Ponatinib Shows Clinical Activity in T315I-Mutated CP-CML

Ponatinib (Iclusig) demonstrated clinical activity in largely resistant patients with chronic myeloid leukemia (CP-CML) in chronic phase, regardless of T315I mutation status at baseline, according to data presented at the 63rd American Society of Hematology Annual Meeting.

Ponatinib, a third-generation tyrosine kinase inhibitor (TKI), is a pan-inhibitor inhibit BCR-ABL1, with or without single resistance mutations such as T315I. Patients with such mutations tend to inadequately respond to earlier-generation BCR-ALB2 TKIs, leading to poor survival outcomes.

The ongoing phase 2 OPTIC trial (Optimizing Ponatinib Treatment in CP-CML; (NCT02467270) is designed to determine the efficacy and safety of ponatinib in patients with CP-CML who are resistant to 2 or more TKIs or who have a T315I mutation. The interventional study has an actual enrollment of 283 participants and a primary end point of participants with molecular response. Secondary end points include percentage of participants with major molecular response, percentage of participation with major cytogenetic response, duration of major molecular response, time to response, progression-free survival, and overall survival.

During the study, patients were randomized 1:1:1 to receive 1 of 3 ponatinib dose levels. In cohort A, patients received 45 mg of ponatinib once daily in each 28-day cycle. Treatment was continued until achievement of ≤ 1% BCR-ABL1IS. Once this was achieved, participants received ponatinib 15 mg orally once daily. In cohort B, patients received ponatinib at 30 mg and followed the same dose schedule as in Cohort A. In cohort C, patients received ponatinib 15 mg daily.

“I would like to point out is, that most of these patients, literally almost everybody stopped prior TKIs due to resistance. About a third of these patients have at least one cardiovascular risk factor. And the best response to prior TKI is about 60%,” said presenter Michael W. Deininger, MD, PhD, an adjunct professor of Oncological Sciences at the University of Utah School of Medicine during a presentation at the conference.

The median age of patients in cohort A (n = 94) was 46 (range, 19-81) and 53% were male. Ninety-nine percent had an ECOG score of 0 or 1, with a median of 5.5 months (range, 1-21) since diagnosis. Thirty-four percent of patients had at least 1 cardiovascular risk factor and 98% stopped their last TKI for resistance. Seventy-nine percent had > 10% BCR-ABL1IS at baseline. Forty-four percent of patients had a mutation and 27% had a T315I mutation.

The median age of patients in cohort B (N = 94) was 51 (range, 21-77) and 40% were male. Ninety-nine percent had an ECOG score of 0 or 1, and the median time since diagnosis was 5.1 years (range, 1-29). Thirty-two percent of patients had at least 1 cardiovascular risk factor and 100% stopped a prior TKI for resistance. Eighty-six percent of patients had > 10% BCR-ABL1IS at baseline. Thirty-seven percent of patients had a mutation at baseline and 22% had a T315I mutation.

The median age of patients in cohort C (n = 94) was 49 (range, 18-81) and 56% were male. All patients had an ECOG score of 0 or 1, with a median of 5.7 years since diagnosis (range, 1-22). Thirty-four percent of patients had at least 1 cardiovascular risk factor and 100% stopped a prior TKI due to resistance. Seventy-eight percent had > 10% BCR-ABL1IS at baseline. Forty-two percent of patients had a mutation at baseline and 22% had a T315I mutation.

In the 45-mg cohort, the 12-month predicted PFS was 91.60% and the predicted OS was 97.8%. The 24-month predicted PFS was 79.99% and the predicted 24-month OS was 91.28%. The predicted 36-month PFS was 73.25% and the predicted OS was 89.29%.

In the 30-mg cohort, the predicted 12-month PFS was 86.13% and the predicted OS was 97.8%. The 24-month predicted PFS was 76.09% and the predicted 24-month OS was 95.14%. The predicted 36-month PFS was 66.33% and the predicted OS was 88.58%.

In the 15-mg cohort, the predicted 12-month PFS was 84.86% and the predicted OS was 97.86%. The 24-month predicted PFS was 78.06% and the predicted 24-month OS was 93.62%. The predicted 36-month PFS was 69.67% and the predicted OS was 91.71%.

When broken down by mutation, little difference was seen in PFS in patients with no mutations at baseline by dose. In patients with a T3151 mutation, the predicted 36-month PFS was the highest in the 45-mg arm (75%) and the lowest in the 30-mg arm (47%). The same was seen in patients with mutations other than T315Imutation, with the predicted 36-month PFS was 78% in the 45-mg cohort and 67% in the 30-mg cohort.

The ORR in the 45-mg cohort was 60% in those with a T315I mutation and 54% in those without a mutation. In the 30-mg cohort, the ORR in patients with a T315I mutation was 35% and 41% in patients with no mutations. In the 15-mg cohort, the ORR in patients with a. T315I mutation was 11% and 42% in patients with no mutations.

In terms of safety, 100% of patients in the 45-mg cohort, 94% of patients in the 30-mg cohort, and 95% of patients in the 15-mg cohort experienced a treatment-related adverse event (TRAE). In the 45-mg cohort, 68% experienced a grade 3 or higher AE, and TEAEs led to dose modification in 73% of patients. In the 30-mg cohort, 65% of patients experienced a dose modification. In the 15-mg cohort, 61% of patients experienced a dose modification.

In order to participate in the study, patients must be 18 years of age or older, have a diagnosis of CP-CML, an ECOG performance status of 0, 1, or 2, have adequate renal function, adequate hepatic function, adequate pancreatic status, and have recovered from toxicities related to prior anticancer therapy.

Patients who have used any approved TKIs or other investigational agents within 2 weeks prior to receiving the study drug, have undergone autologous or allogeneic stem cell transplant within 60 days proper to first study dose, are being considered for hematopoietic stem cell transplant within 6 to 12 months of enrollment, have previously received ponatinib, have active central nervous system metastases, or have an active infection are not eligible to participate.

“The data presented here further support the benefit of using ponatinib post-second-generation TKI for patients with resistant disease, regardless of disease burden, and T315I_{,” said Deininger during the presentation.}

_REFERENCE:

_{Deininger M, Apperley J, Arthur C, et al. Post Hoc analysis of responses to ponatinib in patients with chronic-phase chronic myeloid leukemia (cp-cml) by baseline BCR-ABL1 level and baseline mutation status in the optic trial. Paper presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 307.}

_{Ponatinib in participants with resistant chronic phase chronic myeloid leukemia (CP-CML) to characterize the efficacy and safety of a range of doses (OPTIC). ClinicalTrials.gov. Accessed December 11, 2021. https://bit.ly/3ykkhX2}