Updated findings from the pivotal phase II PACE (Ponatinib Ph+ ALL and CML Evaluation) trial show sustained benefit of the investigational BCR-ABL tyrosine kinase inhibitor (TKI) ponatinib in heavily pretreated patients with resistant or intolerant chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The 12-month data were reported by lead investigator Jorge Cortes, MD, of the department of leukemia at the University of Texas MD Anderson Cancer Center in Houston, Texas, at the 2012 annual meeting of the American Society of Hematology (ASH) meeting in Atlanta.
Researchers at centers in the United States and Europe enrolled 449 patients in the ongoing trial, all with either CML or Ph+ ALL resistant or intolerant to dasatinib or nilotinib, or who have the T315I BCR-ABL gene mutation, against which other TKIs have been ineffective. Nearly all of the patients were previously treated with two or all three of the available TKIs (imatinib, dasatinib, and/or nilotinib). Patients were assigned into six cohorts based on their disease resistance or genetic profile and then treated with ponatinib.
Primary endpoint was major cytogenetic response (defined as > 65% normal cells) within 12 months of treatment for those with chronic phase CML, and major hematologic response (normal white blood cell counts) within 6 months after treatment for those with advanced-phase CML or Ph+ ALL.
Major cytogenetic response was observed in 55% percent of all chronic-phase CML patients (50% of resistant/intolerant patients and 70% with T315I mutation), and major hematologic response was observed in 58% of patients with accelerated-phase CML (57% of resistant/intolerant patients and 50% with T315I mutation), and 34% of those with blast-phase CML/ Ph+ ALL (35% of resistant/intolerant patients and 33% with T315I mutation). The similar response rates observed in patients with and without the T315I mutation are consistent with previous findings suggesting that ponatinib may be efficacious across a wide range of mutations associated with TKI resistance, including instances where mutations are not detected.
Complete cytogenetic response (no Ph+ cells measured in the body) was achieved in 46% of patients with chronic phase CML, with higher response rates in patients who were exposed to fewer prior TKIs and those with shorter disease duration. Ponatinib was well tolerated in all cohorts.
The most common adverse events observed were skin toxicity (including rash or dry skin), elevation of pancreatic enzymes and/or pancreatitis, and myelosuppression). At the time of analysis, 52% of patients remained on the therapy. These results demonstrate ponatinib’s efficacy in CML and Ph+ ALL patients with no other viable treatment options, said Dr. Cortes.
“This therapy may be able to transform highly fatal forms of leukemia into a curable disease in these patients–we have simply never had any treatment produce such high rates of durable response in such a heavily treated group of patients,” he added. “Our next step is to test ponatinib’s potential as an initial therapy in an attempt to prevent the occurrence of relapse that may decrease the prospects of a normal lifespan for patients.”
Additional analyses of data from the PACE trial were highlighted in several other presentations, and updated findings were also reported from an ongoing phase I dose-escalation study. The dose-escalation study of ponatinib enrolled 81 patients with resistant hematologic cancers, including 60 patients with CML and 5 with Ph+ ALL. With median follow-up at 73 weeks, 72% (31 of 43) of patients with chronic-phase CML had a major cytogenetic response, including 92% (11 of 12) who had the T315I mutation, the most common mutation among resistant patients.
“The results with ponatinib were very impressive,” said Hagop Kantarjian, MD, chair of the leukemia department at the MD Anderson Cancer Center, who presented the findings.
Ponatinib is being developed by Ariad Pharmaceuticals Inc, Cambridge, Massachusetts.