Ponatinib is indicated for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in adult patients who are resistant or intolerant to other tyrosine kinase inhibitors (TKIs). The PACE trial found that ponatinib achieved high rates of response in CML and Ph+ ALL patients, including those with the T315I mutation, with durable responses. Common adverse events included rash, hypertension, and myelosuppression. Arterial thrombotic events were observed, with a median onset of 13.8 months, but the exposure-adjusted incidence did not increase over time. Responses were seen in CML and Ph+ ALL

1. Efficacia e tollerabilità di
ponatinib
Massimo Breccia
Azienda Policlinico Umberto I°
Sapienza Università
Roma

2. Indicazioni, posologia e raccomandazioni
Iclusig è indicato in pazienti adulti affetti da:
- LMC in fase cronica, accelerata o blastica resistenti o intolleranti a
dasatinib o nilotinib e per i quali il successivo trattamento con imatinib
non è clinicamente appropriato, oppure in pazienti nei quali è stata
identificata la T315I
- LLA Ph+ resistenti e intolleranti a dasatinib e per i quali il successivo
trattamento con imatinib non è clinicamente appropriato, oppure in
pazienti nei quali è stata identificata la T315I
 La dose raccomandata inizialmente è 45 mg una volta al giorno
 Prima di iniziare il trattamento si deve valutare il profilo
cardiovascolare del paziente e i fattori di rischio cardiovascolare
devono essere gestiti attivamente.

3. Studio fase I

4. Pts disposition

5. Responses

6. Duration of response

7. Profilo di tollerabilità studio di fase 1
 Molti degli eventi avversi registrati erano di entità moderata
 I più frequenti SAEs registrati sono stati: dolori addominali, ipertensione,
incremento di lipasi, fibrillazione atriale, infarto miocardico e pancreatite
 Molti degli eventi avversi sono avvenuti nel primo anno di terapia.
 Tempo mediano di insorgenza di ATEs: 13.8 mesi
 Tempo mediano di insorgenza VTEs: 18.4 mesi
 4 pts hanno sospeso per ATE, 1 pt per VTE. No decessi
Talpaz et al, ASH 2014 abst 4558

8. Studio PACE

9. Methods
• The PACE trial design has previously been described.1
The primary endpoints were MCyR by 12
months for CP-CML and MaHR by 6 months for AP-CML, BP-CML, and Ph+ ALL. Secondary
endpoints included major molecular response (MMR), time to and duration of response,
progression-free survival (PFS), overall survival (OS), and safety
• Response assessments were conducted every 3 months for CP-CML patients
• While 45 mg QD was the starting ponatinib dose, dose reductions to 30 mg QD or 15 mg QD
were allowed to manage AEs
• In October 2013, a partial clinical hold was placed on new patient enrollment in ARIAD-sponsored
ponatinib trials following an accumulation of ATEs with longer-term follow-up2
• Unless benefit–risk analysis justified treatment with a higher dose, the following dose reductions
were recommended in October 2013 for ongoing PACE patients:
– 15 mg/day for CP-CML with MCyR
– 30 mg/day for CP-CML without MCyR
– 30 mg/day for advanced-phase CML
• Exposure-adjusted AE rates were calculated as: [Number of patients with first event in the
specified interval/total exposure for the interval (person years)] × 100
1. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome–positive leukemias. N Engl J Med. 2013;369:1783-
1796.
2. ARIAD announces changes in the clinical development program of Iclusig [press release]. Cambridge, MA: ARIAD Pharmaceuticals, Inc.; October 9,
2013.

10. Baseline Characteristics and Patient
Disposition
Totala,b
N=449
CP-CML
n=270
Median age (range), y 59 (18–94) 60 (18–94)
Median time since diagnosis (range), y 6 (0.3–28) 7 (0.5–27)
Prior TKI therapy,c
n (%)
≥2 TKIs 418 (93) 252 (93)
≥3 TKIs 262 (58) 161 (60)
Median duration of treatment (range), mo 16.7 (0.03–48.5) 32.1 (0.1–48.5)
Median follow-up (range), mo 34.2 (0.1–48.6) 38.4 (0.1–48.6)
Ongoing, n (%) 150 (33) 121 (45)
Discontinued treatment, n (%) 299 (67) 149 (55)
Progressive disease 96 (21) 25 (9)
AE 66 (15) 46 (17)
Deathd
24 (5) 8 (3)
Othere
113 (25) 70 (26)
a
Includes 5 patients (3 CP-CML, 2 AP-CML) who were non–cohort assigned (post-imatinib, non-T315I), but treated; 4 of 5 remain on study; b
44% of
patients had no mutation (51% CP-CML), and 26% had mutations other than T315I (25% CP-CML) at study entry; c
Includes approved and investigational
TKIs; d
7 deaths were assessed by investigators as possibly or probably related to ponatinib (CP-CML: pneumonia, acute myocardial infarction; AP-CML:
fungal pneumonia, gastrointestinal hemorrhage; BP-CML/Ph+ ALL: cardiac arrest, gastric hemorrhage, mesenteric arterial occlusion); e
Includes
withdrawal by subject (including for transplant), lack of efficacy, investigator decision, loss to follow-up, noncompliance, protocol violation, and other
reasons
Data as of 06 October 2014

