Ponatinib Versus Imatinib in Patients with Newly Diagnosed Ph+ ALL: Subgroup Analysis of the Phase 3 Phallcon Study

Background: BCR::ABL1 tyrosine kinase inhibitors (TKIs) in combination with chemotherapy or steroids remain the standard of care in patients with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Most patients treated with first- or second-generation TKIs eventually experience disease progression due to treatment resistance. Ponatinib is the only currently approved pan-BCR::ABL1 inhibitory TKI that potently inhibits wild-type and single resistance mutation variants of BCR::ABL1, including T315I. Multiple studies have shown promising minimal residual disease (MRD) negativity (neg) rates and survival outcomes with ponatinib in combination with chemotherapy or chemotherapy-free regimens. PhALLCON (NCT03589326) is the first randomized study comparing frontline TKIs in adults with Ph+ ALL. The primary endpoint for PhALLCON was met, with a clinically significantly higher MRD-neg complete remission (CR) rate at end of induction (EOI) with ponatinib vs imatinib (34.4% vs 16.7%; risk difference: 0.18 [95% confidence interval (CI): 0.06‒0.29]; P=0.0021) and a manageable safety profile comparable with imatinib. Here we report subgroup efficacy analyses from PhALLCON. Methods: This global, registrational, phase 3, open-label study randomized newly diagnosed adult patients with Ph+ ALL 2:1 to receive ponatinib (30 mg once daily [QD]) or imatinib (600 mg QD) plus reduced-intensity chemotherapy through EOI (Cycles 1-3), consolidation (Cycles 4-9), and post-consolidation (Cycles 10-20). Following post-consolidation, patients continued to receive single-agent ponatinib or imatinib until disease progression or unacceptable toxicity. The composite primary endpoint was MRD-neg ( BCR:: ABL1 ≤0.01% [MR4])CR for 4 weeks at EOI. Event-free survival (EFS; any-cause death, failure to achieve CR by EOI, relapse from CR) was a key secondary endpoint. A post-hoc analysis of progression-free survival (PFS; EFS-defined events, failure to achieve MRD-neg by the end of treatment, and loss of MRD-neg) was conducted. Subgroup analyses were performed relative to baseline demographic and disease characteristics. Results: Of 245 randomized patients, 232 (ponatinib, n=154; imatinib, n=78) had baseline BCR::ABL1 p190/p210 variants verified by central lab (efficacy-evaluable population); median age was 54 years (37.1% ≥60 years). As of Aug 2022, 78 patients (ponatinib/imatinib: 68 [41.5%]/10 [12.3%]) remained on study treatment; the top 3 reasons for discontinuation were hematopoietic stem cell transplantation (HSCT; 30.5%/37.0%), adverse events (12.2%/12.3%), and lack of efficacy (7.3%/25.9%). Median follow-up in the ponatinib and imatinib arms was 20 months and 18 months, respectively. Benefit for ponatinib was observed across all subgroups analyzed ( Table). All age subgroups had higher rates of MRD-neg CR with ponatinib vs imatinib, with the greatest benefit observed in patients ≥60 years (40.0% ponatinib vs 10.3% imatinib; P=0.0005). MRD-neg CR rate was higher for ponatinib vs imatinib among those with the BCR::ABL1 p190 variant (38.6%/17.0%; P=0.0017); it was higher for the p210 variant as well, but not significantly (22.5% vs 16.0%; P=0.51). Median PFS was longer with ponatinib vs imatinib regardless of age, with the greatest difference observed in the subgroup of patients ≥60 years (22.5 months for ponatinib vs 8.3 months for imatinib; hazard ratio: 0.594 [95% CI: 0.332-1.063]). Conclusions: Ponatinib was superior to imatinib in combination with reduced-intensity chemotherapy in the front-line setting for patients with Ph+ ALL, with a clinically significantly higher MRD-neg CR rate at EOI. Benefit was observed across all subgroups, particularly for patients ≥60 years and for those with the BCR::ABL1 p190 variant.