Study of Ponatinib Versus Imatinib Meets Primary End Point in Ph+ ALL

Takeda Pharmaceuticals announced that the phase 3 PhALLCON trial of ponatinib for Philadelphia-positive acute lymphoblastic leukemia succeeded in improving the rate of minimal residual disease–negative complete remission.

Ponatinib (Iclusig) showed superiority to imatinib (Gleevec) in the primary end point of the multicenter, randomized phase 3 PhALLCON trial (NCT03589326) in patients with newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL), according to a press release from Takeda Pharmaceuticals.1

The end point of minimal residual disease (MRD)–negative complete remission (CR) favored patients who received ponatinib vs imatinib in addition to reduced-intensity chemotherapy. No new safety signals were observed in the trial.

“Ph+ ALL is a fast-progressing disease with no targeted treatments currently approved in the frontline for patients in the [United States]. There is an urgent need for an effective treatment that can suppress the development of difficult-to-treat mutations, which are associated with poor long-term outcomes,” Awny Farajallah, MD, head of global medical affairs oncology at Takeda, said in a statement.

Ph+ ALL, which affects 25% of adult patients with ALL in the United States, is associated with the BCR-ABL1 gene sequence fusion due to a translocation in chromosomes 9 and 22. Ponatinib is a third-generation tyrosine kinase inhibitor of BCR-ABL1 that inhibits both native BCR-ABL1 and mutated forms associated with resistance to targeted therapy, including the most resistant T315I mutation.

It is approved for treatment of patients with chronic-phase chronic myeloid leukemia (CML) who have received 2 prior kinase inhibitors, those with accelerated-phase or blast-phase CML or Ph+ ALL for whom no other kinase inhibitor is indicated, and those with CML or Ph+ ALL with a T315I resistance mutation.

A phase 2 trial showed efficacy of frontline ponatinib plus chemotherapy, with a 5-year event-free survival (EFS) rate of 67% and a 5-year overall survival rate (OS) of 71%.2

The phase 3 PhALLCON trial will enroll approximately 230 treatment-naive patients with Ph+ ALL in 117 sites across 18 countries starting January 2019.2 As of February 2022, about 226 were randomly assigned on a 2:1 basis to receive either 30 mg of daily ponatinib orally or 600 mg of daily imatinib orally along with reduced-intensity chemotherapy.

The primary end point was MRD-negative CR rate at the end of induction, which is associated with improvement in long-term outcomes.1 A key secondary end point was EFS. Other secondary end points include MRD-negative CR duration, overall response rate, CR duration, time to treatment failure, OS, and safety. There will be a subgroup analysis in patients who did or did not receive a hematopoietic stem cell transplant and an exploratory analysis based on mutational status.

Based on higher rates of MRD-negative CR in those who received ponatinib versus imatinib in the phase 3 trial, the primary end point was met.1 Takeda stated that the results will be presented to regulators and the scientific community in the future.

“We are excited to see how Iclusig may be able to address this gap in care for these patients and look forward to sharing the results,” concluded Farajallah.

References:

1. Phase 3 Trial of ICLUSIG® (ponatinib) met primary endpoint in newly-diagnosed Ph+ ALL, a setting with no targeted treatments approved in the US. Takeda Pharmaceuticals. November 17, 2022. Accessed November 29, 2022. https://bit.ly/3OO9e08

2. Jabbour E, Martinelli G, Vignetti M, et al. PB1762: Ponatinib versus imatinib with reduced-intensity chemotherapy in patients with newly diagnosed Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL): PhALLCON study. Hemasphere. 2022;6(Suppl ):1643-1644. doi:10.1097/01.HS9.0000849904.09812.c6