Ponatinib Could Herald "Revolution" in CML Treatment

Published on: 
OncologyLive, December 2012, Volume 13, Issue 12

For the past six years, researchers have been working to develop a treatment for patients with CML who have become resistant to the groundbreaking drug imatinib and to the TKIs dasatinib and nilotinib that were developed subsequently.

Michael J. Mauro, MD

Associate Professor

Knight Cancer Institute

Oregon Health & Science University

Portland, OR

For the past six years, researchers have been working to develop a treatment for patients with chronic myeloid leukemia (CML) who have become resistant to the groundbreaking drug imatinib and to the tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib that were developed subsequently. Now a new therapy, ponatinib, is ready and recently approved by the FDA.

In October, the FDA accepted a New Drug Application for ponatinib as treatment for patients with refractory chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphocytic leukemia (Ph+ ALL), according to Ariad Pharmaceuticals, the Cambridge, Massachusetts, company developing the drug. The FDA agreed to give the application a priority review, which resulted in an approval of the agent 3 months ahead of schedule (Find out more).

Ponatinib is particularly promising because it can treat patients who exhibit a T315I mutation, something no other approved TKI has been able to do, researchers have said. In the pivotal PACE trial, 29% of the participating patients harbored that mutation, according to research presented at the 2012 American Society of Hematology Annual Meeting.1

Moreover, the drug is effective “across the board” for patients with CML, regardless of whether they have resistance mutations or what form those mutations take, said Michael J. Mauro, MD, who manages CML clinical trials at the Knight Cancer Institute at Oregon Health & Science University (OHSU). Mauro partners with Brian J. Druker, MD, who pioneered the development of imatinib there.


In a recent interview with OncologyLive, Mauro provided details about ponatinib.

OncologyLive: How was ponatinib designed?Mauro: Ponatinib is a rationally designed, small-molecule organic compound developed by Ariad in Cambridge, Massachusetts. Unlike Gleevec [imatinib], which was not built for CML but taken from a library of drugs with the right properties, ponatinib was created based on the need for a drug that worked where others would not. Ariad grew the pathway and asked, “How do we build a molecule that will fit this target, bcr-abl, when the T315I mutation exists?” Then, they designed ponatinib rationally to meet this specific need, in addition to the ongoing need to inhibit other BCR-ABL configurations (normal, also known as wild type, and other common mutations).

What kinds of results were seen in early testing of ponatinib?

Before the first-in-human (phase I) trial, our lab conducted studies using leukemia cells that were likely to generate mutations to outsmart a treatment. Ponatinib stopped the outgrowth of any mutation in this setting, something no other drug could do. Our site was keen to move forward and was one of five centers that ran the initial clinical trial.

Phase I results, which will soon be published, confirmed that ponatinib was effective across the board, regardless of mutational status, and seemingly particularly effective against the T315I mutation. The cytogenic response rate was over 70% for all patients and 90% for patients with T315I.

A much larger global phase II trial, which our site and many others participated in, clearly supported the effectiveness of ponatinib. With limited exposure (less than one year), the drug elicited hematologic response and major cytogenic response (MCyR) in between one-third and onehalf of patients with advanced forms of CML. In the chronic phase, overall, half of patients achieved MCyR and more than a third complete cytogenic response (CCyR), with a number in major molecular response at this early time point. As had been demonstrated previously, there was a higher response rate among chronic-phase patients with the T315I mutation.

Remissions in long-term follow-up of phase I patients have been very durable. The length of follow-up has been shorter in the larger phase II trial; it is thus a bit early to analyze progression-free or overall survival, which will be best looked at year to year.

Is further study of ponatinib planned?

A phase III trial is beginning that will enroll newly diagnosed CML patients and randomize them to receive either imatinib or ponatinib. It will be interesting because, while imatinib is certainly a proven option, people now can use multiple different medications as their first choice. The trial will likely best help us to understand the comparative risks and benefits in newly diagnosed CML patients of taking more powerful drugs, and the potential ability of ponatinib to prevent resistance, which could represent an improvement over the resistance prevention offered by all current options for newly diagnosed CML.

Where does ponatinib fit into the treatment paradigm for CML?

Today, the majority of CML patients have a very good outcome. While ponatinib is proven to work very well with multidrug-resistant CML, how soon we use it and whether we use it initially will depend on more data on safety and further trial outcomes. Ponatinib will have to perform better than existing TKIs, stop resistance, and be very safe–it will have to be a “high jumper.” That said, if the drug can fill both the gap in our armor of drugs to treat highly resistant cases and prove to be our best initial choice, it will truly be declared another revolution in CML treatment and bring us closer to a cure.


1. Cortes JE, Kim D-W, Pinilla-Ibarz J, et al. A pivotal phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) resistant or intolerant to dasatinib or nilotinib, or with the T315I BCR-ABL mutation: 12-month follow-up of the PACE trial. Presented at: 54th ASH Annual Meeting and Exposition; December 8-11, 2012; Atlanta, GA. Abstract 163.