If a patient lost MRD negativity at any time after a response-based dose reduction to 15 mg, re-escalation to 30 mg once daily was allowed. Only patients who achieved CR or incomplete complete remission (CRi) with MRD negativity at the end of induction could continue study treatment at the investigator's discretion.

Study Phases and Regimens:

• Induction Phase: Patients received three 28-day cycles of Iclusig starting dose of 30 mg orally once daily or imatinib starting dose of 600 mg orally once daily; administered from Day 1 to Day 28 of Cycles 1 to 3 of the treatment regimen in combination with:
  • Vincristine: 1.4 mg/m², IV, Days 1 and 14; capped at 2 mg and
  • Dexamethasone: Patients <60 years old received 40 mg, orally, Days 1 to 4 and Days 11 to 14. Patients ≥60 years old: 20 mg, orally, Days 1 to 4 and Days 11 to 14.
• Consolidation Phase (alternating methotrexate and cytarabine): Patients received six 28-day cycles of Iclusig starting with the last induction phase dose; modified dose based on MRD negative CR results or imatinib starting with the last induction phase dose; administered from Day 1 to Day 28 of Cycles 4 to 9 of treatment regimen in combination with:
  • Methotrexate: Patients <60 years old received 1 000 mg/m², IV, Day 1, 24-hour infusion. Patients ≥60 years old received 250 mg/m², IV, Day 1, 24-hour infusion. Rescue: folinic acid. Study Cycles 4, 6, and 8.
  • Cytarabine: Patients <60 years old received 1 000 mg/m² every 12 hours IV, Days 1, 3, and 5, 2-hour infusion. Patients ≥60 years old received 250 mg/m² every 12 hours IV, Days 1, 3, and 5, 2-hour infusion. Study Cycles 5, 7, and 9.
• Maintenance Phase: Patients received eleven 28-day cycles of Iclusig starting with the last consolidation phase dose; modified dose based on MRD negative CR results or imatinib starting with the last consolidation phase dose; administered from Day 1 to Day 28 of Cycles 10 to 20 of treatment regimen in combination with:
  • Vincristine: 1.4 mg/m², IV, injected over 1 minute on Day 1 of each maintenance phase cycle, 1 injection/month; capped at 2 mg and
  • Prednisone: Patients <60 years old: 200 mg/d, orally, on Days 1 to 5. Patients ≥60 to 69 years old: 100 mg/d, orally, on Days 1 to 5. Patients ≥70 years old: 50 mg/d, orally, on Days 1 to 5.

Following 20 cycles of Iclusig or imatinib in combination with the chemotherapy, patients continued to receive Iclusig (21%) or imatinib (9%) as single-agent therapy until relapse from complete remission (CR), progressive disease (PD), proceeded to HSCT, proceeded to alternative therapy, or unacceptable toxicity. Baseline demographic characteristics of the randomized population are described in Table 20.

Table 20. Demographic and disease characteristics for PhALLCON:

^a Randomization was stratified by age (18 through <45 years; ≥45 through <60 years; and ≥60 years)
^b White blood cell count based on 10^9/L

The major efficacy outcome measure was MRD negative CR at the end of induction. MRD negativity was defined as ≤0.01% BCR-ABL1 as determined by central laboratory tests. CR status was defined as having <5% blasts in the bone marrow and no extramedullary disease with hematologic recovery for at least 4 weeks as assessed by the investigator.

The patient population for analysis of MRD negative CR and molecular response included 232 randomized patients who had a baseline BCR-ABL1 dominant variant of p190 or p210 as determined by central laboratory tests (154 patients in the Iclusig arm and 78 in the imatinib arm).

The key secondary efficacy outcome measure of event-free survival (EFS) was defined as the time from randomization to the first occurrence of any of the following events: failure to achieve CR by the end of induction, relapse from CR, or death due to any cause. The patient population for EFS was based on 245 randomized patients in the ITT population with 164 randomized patients in the Iclusig arm (including 1 patient who died due to COVID before receiving the first dose) and 81 randomized patients in the imatinib arm, unless otherwise specified.