11. Efficacy of Ponatinib in CP-CML
• 39% of CP-CML patients achieved MMR or better
– Median times to MCyR, CCyR, and MMR for responders were 2.8 (1.6–24.5) months, 2.8 (1.6–35.7)
months, and 5.5 (1.8–32.9) months, respectively
• Responses were durable, with an estimated 83% of patients remaining in MCyR at 36 months
MR4, 4-log molecular response, ≤0.01% BCR-ABLIS
; MR4.5, 4.5-log molecular response, ≤0.0032% BCR-ABLIS
Responses at Any Time Duration of Response
Data as of 06 October 2014

12. Progression-Free Survival and Overall
Survival in CP-CML
a
Progression from CP was defined as death, development of AP or BP, loss of complete hematologic response (in absence of cytogenetic response), loss of
MCyR, or increasing white blood cell count without complete hematologic response
Data as of 06 October 2014

13. Overall Survival in AP-CML, BP-CML, and Ph+ ALL
a
Includes myeloid BP (n=52) and lymphoid BP (n=10) Data as of 06 October 2014

14. Denominator only includes patients who were evaluable at the landmark time point
Patients Achieving Landmark Responses
PatientsAchieving
LandmarkResponse(%)
209 203 175 225 230 191 188 161 207 211 141 137 121 158 162

15. PFS and OS by 3-Month
BCR-ABL ≤1% vs >1%
Two-year PFS and OS based on Kaplan-Meier estimates and calculated from landmark time point (3 months)
Progression defined as death, development of AP or BP, loss of CHR (in absence of cytogenetic response), loss of MCyR, or increasing WBC without CHR
75 68 54 25
133 90 61 27
No. at risk
77 71 65 27
148 128 110 55
2y PFS=87%
2y PFS=62%
2y OS=90%
P=0.0357
2y OS=84%
P=0.0003
2 Years 2 Years
PFS OS

16. PFS and OS by 3-Month
MMR vs No MMR
Two-year PFS and OS based on Kaplan-Meier estimates and calculated from landmark time point (3 months)
32 28 23 11
180 134 95 42
33 30 28 12
197 173 150 71
2y PFS=97%
2y PFS=67%
2y OS=97%
2y OS=84%
P=0.0324P=0.0006
2 Years 2 Years
PFS OS
No. at risk

17. BCR-ABL ≤0.1%
BCR-ABL >0.1–1%
BCR-ABL >1–10%
BCR-ABL >10%
Molecular Response at 3 Months
Correlated With MR4.5
Over Time

18. Profilo di tollerabilità studio PACE
 I più frequenti AEs registrati sono stati: rash e cute secca, sintomi
costituzionali (costipazione, cefalea, fatigue, febbre, nausea, vomito e
diarrea), ipertensione, incremento lipasi, mielosoppressione
(piastrinopenia, neutropenia e anemia)
 I più frequenti SAEs (grado 3/4): piastrinopenia, neutropenia, anemia,
incremento lipasi, ipertensione.
Cortes et al, ASH 2014 abst 3135

19. Eventi CV studio PACE
 Tempo mediano
di insorgenza di
ATEs in CP:
13.8 mesi
 Tempo mediano
di insorgenza
VTEs in CP:
21 mesi
Cortes et al, ASH 2014 abst 3135

20. Exposure-adjusted yearly incidence rate per
studio PACE
Cortes et al, ASH 2014 abst 3135
• Non c’è incremento nell’incidenza di nuovi eventi trombotici arteriosi e venosi con
l’aumentare del tempo di esposizione

21. Rischio di eventi trombotici arteriosi per categoria
Cortes et al, ASH 2014 abst 3135
 Sono da considerare
come fattori di rischio per
ATE:
• Età > 65
• Sesso M
• Diabete
• Precedente ischemia
cardiaca
• Ipertensione
• Ipercolesterolemia
• Avere più di 3 fattori di
rischio concomitanti

