Ponatinib Demonstrates Efficacy Over Time for Patients With CP-CML After Prior TKI Failure


High response rates and robust survival outcomes among patients with chronic-phase chronic myeloid leukemia who failed prior treatment with a second-generation tyrosine kinase inhibitor were observed in 2 clinical trials of ponatinib,.

Hapog Kantarijian, MD

High response rates and robust survival outcomes among patients with chronic-phase chronic myeloid leukemia(CP-CML) who failed prior treatment with a second-generation (2G) tyrosine kinase inhibitor (TKI) were observed in 2 clinical trials of ponatinib (Iclusig), according to a presentation given during the 2020 American Society of Hematology (ASH) Annual Meeting.

Findings on ponatinib in the difficult-to-treat patient population were from the pivotal single-arm phase 2 PACE trial (NCT01207440), and the interim analysis of the multicenter randomized phase 2 OPTIC trial (NCT02467270. In PACE, 270 patients with resistant or intolerant CP-CML had deep and durable responses to therapy. In the OPTIC trial, response-based ponatinib dosing was found to be clinically safe for use in 93 patients with highly resistant CP-CML.

Investigators led by Hapog Kantarijian, MD, professor and chair of the Department of Leukemia at The University of Texas MD Anderson Cancer Center, evaluated the use of ponatinib as treatment of patients with CP-CML over time to determine whether the TKI is a safe and effective therapy for patients to switch to after failing a prior 2G TKI.

Ponatinib was administered at 45 mg daily in both clinical trials. Patients eligible for enrollment in the PACE trial were those resistant or intolerant to a prior TKI or BCR-ABL T315I+ inhibitor. The median follow-up in the PACE study was 56.8 months. In the ongoing OPTIC study, the treatment duration for the interim analysis was 24 months. Dosing of ponatinib was notably decreased to 15 mg per day in the OPTIC study for patients who achieved a response. Overall, the patient population assessed to investigate the safety and efficacy of ponatinib in CP-CML included 350 individuals.

At baseline, the median age of patients was 61 years in the PACE group and 46 years in the OPTIC group. The PACE group was predominantly male (52%), as was the OPTIC group (53%). The median time to diagnosis of CP-CML was 7 years for those enrolled in PACE, and 6 years for those in OPTIC. BCR-ABL1 mutations were found in 47% of the PACE patients and 43% of the OPTIC patients at baseline. Of the BCR-ABL1 mutations found, T315I was found in 21% of the PACE group and 26% of the OPTIC group. BCR-ABL1 mutations other than T315I was also found in 26% of patients in PACE and 17% of those in OPTIC.

Many patients presented with cardiovascular risk factors at baseline including hypertension, diabetes, and hypercholesterolemia. In the PACE and OPTIC cohorts, respectively, 39% and 31% had hypertension, 13% and 5% had diabetes, and 25% and 3% had hypercholesterolemia.

The majority of patients in both cohorts were previously treated for resistance prior to discontinuation of the therapy they developed resistance to. Prior resistance was noted at baseline in 96% of the PACE group and 98% of those enrolled in OPTIC. Most patients had 3 prior 2G TKIs, including 57% of patients in the PACE study and 45% in the OPTIC study. Overall, 98% of all patients received 2 or more ≥2 prior 2G TKIs, 60% received ≥3, and 97% were resistant to at least 1 prior 2G TKI.

Response to prior 2G TKI treatment was assessed at baseline and showed that more patients in the OPTIC study (58%) had a complete hematologic response (CHR) compared with patients in the PACE study (27%). A CHR or worse was observed in 56% of patients from the 2 trials combined. The cohorts appeared to have similarly high BCR-ABL1IS expression, and overall, only 4% of patients in these studies had an expression ≤1.

Efficacy of ponatinib in the PACE and OPTIC trials over time was assessed through ≤1 BCR-ABL1IS, as well as progression-free survival (PFS), and overall survival (OS) rates. The response rate for patients with ≤1 BCR-ABL1IS at 12 months was 42% for the PACE patients and 47% for the OPTIC patients. At 24 months, the response rate was 46% and 52%, respectively. Finally, at 60 months, the response rates were 47.1% and not applicable (NA), respectively.

Ponatinib led to a 67% 2-year PFS rate in the PACE population and an 81% 2-year PFS rate in the OPTIC population. At 5 years, the PFS rates were 52% and NA, respectively. The 2-year OS rate was 85% for patients in the PACE study and 93% for those in the OPTIC study. The 5-year OS observed in PACE was 73% and in OPTIC, the rate was NA.

Differences in efficacy in both studies based on the number of prior 2G TKIs varied according to which efficacy outcome was being evaluated. Patients with BCR-ABL1IS mutations in the PACE study appeared to have comparable response rates of 47% and 39% with 1 prior line versus 2 or more prior line of therapy at 12 months. However, response rates were more than 10% higher at the 24- and 60-month mark in patients who received 1 prior 2G TKI compared with those who received ≥2. In the OPTIC study, response rates were consistent between the patients with 1 or more prior 2G TKIs across the board. There was also a more than 10% difference in 3- and 5-year PFS rates among patients with 1 or more prior 2G TKIs in the PACE study, but the rates in the OPTIC study appeared comparable. OS rates were similar overall.

Kantarijian noted during his presentation that the efficacy of ponatinib as observed in PACE and OPTIC occurred regardless of mutational status.

The safety analysis showed that grade 3/ 4 adverse events (AEs) occurred in 89% of the PACE population and 67% of the OPTIC population. In addition, grade 3 or 4 treatment-emergent arterial occlusive events (TE-AOEs) were observed in 16% of the PACE group and 3% of the OPTIC.

Over time, the percentage of patients from the PACE trial with TE-AOEs was 7.8 and 7.0% had serious TE-AOEs after less than a year of treatment with ponatinib. After 1 to <2 years of therapy, 15.1% had TE-AOEs and 13.4% had serious TE-AOEs. Just over 11% of patients treated with ponatinib for 2 to <3 years experienced TE-AOEs and 10.3% had serious events. Finally, of the patients in the PACE study who were exposed to ponatinib for 3 years or more, TE-AOEs developed in 14.4% and serious TE-AOEs occurred in 12.8%.

In the OPTIC patient population where the median follow-up was just 21 months, 4.3% of patients who received 1 year or less of ponatinib experienced TE-AOEs, and 1.1% had serious events. Only 2% of patients experienced TE-AOEs and serious TE-AOEs after 1 to <2 years of treatment with ponatinib.

The unadjusted TE-AOE rate for the 38 PACE patients was 0.1413 (95% CI, 0.0996-0.1829) with a 469-day (range, 328-595) median time to first AOE. The 10 patients in the OPTIC study who experience TE-AOEs had an unadjusted TE-AOE rate of 0.03333 (95% CI, 0.0119-0.0547) with a median time to fist AOE of 408 days (range, 272-486). The overall adjusted TE-AOE rate was 0.3564 (95% CI, 0.1961-0.6480).

This safety analysis shows very low toxicity in OPTIC compared with the PACE trial, but the benefit-risk profile of ponatinib was favorable overall among all TKIs for the treatment of patients with CP-CML who failed prior 2G TKIs, regardless of mutation status.


Kantarijian H, Deininger M, Abruzzese E, et al. Efficacy and safety of ponatinib (PON) in patients with chronic-phase chronic myeloid leukemia (CP-CML) who failed one or more second-generation (2G) tyrosine kinase inhibitors (TKIs): Analyses based on PACE and Optic. Presented at: 2020 ASH Annual Meeting and Exposition; December 5-8, 2020; Virtual. Abstract 647.

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