Molecular Response of ≤10% BCR::ABL1IS Is Predictive of Positive Outcomes in Treatment-Resistant Patients with Chronic Phase Chronic Myeloid Leukemia (CP-CML) Treated with Ponatinib from the Phase 2 Optic Trial

Background: BCR::ABL1 mutations are key contributing factors to tyrosine kinase inhibitor (TKI) resistance in patients with chronic myeloid leukemia (CP-CML). Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) designed to potently inhibit BCR::ABL1 with or without any single resistance mutation, including T315I. The Phase 2 OPTIC trial evaluated benefit/risk outcomes of ponatinib using a novel response-based dosing strategy in patients with heavily pretreated resistant CP-CML. In the OPTIC trial, all 3 dosing regimens demonstrated benefit in resistant patients, with optimal benefit/risk outcomes observed in patients who received the response-based dosing of 45 → 15 mg/day. Here we present a post hoc analysis of long-term outcomes (progression-free survival [PFS] and overall survival [OS]) of patients in the OPTIC trial who reached landmark clinical responses (≤1%, >1%–≤10%, and >10% BCR::ABL1^IS by Months 3, 6, and 12).

Methods: The OPTIC trial design has been previously described (Cortes J, et al. Blood. 2021;138:2042-50). Overall, 99% of patients had treatment-resistant disease; 61% of patients had a best response to their last prior therapy of complete hematologic response or worse; and 84% had a best response of >10% BCR::ABL1^IS to prior therapy. This landmark analysis describes PFS and OS in patients with ≤1%, >1%–≤10%, and >10% BCR::ABL^IS by Months 3, 6, and 12. Disease progression was defined as the loss of complete hematologic response or major cytogenetic response, development of acute- or blast-phase CML, death, or 2 instances of white blood cell count increases (>20,000 cells/μL, ≥4 weeks apart) after the first 4 weeks of treatment. Patients with ≤1% BCR::ABL1^IS at baseline were excluded from this analysis. The probabilities of PFS and OS at 24 months were calculated using the Kaplan-Meier method. The proportion of patients attaining ≤1% BCR::ABL^IS by 36 months was also assessed.

Results: A total of 276 patients with resistant CP-CML were included in the intention-to-treat (ITT) population: 45-mg (n=93), 30-mg (n=93), and 15-mg (n=90) starting dose cohorts. At the cutoff date of May 9, 2022, 56 (20%), 78 (28%), and 95 patients (34%) had reached ≤1% BCR::ABL1^IS by Months 3, 6, and 12, respectively. Among patients remaining within each dosing cohort at 36 months, most had attained ≤1% BCR::ABL^IS (57%–65%). Among all ITT patients within each dosing cohort (45 mg, n=93; 30 mg, n=93; 15 mg, n=90), the highest response rate by 36 months was observed in the 45-mg cohort (35%). Four patients with ≤1% BCR::ABL1^IS at baseline were excluded from the landmark analysis. Based on this landmark analysis, regardless of starting dose, patients who attained landmark response levels of ≤1% and >1–≤10% BCR::ABL1^IS in 3–12 months had substantially improved PFS outcomes at 24 months compared with patients with >10% BCR::ABL1^IS (Table). In the landmark analysis population, patients who did not reach ≤10% BCR::ABL1^IS within 12 months had unfavorable PFS outcomes (Table). Long-term OS outcomes in the landmark analysis population were similar across all BCR::ABL1^IS levels, regardless of whether response was reached by 3, 6, or 12 months (Table).

Conclusion: Ponatinib provided robust responses in the OPTIC trial population comprising patients with heavily pretreated, TKI-resistant CP-CML. In this landmark analysis, attainment of ≤10% BCR::ABL1^IS with ponatinib within 12 months was associated with improved long-term PFS outcomes compared with PFS outcomes associated with remaining at >10% BCR::ABL1^IS. These findings underpin the clinical benefit of achieving molecular responses with ponatinib, especially achieving ≤10% BCR::ABL ^IS within 12 months.