Ponatinib Demonstrates Deep and Durable Responses vs Imatinib in Ph+ ALL

Elias Jabbour, MD

Treatment with ponatinib (Iclusig) led to significantly higher minimal residual disease (MRD)-negativity complete response (CR) rates in patients newly diagnosed Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) compared with imatinib (Gleevec) in the phase 3 PhALLCON trial (NCT03589326).

In the study, ponatinib led to more deep and durable responses, and showed a trend toward improved event-free survival in this patient population. The primary end point of MRD-negative CR rate at the end of induction was 34% vs 17% (P = .0021), and there was an MRD-negativity rate of 42% vs 21% for the ponatinib vs imatinib arms.

Additionally, there was comparable safety data between arms. These findings show that the combination of ponatinib and reduced-intensity chemotherapy may be more effective compared with imatinib in this patient population.

“The PhALLCON trial is showing superior efficacy with ponatinib compared with imatinib in combination with low-dose chemotherapy in patients with newly diagnosed Ph+ ALL with a significantly higher rate and clinically meaningful MRD-negativity complete remission rate at the end of induction,” stated Elias Jabbour, MD, professor of medicine at The University of Texas MD Anderson Cancer Center, in a presentation of findings from the PhALLCON trial during the February 2023 ASCO Plenary Session.

The current standard of care for patients with newly diagnosed Philadelphia chromosome

Ph+ ALL is BCR-ABL1 tyrosine kinase inhibitor (TKIs) in combination with chemotherapy or steroids. Now, the phase 3, open-label, randomized, PhALLCON trial (NCT03589326) is the first randomized study comparing TKIs in patients with Ph+ALL. In the trial, investigators are evaluating ponatinib vs imatinib in combination with reduced-intensity chemo in this newly diagnosed patient population.

The study randomized patients 2:1 to receive ponatinib at 30 mg once daily or imatinib at 600 mg once a day with reduced-intensity chemo through the end of induction, consolidation, and post-consolidation. After cycle 20, patients were given single-agent ponatinib or imatinib until disease progression or unacceptable toxicity.

Investigators evaluated the primary end point was MRD-negativity CR for 4 weeks, and the secondary end point of EFS.

A total of 245 patients were randomized to receive either ponatinib (n = 164) or imatinib (n = 81). The median age of those enrolled was 54 years in the ponatinib arm (range, 19-82) and 52 years in the imatinib arm (range, 19-75). Male patients made up 45% and 47% of patients and 96% and 94% had an ECOG performance status of 0 or 1 in the ponatinib vs imatinib arms. The median range of leukocyte count was 4.4 (range, 0.4-198) and 3.2 (range, 0.2-81). Ninety-two and 52 patients had greater than 1 CV comorbidities, and 45 and 27 patients had 2 or greater CV comorbidities between arms.

At the data cutoff date of August 2022, 78 patients were administered the study treatment, including 42% given ponatinib and 12% given imatinib. Discontinuation on the trial was attributed to hematopoietic stem cell transplantation in 31% of patients given ponatinib vs 37% given imatinib, adverse events (AEs; 12% vs 12%), and lack of efficacy (7% vs 26%).

A total of 37% of the 81 patients who discontinued treatment with imatinib received a second- or third-line generation TKI and/or immunotherapy. Sixteen percent of the 81 patients who received ponatinib then discontinued. In the ponatinib arm, 35% of patients received any subsequent anticancer therapy compared with 57% in the imatinib arm.

The median follow-up for the ponatinib vs imatinib arms were 20 months vs 18 months. Findings revealed that the primary end point was met with a significantly higher MRD-neg CR rate for ponatinib vs imatinib (34.4% vs 16.7%; P = .0021).

While the survival data were not mature, the median EFS was reached in the imatinib arm while it was not reached in the ponatinib arm, and there was a trend toward improvement (HR, 0.652, 95% CI, 0.385-1.104). The PFS in the ponatinib arm was 20.0 (95% CI, 11.8-NE) and was 7.9 (95% CI, 6.2-12.4) in the imatinib arm. OS was also nor reached in either arm at the data cutoff date.

For safety, treatment-emergent AEs (TEAEs) were comparable between arms. Serious TEAEs occurred in 60% vs 56%, grade 3-4 TEAEs were seen in 90% and 93%, and grade 5 TEAEs were observed in 5% in both the ponatinib and imatinib arms. Rates of arterial occlusive events were infrequent and similar between the arms with them being observed in 4 patients in the ponatinib arm vs 1 in the imatinib arm.

“Ponatinib had a safety profile that was comparable with imatinib, which is known to be a very well-tolerated tyrosine kinase inhibitor. The safety profile included similar and lower rates of adverse events. Taken together for this patient population, the efficacy and safety results demonstrate a favorable benefit/risk assessment for ponatinib and should be considered a standard of care for frontline therapy in patients who are newly diagnosed with ALL,” added Jabbour.

REFERENCES:

Jabbour E, Kantarjian HM, Aldoss I, et al. First report of PhALLCON: A phase 3 study comparing ponatinib (pon) vs imatinib (im) in newly diagnosed patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Presented at: 2023 February ASCO Plenary Series. Abstract 398868.