Efficacy and Safety of Ponatinib in CP-CML Patients By Number of Prior Tyrosine Kinase Inhibitors: 4-Year Follow-up of the Phase 2 PACE Trial

Introduction: Ponatinib is a potent oral tyrosine kinase inhibitor (TKI) approved for use in patients with refractory CML and Ph+ ALL, including patients with the resistant BCR-ABL^T315I mutation. To evaluate whether patient characteristics and outcomes with ponatinib differed by extent of pretreatment with other TKIs, this post hoc analysis examines results among CP-CML patients enrolled in the phase 2 PACE trial (NCT01207440) according to the number of TKIs received prior to study entry. Updated data with 4 years of follow-up will be presented.

Methods: Patients with CML or Ph+ ALL who were resistant or intolerant to dasatinib or nilotinib or who had the T315I mutation were enrolled (N=449). Ponatinib was initiated at 45 mg once daily. CP-CML patients were evaluated based on previous treatment with 1, 2, 3, or 4 prior TKIs approved for use in CP-CML (ie, imatinib, dasatinib, nilotinib, and bosutinib). Data reported in this abstract are as of February 2, 2015.

Results: Overall, 270 CP-CML patients were enrolled and treated in PACE. Patient characteristics and disposition varied by number of prior TKIs (Table 1). Both median age and median time from diagnosis increased with number of prior TKIs; median dose intensity was highest in patients who had received only 1 prior TKI. The most common reasons for discontinuation across groups were adverse events (AEs) and withdrawal by patient request. Responses by number of prior TKIs are shown in Table 2. Rates of cytogenetic and molecular response to ponatinib were higher with fewer prior TKIs. While the frequency of individual AEs did not follow a consistent trend, the incidence of grade ≥3 AEs appeared to increase with the number of prior TKIs received (68%, 86%, 89%, and 100%, respectively); grade ≥3 AEs in ≥10% of CP-CML patients overall were thrombocytopenia (35%), neutropenia (17%), hypertension (13%), increased lipase (12%), and abdominal pain (10%). A similar frequency pattern was observed for serious AEs, which occurred in 58%, 53%, 62%, and 92% of patients who had previously received 1, 2, 3, and 4 approved TKIs, respectively. Serious AEs in ≥5% of CP-CML patients overall were pancreatitis (7%), angina pectoris (5%), and pneumonia (5%). The frequency of arterial occlusive events (AOEs) was 32% (6/19), 26% (25/98), 28% (39/141), and 42% (5/12) by increasing number of prior TKIs; exposure-adjusted incidence rates of new AOEs were 11.75, 10.4, 12.6, and 33.3 events per 100 patient-years, respectively.

Conclusions: With 4 years of follow-up, ponatinib continues to provide benefit to ongoing CP-CML patients in the PACE trial. Analysis by treatment history indicates that patients who had received fewer TKIs prior to study entry appear to exhibit better efficacy and safety profiles. However, treatment decisions should be primarily guided by individual patient and disease factors, including mutation status, and physicians should weigh both the benefits and risks of prescribing ponatinib.

Table 1. Patient Characteristics and Disposition by Number of Prior TKIs

	1 TKI (n=19)	2 TKIs (n=98)	3 TKIs (n=141)	4 TKIs (n=12)
Median age at baseline, years	52	58	63	67
Median time from diagnosis to first dose, years	2.8	5.2	7.9	12.4
Median dose intensity, mg/d	34.0	28.7	29.9	31.0
Mutations detected at baseline, %	68	51	43	75
T315I mutation detected at baseline, %	63	31	16	0
Prior TKI exposure, %, imatinib/dasatinib/nilotinib/bosutinib	68/21/5/5	97/66/36/1	100/96/96/7	100/100/100/100
Remain on study, %	53	48	40	8
Discontinued, %	47	52	60	92
Primary reason for discontinuation, %
AE	16	18	17	33
Withdrawal by patient request	5	11	11	25
Disease progression	16	5	13	0
Lack of efficacy	0	2	9	8
Death	0	2	3	17
Othera	11	13	8	8
Median follow-up, months	42.3	42.9	42.1	28.2

^a Includes noncompliance, physician decision, protocol violation, and other reasons

Table 2. Responses to Ponatinib by Number of Prior TKIs

	1 TKI (n=16a)	2 TKIs (n=98)	3 TKIs (n=141)	4 TKIs (n=12)
MCyR	12 (75)	69 (70)	69 (49)	7 (58)
CCyR	12 (75)	63 (64)	63 (45)	4 (33)
MMR	10 (63)	41 (42)	51 (36)	1 (8)
MR4	6 (38)	30 (31)	38 (27)	1 (8)
MR4.5	4 (25)	22 (22)	34 (24)	1 (8)

All responses are n (%)

^a 16/19 patients were evaluable for efficacy