22. Occorrenza di ATEs in accordo alla
riduzione di dose (studio PACE)
Cortes et al, ASH 2014 abst 3135
 5/70 (7%) pazienti senza precedenti ATEs hanno avuto un nuovo evento trombotico
arterioso dopo una riduzione prospettica del dosaggio
 7/67 (10%) pazienti che hanno mantenuto la dose e non avevano avuto un precedente
evento trombotico arterioso hanno avuto un nuovo evento

23. Subanalisi per pts con T315I

24. Baseline Characteristics of Patients With T315I
CP-CML
(n=76)
AP-CML
(n=19)
BP-CML
(n=26)
Ph+ ALL
(n=26)
Total
(N=147)
Median age, years (range) 50 (18–87) 52 (24–78) 47 (18–74) 62 (23–80) 52 (18–87)
Median time since diagnosis,a
years (range) 4.6 (0.8–19) 6.3 (1.1–16) 2.3 (0.5–14) 1.3 (0.5–7) 3.6 (0.5–19)
Median follow-up, months (range) 36 (1.5–70) 21 (3.1–45) 2.9 (0.4–9) 2.7 (0.1–40) 8.9 (0.1–70)
Median dose intensity, mg/day (range) 34 (4.9–56) 38 (7.3–45) 44 (8.0–47) 45 (1.7–60) 39 (1.7–60)
Stem cell transplant, n (%) 1 (1) 2 (11) 6 (23) 5 (19) 14 (10)
Prior TKI therapy, n (%)
1 TKI 11 (14) 3 (16) 1 (4) 7 (27) 22 (15)
2 TKIs 35 (46) 6 (32) 13 (50) 12 (46) 66 (45)
≥3 TKIs 30 (39) 10 (53) 12 (46) 7 (27) 59 (40)
Data as of 26 September 2014 (Phase 1) and 6 October 2014
a
Time from initial diagnosis to first dose date; AP, accelerated phase; BP, blast phase
> The analysis included 147 patients with a baseline T315I mutation from the phase 1 (n=19)
and PACE (n=128) trials, with a median follow-up of 3 years for CP-CML patients
> Overall, PACE patients with T315I at baseline were younger, less heavily treated, and had a
shorter time since diagnosis, compared with the overall PACE population1,2
1. Cortes JE, et al. N Engl J Med. 2013;369:1783-1796. 2. Cortes JE, et al. ASH 2014 (abstract 3135).

25. Response at Any Time in Patients with T315I
n (%)
CP-CML
(n=76)
AP-CML
(n=19)
BP-CML
(n=26)
Ph+ ALL
(n=26)
MaHR NA 11 (58) 7 (27) 10 (38)
MCyR 57 (75) 12 (63) 8 (31) 10 (38)
CCyR 55 (72) 8 (42) 5 (19) 8 (31)
MMR 46 (61) 7 (37) 1 (4) 2 (8)
MR4 34 (45) 0 0 1 (4)
MR4.5 28 (37) 0 0 0
CCyR, complete cytogenetic response; MaHR, major hematologic response; MCyR, major cytogenetic response; MMR, major molecular response; MR4, 4-log
molecular response, ≤0.01% BCR-ABLIS
; MR4.5, 4.5-log molecular response, ≤0.0032% BCR-ABLIS
; NA, not applicable
In the phase 1 trial, CP-CML patients with T315I (n=12) had the following responses, n (%): MCyR, 11 (92); CCyR, 10 (83); MMR, 9 (75); MR4, 8 (67); MR4.5, 6 (50)
In the PACE trial, CP-CML patients with T315I (n=64) had the following responses, n (%): MCyR, 46 (72); CCyR, 45 (70); MMR, 37 (58); MR4, 26 (41); MR4.5, 22 (34)
Data as of 26 September 2014 (Phase 1) and 6 October 2014

26. Duration of MCyR and CCyR in CP-CML Patients With T315I
a
Loss of response is defined as a single time point at which the criteria for response are not met
> Majority of CP-CML patients with the T315I mutation at baseline maintained response
- 83% of patients were estimated to remain in MCyR at 3 years
- 81% of patients were estimated to remain in CCyR at 3 years
> Median duration of response not reached
Data as of 26 September 2014 (Phase 1) and 6 October 2014

