On March 19, 2024, the treatment paradigm expanded when the FDA green lit ponatinib (Iclusig) for use in combination with chemotherapy for adult patients with newly diagnosed, Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL).

The indication, which was granted under the accelerated approval pathway, was based on findings from the phase 3 PhALLCON trial (NCT03589326) which evaluated the addition of ponatinib to chemotherapy (n = 164) vs imatinib (Gleevec) plus chemotherapy (n = 81). Results showed that ponatinib plus chemotherapy led to a minimal residual disease (MRD)–negative complete remission (CR) rate of 30% at the end of induction vs 12% with imatinib plus chemotherapy (risk difference, 0.18; 95% CI, 0.08-0.28; P = .0004).

“We’re very excited about the completion of the study and meeting the primary end points, as well as the approval of ponatinib,” Ibrahim Aldoss, MD, reported in an interview with OncLive. “As the treatment of [patients with] Ph-positive ALL continues to evolve, this approval introduces more effective agents early in the treatment paradigm, potentially sparing more patients from the need of treatment at the time of relapse.”

In the interview, Aldoss reported on the recent FDA approval of ponatinib in combination with chemotherapy for the treatment of adult patients with newly diagnosed, Ph-positive ALL, highlighting the agent’s efficacy and safety in this treatment landscape.

Aldoss is a hematologist-oncologist, as well as an associate professor in the Division of Leukemia, Department of Hematology and Hematopoietic Cell Transplantation at City of Hope in Duarte, California. He is also a member of the Gehr Family Center for Leukemia Research and is the codirector of the Hematology Tissue Bank at City of Hope and the Leukemia Registry.

OncLive: What is the significance of this approval?

Aldoss: This is the first drug to get approved for newly diagnosed adults with Ph-positive ALL. We [only had] tyrosine kinase inhibitors [TKIs] available. [Ponatinib] is the first drug that is approved as a frontline therapy [in this patient population].

The significance of the [PhALLCON] study itself is that this is the only frontline randomized study performed in adults with newly diagnosed, Ph-positive ALL comparing different TKIs, showing that ponatinib can produce higher MRD-negative CRs at the end of induction compared with what we consider standard of care [therapy with the TKI] imatinib.

Please expand on the mechanism of action of ponatinib.

Ponatinib inhibits BCR:ABL1 and all single-mutation variants, including a very resistant one: the T315I mutation. Usually, first- and second-generation TKIs are resistant to the T315I mutation, which frequently emerges when the patient is treated with frontline TKIs like imatinib. There are some indirect comparisons that suggest ponatinib therapy may improve long-term outcomes compared with these agents when used as a frontline therapy by increasing early and deep MRD-negative rates or by suppressing the emergence of the BCR:ABL1 resistance mutation.

What was the design of the PhALLCON study?

The PhALLCON trial is a global, registrational, phase 3, open-label trial conducted in adults aged 18 years or older with newly diagnosed Ph-positive ALL. Patients were randomly assigned 2:1 to receive ponatinib or imatinib given with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after cycle 20. The study enrolled 245 patients, but the intention-to-treat population consisted of 232 patients who had documented confirmed mutations such as p190 or p210.

The randomization was stratified by the patient’s age when enrolled. Ponatinib dosing was 30 mg given once daily. Once the patient achieved complete molecular remission at the end of the induction or after, the dose was reduced to 15 mg daily to reduce some of the toxicity. The study allowed for re-escalation of the dose of ponatinib to 30 mg if the patient experienced loss of MRD negativity.

For imatinib, the dose was 600 mg daily, which we consider the standard dosing in Ph-positive ALL. The primary end point of the study was MRD-negative CR that [was] maintained for 4 weeks at the end of cycle 3. The reason why [investigators] selected this as the primary end point is achievement of complete molecular remission in the first 3 months of TKI treatment has been correlated with superior long-term survival outcomes. The study included secondary end points like event-free survival [and] overall survival.

What were some of the other notable efficacy findings seen in this trial?

When you account for all MRD negativity at the end of induction, regardless of whether a CR was maintained or not, it was also higher in the ponatinib arm, at 43% vs 22% [in the standard of care arm]. At the data cut-off, event-free survival had not met the prespecified number of events, but progression-free survival [PFS] was evaluated as a new post-hoc analysis end point. The median PFS was significantly higher with ponatinib compared with imatinib and was 12 months longer in the ponatinib arm.

If we look at the study population, there was a greater proportion of patients who are continuing study treatment in the ponatinib group compared with the imatinib group. The proportion of patients who discontinued treatment for lack of efficacy was lower with ponatinib vs imatinib, whereas discontinuation of the study due to adverse effects [AEs] was similar between both arms.

Are there any patients for whom you would hesitate to use this agent because of the AEs that are associated with it?

The most common AEs were similar between the 2 arms. The rate of discontinuation of the treatment was comparable between both arms. Due to toxicity, it was approximately 12% in each group, so it wasn’t significantly different between groups.

One of the concerns when we use ponatinib is the risk of arterial occlusive events [like] venous thromboembolism, and these events were comparable in both arms. For example, arterial occlusive events were only reported in 2.5% vs 1.2% of patients in the ponatinib and imatinib arms, respectively, and the rate of venous thromboembolism was also comparable between both arms, reported at close to 12% in each arm.

The reason why we think the rate of arterial events was low––because that’s one of the concerns with ponatinib––was due to reduced start ponatinib unlike the previous 45-mg dosing. Here, the starting dose was 30 mg and the study recommended lowering the dose to 15 mg if the patient achieved a complete molecular remission. Additionally, there was more stringent exclusion criteria based on previous cardiovascular risk for each patient.

What would you like your colleagues to know about the now FDA-approved agent, ponatinib?

Ponatinib demonstrated superior efficacy vs imatinib combined with reduced-intensity chemotherapy in adults with newly diagnosed, Ph-positive ALL, with significantly higher MRD-negative CR [rates] at the end of induction. Hopefully, with longer follow-up we can have other important secondary end points showing whether ponatinib is superior to imatinib. The overall safety profile for ponatinib was comparable to imatinib.

Reference

FDA grants accelerated approval to ponatinib with chemotherapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. FDA. March 19, 2024. Accessed April 9, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-ponatinib-chemotherapy-newly-diagnosed-philadelphia-chromosome