ATLANTA – Ponatinib succeeds when other drugs for chronic myeloid leukemia begin to fail, investigators reported at the annual meeting of the American Society of Hematology.
In heavily pretreated patients with relapsed or refractory chronic-phase chronic myeloid leukemia (CML), the investigational drug produced a major cytogenetic response (MCyR) in 56% of patients, and a complete cytogenetic response (CCyR) in 46% of patients – many of whom were resistant or intolerant to second- or third-line therapy with dasatinib (Sprycel) and nilotinib (Tasigna).
Approximately half of the patients carried the notorious T315I mutation that confers resistance to multiple tyrosine kinase inhibitors (TKIs), but not, evidently, to ponatinib, said Dr. Jorge Cortes from the University of Texas M.D. Anderson Cancer Center in Houston.
"These results suggest that ponatinib has outstanding clinical activity in patients with chronic myeloid leukemia, or Philadelphia [chromosome]-positive patients with acute lymphoblastic leukemia. These responses have been regardless of the stage of disease and regardless of the presence or absence of mutations. And the responses are very deep, rapid, and sustained to the extent of the follow-up we have so far, with a drug that is very well tolerated," he said at a press briefing.
Major responses, the primary endpoint, were also seen in patients with every other mutation commonly seen in clinic, Dr. Cortes said in an interview.
Dr. Aaron Schimmer
"This is potentially really huge," commented Dr. Aaron Schimmer, a clinician scientist at the Princess Margaret Cancer Centre of the University Health Network in Toronto.
"From a broad scientific perspective, when you think about it, we’ve identified the cause of resistance in a mutation in patients receiving standard therapy, and now they’ve actually designed a drug that specifically works on that mutation," he said in an interview.
"From a patient’s standpoint, think of the patients who no longer respond to standard tyrosine kinase inhibitors: Their options at this point are exceptionally limited, survival rates are not good, and now we’ve got a new drug that’s very well tolerated and is producing response rates in a high percentage of these patients, and that’s really amazing at that individual level," he added.
Ponatinib Blocks T315I
Dr. Cortes reported on 12-month follow-up data from the PACE (Ponatinib Ph+ ALL and CML Evaluation) trial, a single-arm study of oral ponatinib in 449 patients with chronic phase, accelerated phase, or blast phase CML and Ph-positive acute lymphocytic leukemia (ALL) who are resistant or intolerant to dasatinib or nilotinib or have the T315I mutation in BCR-ABL kinase.
Ponatinib is an oral pan-BCR-ABL tyrosine kinase inhibitor with potent activity against native and mutated BCR-ABL and other kinases, and was specially designed to thwart T315I’s ability to block other TKIs. Dr. Cortes explained.
Approximately 92% of patients in each of the three CML phase groups (patients with Ph-positive ALL were included in the blast-phase CML [BP-CML] group) had received at least two prior TKIs, and more than half (53%-60%) had received at least three.
Best MCyR rates to recent therapies were 26% in patients with chronic phase CML (CP-CML), 15% in those in accelerated phase (AP-CML), and 16% of those in BP-CML.
Dr. Jorge Cortes
Among patients with CP-CML, those who were resistant to dasatinib or nilotinib 51% had a major cytogenetic response, as did 70% of patients with the T315I mutation. Among patients with AP-CML, 58% of resistant/intolerant patients and half of those with the mutation had a major hematologic response (MaHR). Among patients in the BP-CML group, the respective MaHR rates were 35% and 33%.
Among the 267 patients in CP-CML, 67% had any cytogenetic response, 56% had a MCyR, 46% had a CCyR, and 34% had a major molecular response (MMR). The median time to MCyR was 2.8 months, and to MMR was 5.5 months.
Responses Durable at 1 Year
In all, 91% of patients with CP-CML and a MCyR were estimated to remain in response at 12 months.
As with other TKIs, the drug was well tolerated with the most common side effects being dry skin or skin rash, mostly mild and manageable. Grade 3 pancreatitis occurred in 6% of patients but was well managed, and only one patient had to discontinue because of this adverse event, Dr. Cortes said.
Dr. Cortes disclosed receiving research support and serving as a consultant to Aria, maker of ponatinib. Dr. Schimmer reported no relevant disclosures.