The overall rate of HSCT was 34% (56/164) in the Iclusig arm versus 48% (39/81) in the imatinib arm.

The median duration of follow-up for overall survival was 20.43 months (95% CI: 18.39, 23.93) in the Iclusig arm and 18.14 months (95% CI: 13.86, 24.25) in the imatinib arm.

The study demonstrated a statistically significant higher MRD negative CR rate at the end of induction for patients randomized to the Iclusig arm compared to the imatinib arm.

At the data cutoff point, the results for the key secondary efficacy outcome measure of EFS were not mature, with 33.5% of the required events for final analysis (34/164 events in the Iclusig arm and 24/81 events in the imatinib arm).

Efficacy results are summarized in Table 21.

Table 21. Efficacy results in patients with Ph+ ALL in PhALLCON^a:

MRD: minimal residual disease; CR: complete response; MR: molecular response; BCR-ABL1: breakpoint cluster region-Abelson.
^a Based on 232 randomized patients who had a BCR-ABL1 dominant variant of p190 or p210 as determined by central laboratory tests at baseline.
^b MRD-negative CR rate is defined as the proportion of patients who achieved MRD-negative CR (≤0.01% BCR-ABL1/ABL1 or undetectable BCR-ABL1 transcripts in cDNA with ≥10,000 ABL1 transcripts, and meeting criteria for CR).
^c Difference and 95% CI: adjusted risk ICLUSIG – adjusted risk imatinib, and its 95% CI.
^d p-value is based on Cochran-Mantel-Haenszel (CMH) chi-square test, with stratification according to randomization strata (age): 18 through <45 years, ≥45 through <60 years, and ≥60 years
^e Adjusted Relative Risk and its 95% CI based on CMH method as defined in Footnote [d].

Paediatric population

CP-CML

A phase ½ open-label, single-arm study (Study 102) in paediatric population has evaluated the tolerability, safety, PK/pharmacodynamics, and efficacy of oral ponatinib in 61 paediatric participants (≥1 to <18 years old) with recurrent or refractory leukemias, lymphomas, or solid tumors, with a CP-CML expansion cohort.

A total of 10 patients from 6 to <18 years of age with CP-CML who were resistant to or intolerant of at least 1 prior BCR-ABL–targeted TKI therapy or who had the kinase domain mutation T315I received ponatinib treatment.

In participants with CP-CML, the median exposure to ponatinib was 533 days (range: 72, 1 100) and the median average daily dose was 40.59 mg.

The primary efficacy endpoint for participants with CP-CML was MCyR by 12 months assessed by conventional cytogenetics or FISH. The secondary endpoints were CHR at 6 months, CCyR at 12 months, Major molecular response (MMR) at 12 months, TTR, DoR, PFS, and OS.

All participants (100%) with CP-CML had received prior BCR-ABL TKI treatment.

In those participants, Major Cytogenetic Response Rate (MCyR) by 12 months was 90.0%. The Complete hematologic response (CHR) at 6 months was 90%. the median time to CyR was 1 month and to MR 2.83 months. The clinical efficacy and safety profile of ponatinib in the paediatric CP-CML population was consistent with the profile observed in the adult CP-CML population.

Ph+ALL

A phase 1/2, single-arm, open-label, multicenter study (Study 1501) in 11 paediatric participants aged 9-17 years has evaluated the safety, tolerability, PK, and efficacy of ponatinib when administered in combination with multiagent chemotherapy, for the treatment of Ph+ ALL in children with Ph+ ALL, Ph+ MPAL, or Ph-like ALL disease that had relapsed or was resistant or intolerant to at least 1 prior BCR-ABL TKI-containing therapy, or with Ph+ ALL disease with T315I mutation.

The study in paediatric participants with R/R Ph+ ALL treated with ponatinib in combination with an intensive, 4-agent induction chemotherapy regimen (PEG-asparaginase, daunorubicin, dexamethasone, and vincristine) demonstrated that the combination of ponatinib once a day with an intensive, 4-agent chemotherapy regimen is not tolerated in those patients.