27. Progression-Freea
and Overall Survival in Patients With
T315I Mutation in the PACE Trial
a
Progression from CP was defined as death, development of AP or BP, loss of complete hematologic response (in absence of cytogenetic response), loss of
MCyR, or increasing white blood cell count without complete hematologic response
> In the phase 1 trial (OS and PFS not collected), 11/12 CP-CML patients are alive and
ongoing; 1 patient discontinued because of disease progression
Data as of 26 September 2014 (Phase 1) and 6 October 2014
36-mo PFS: 59%
36-mo PFS: 40%
Median: 31.5 mo
36-mo PFS: 0% (BP-CML)
Median: 4.1 mo
36-mo PFS: 0% (Ph+ ALL)
Median: 2.6 mo
36-mo OS: 78%
36-mo OS: 63%
36-mo OS: 0% (BP-CML)
Median: 6.9 mo
36-mo OS: 7% (Ph+ ALL)
Median: 6.5 mo

28. Studio EPIC

35. • Fino ad oggi sono noti pochi effetti diretti di ponatinib sulle cellule
vascolari, ma preliminari osservazioni (P. Valent et al) sono state
fornite di effetto sulla crescita e sopravvivenza, al pari di nilotinib.
• Sono in corso studi di valutazione su eventuali target molecolari
responsabili di effetti “off-target”: VEGF, KDR (target di ponatinib) e
TEK/Tie-2.
• Per nilotinib al contrario sono stati evidenziati: meccanismi
metabolici (iperglicemia, ipercolesterolemia), effetti diretti pro-
aterogenici (up-regolazione molecole di adesione sulle cellule
endoteliali e vasospasmo), effetti anti-angiogenici (effetto inibitorio
diretto sulla crescita delle cellule endoteliali con conseguente
ridotta ricanalizzazione), funzioni piastriniche alterate, riduzione
mast-cells.
Meccanismi potenziali per eventi CV
Valent et al, Blood 2014

36. • Attività in vitro di ponatinib e altri TKIs su colture cellulari (Ba/F3),
ASMC (aortic smooth muscle cells), HUVEC (umbilical vein), HAEC
(aortic), HPAEC (pulmonary artery endothelial cells).
• Ponatinib inibisce in vitro l’attività di kinasi multiple con IC50s entro
10-fold di ABL, incluso VEGFR, PDGFR, FGFR, EPH receptor e SRC
kinases, KIT, RET, TIE2, e FLT3.
• Per le cellule derivate da colture vascolari, ponatinib inibisce la
viabilità e la crescita di HUVEC con IC50 di 261 nM, mentre gli altri
TKIs hanno un IC50s >2000 nM. Effetti modesti di ponatinib su
HAECs, HPAECs e ASMCs (rispettivamente, IC50s 1533, 490 e 750
nM).
• Ponatinib (IC50 20 nM) e altri inibitori di VEGFR2 inibiscono
potentemente la sopravvivenza e la crescita di HUVECs.
Comparative TKI Profiling Analyses to Explore Potential
Mechanisms of Ponatinib-Associated Arterial Thrombotic Events
Rivera et al, ASH 2014; abstr 1783

37.  Iclusig non dovrebbe essere utilizzato in pazienti con storia
pregressa di infarto miocardico, precedente rivascolarizzazione o
stroke, bilanciando rischi-benefici del trattamento. In questi pazienti
dovrebbero essere considerate strategie terapeutiche opzionali.
 Un monitoraggio continuo per occlusioni vascolari e possibile
tromboembolismo dovrebbe essere eseguito e il farmaco
interrotto immediatamente in caso di occlusione. Considerare poi i
rischi/benefici per riprendere successivamente la terapia.
 L’ipertensione può contribuire al rischio di eventi arteriosi
trombotici. Durante il trattamento con Iclusig è importante
monitorizzare la pressione arteriosa e correggerla ad ogni visita
di controllo. Iclusig dovrebbe essere temporaneamente interrotto se
la pressione arteriosa non è controllata.
Raccomandazioni (II)
Iclusig SmPC Sep 2014

38. Impact of Dose Intensity of Ponatinib on Selected Adverse
Events: Multivariate Analyses from a Pooled Population of
Clinical Trial Patients
• Univariate and multivariate logistic regression analyses were conducted
for each outcome (presence/absence of treatment-emergent AEs) and
dose intensity measure (average daily dose through day of event) in 671
patients with all baseline covariates (diabete, storia di eventi CV, età, etc).
• Dall’analisi risulta che, aggiustando per i fattori predisponenti, alcuni
eventi avversi (pancreatite, rash ed eventi CV) risultano fortemente
correlati alla dose intensity.
Knickerbocker et al ASH 2014; abstr 4546

39. Conclusioni
• Dagli studi presentati conferma dell’efficacia
di ponatinib in varie fasi di malattia
• Dosaggio raccomandato attuale ancora 45 mg
• Seguire raccomandazioni come da scheda
tecnica