070: Population Pharmacokinetic & Exposure-Response Analyses for the Phase 3 PhALLCON Study of Ponatinib in Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

Statement of Purpose, Innovation or Hypothesis: Ponatinib is a tyrosine kinase inhibitor with potent activity against all clinically relevant variants of BCR::ABL1, including the T315I mutation. The phase 3 PhALLCON study (NCT03589326) is comparing ponatinib versus imatinib in combination with reduced-intensity chemotherapy in adults with newly diagnosed Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). The study met its primary endpoint, demonstrating a higher rate of minimal residual disease (MRD)–negative complete remission (CR) at end of induction (EOI) with ponatinib (34.4%) versus imatinib (16.7%; P=0.002). Here, we report population pharmacokinetic (PK) and exposure-response analysis results for ponatinib-treated patients in PhALLCON (data cutoff date: August 12, 2022).

Description of Methods & Materials: Eligible patients were randomized 2:1 to ponatinib or imatinib in combination with 20 cycles of reduced-intensity chemotherapy (induction: 3 cycles; consolidation: 6 cycles; maintenance: 11 cycles). Ponatinib was administered at a starting dosage of 30 mg QD with reduction to 15 mg QD upon achievement of MRD-negative CR at EOI. Sparse PK samples were collected during Cycles 1–12 to measure plasma concentrations of ponatinib. Individual PK parameters were derived using a Bayesian re-estimation approach based on a published population PK model (Hanley, J Clin Pharmacol. 2022;62:555-567). Exposure-response analyses evaluated relationships between ponatinib normalized cumulative exposure and 1) MRD-negative CR at EOI; 2) clinically relevant adverse events (AEs), including arterial occlusive events (AOEs), venous thromboembolic events (VTEs), hypertension, thrombocytopenia, increased lipase, and increased alanine aminotransferase (ALT); and 3) time to first AE-related dose reduction or interruption.

Data & Results: Ponatinib PK was similar between patients in PhALLCON and patients in the previous population PK analysis. No significant relationship was identified between ponatinib exposure and the probability of achieving MRD-negative CR at EOI (odds ratio [OR]: 1.01 [95% CI: 0.982–1.03]; P=0.619), thereby suggesting a consistent efficacy benefit of ponatinib across the exposure range. In the exposure-safety analyses, ponatinib exposure was not a significant predictor of AOEs, VTEs, increased lipase, or thrombocytopenia; however, higher ponatinib exposures were associated with higher probability of experiencing hypertension and increased ALT (Table 1). A ponatinib dose reduction from 30 mg to 15 mg was predicted to decrease the odds of experiencing hypertension by 37.7% (OR: 0.623 [95% CI: 0.403–0.963]) and increased ALT by 44.2% (OR: 0.558 [95% CI: 0.376–0.828]), which supports current dose reduction recommendations for patients experiencing treatment-emergent toxicities. Ponatinib exposure was not predictive of time to first AE-related dose reduction or interruption from Cycle 1 Day 1 to EOI (hazard ratio [HR]: 0.992 [95% CI: 0.975–1.01]; P=0.321). For patients who achieved MRD-negative CR at EOI and without AE-related dose reductions or interruptions during induction, ponatinib exposure was a significant predictor of time to first AE-related dose reduction or interruption after EOI (HR: 1.06 [95% CI: 1.00–1.12]; P=0.0454).

Interpretation, Conclusion or Significance: The exposure-efficacy and exposure-safety analysis results support a favorable benefit-risk profile of the approved ponatinib dosing regimen of a 30 mg QD starting dose with reduction to 15 mg QD upon achievement of MRD-negative CR at EOI, in combination with reduced-intensity chemotherapy, for patients with newly diagnosed Ph+ ALL.

Disclosures: Michael J. Hanley: Employment (Takeda), Thomas R. Larson: Employment (Takeda), Paul Diderichsen: Employment (Certara), consulting (Takeda), Katrina Hui: Employment (Certara), consulting (Takeda), Anna Largajolli: Employment (Certara), consulting (Takeda), Jaydeep Srimani: Employment (Takeda), Bingxia Wang: Employment (Takeda), Alexander Vorog: Employment (Takeda), Neeraj Gupta: Employment (Takeda).

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