Background
PACE was a phase 2, open-label, single-arm trial (N=449) of ponatinib in CML (all phases) or Ph+ ALL: CP-CML n=267, AP-CML n=83, BP-CML n=62, Ph+ ALL n=32. Eligibility: T315I mutation (any prior TKI) OR resistance/intolerance to ≥2 prior TKIs. Ponatinib is a 3rd-generation pan-BCR-ABL1 inhibitor designed to overcome the T315I gatekeeper mutation.
Interventions and follow up
Regimen: Ponatinib 45 mg PO daily until progression or unacceptable toxicity (later modified to dose-reduction strategies post-marketing)
Primary endpoint: MCyR (CP-CML); MaHR (AP-CML, BP-CML, Ph+ ALL)
mFollow up: 15 months (primary); 60 months (Blood 2018 update)
Primary endpoint: MCyR (CP-CML); MaHR (AP-CML, BP-CML, Ph+ ALL)
mFollow up: 15 months (primary); 60 months (Blood 2018 update)
Results
MCyR (CP-CML): 56% overall; T315I subgroup 70%; no T315I 51%
CCyR (CP-CML): 46%
MMR (CP-CML): 34%
MaHR (AP-CML): 55%
MaHR (BP-CML/Ph+ ALL): 31–38%
5-yr EFS (CP-CML): 53%
5-yr OS (CP-CML): 73% (Blood 2018)
CCyR (CP-CML): 46%
MMR (CP-CML): 34%
MaHR (AP-CML): 55%
MaHR (BP-CML/Ph+ ALL): 31–38%
5-yr EFS (CP-CML): 53%
5-yr OS (CP-CML): 73% (Blood 2018)
Adverse events
Vascular: Arterial thrombotic events 27% at 5-yr (cardiac 13%, cerebrovascular 9%, peripheral vascular 9%) — the major safety concern; VTE 6%; hypertension grade ≥3 16%
Gastrointestinal/Other: Pancreatitis any grade 6%, grade ≥3 5%; serious AEs 67%; grade ≥3 AEs 69% (CP-CML); AE-related discontinuation 22%
Gastrointestinal/Other: Pancreatitis any grade 6%, grade ≥3 5%; serious AEs 67%; grade ≥3 AEs 69% (CP-CML); AE-related discontinuation 22%
Conclusions
Ponatinib achieved a 56% MCyR in heavily pretreated or T315I-mutant CP-CML — uniquely active against T315I (70% MCyR) — filling a critical unmet need as no other approved TKI overcomes T315I. The 27% 5-yr arterial thrombotic event rate at 45 mg represents a substantial cardiovascular burden requiring dose optimization.
Key Limitations
Single-arm trial: No comparator
Vascular toxicity: High ATE rate at 45 mg continuous dosing led to FDA REMS and label restriction to TKI-resistant or T315I-mutant disease
Dose dependency: Optimal dosing not defined in PACE; the subsequent OPTIC trial established dose-reduction strategies
Vascular toxicity: High ATE rate at 45 mg continuous dosing led to FDA REMS and label restriction to TKI-resistant or T315I-mutant disease
Dose dependency: Optimal dosing not defined in PACE; the subsequent OPTIC trial established dose-reduction strategies
Clinical Context
Ponatinib was FDA-approved for T315I-mutant CML or CML resistant/intolerant to ≥2 prior TKIs (December 2012 accelerated; confirmed). It remains the only ATP-competitive TKI active against T315I. The EPIC trial (ponatinib 1L vs imatinib) was terminated early for vascular toxicity, and OPTIC established a response-adjusted dose-reduction strategy (start 45 mg, reduce to 15 mg on achieving ≤1% BCR-ABL) that preserves efficacy while lowering ATE risk. ELN recommends ponatinib for T315I-mutant or multiply TKI-resistant disease.