Ariad Pharmaceuticals recently presented data from three studies showing that Iclusig (ponatinib), its approved BCR-ABL inhibitor, provides clinical benefit in leukemia patients who had failed previous treatments with tyrosine kinase inhibitors (TKIs).
The leukemia patients who seem to benefit from Iclusig have resistant or intolerant chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).
The data was presented at the 57th Annual Meeting of the American Society of Hematology (ASH) Dec 3-6 in San Diego.
The first study, presented in a poster titled “Ponatinib in Chronic-Phase Chronic Myeloid Leukemia Patients: Final Report from a Phase 1 Trial” (#92516), showed data from a Phase 1 study (NCT00660920) designed to determine the maximum tolerated dose or a recommended dose of oral Iclusig in a defined schedule in patients with refractory or advanced CML and other refractory hematologic malignancies.
A total of 81 patients, including 43 with chronic-phase CML (CP-CML), received Iclusig at a starting dose that ranged from 2 to 60 mg once daily. The majority of patients had failed at least two or three previous TKIs.
After a median follow-up of four years, Iclusig continues to provide anti-leukemic benefits to heavily pre-treated CP-CML patients, the researchers concluded.
Specifically, the data shows that 72% of CP-CML patients had a major cytogenetic response (MCyR), a response to treatment that occurs in the bone marrow, rather than just in the blood, meaning no Ph+ cells can be measured. In addition, the results showed that 65% of patients had a complete cytogenetic response (CCyR) and 56% of patients achieved a major molecular response (MMR), meaning that no BCR-ABL protein is detectable in the bone marrow.
The researchers also found that among the 12 patients with the T315I mutation, 11 exhibited a MCyR, 10 achieved a CCyR, and nine patients achieved a MMR. The probability of CP-CML patients sustaining MCyR at four years was 72 percent, the researchers estimated.
Ten of the 15 CP-CML patients who started Iclusig at a dose of 30 mg or less achieved MCyR, comparable to the overall response rate of 72%.
Rash, fatigue, abdominal pain, headache, and arthralgia were the most common treatment-emergent adverse events. Forty-four percent of CP-CML patients experienced treatment-emergent arterial occlusive events, including 16% in which they were reported as serious adverse events.
The two other studies presented at the meeting evaluated the effectiveness and safety of Iclusig.
The poster titled “Long-Term Follow-up of the Efficacy and Safety of Ponatinib in Philadelphia Chromosome-Positive Leukemia Patients with the T315I Mutation” (#93206), described data from a pooled analysis in patients with a T315I mutation enrolled in the previously mentioned Phase 1 dose-escalation study and in the four-year follow-up of the PACE study (NCT01207440).
The analysis showed that Iclusig continues to provide long-lasting responses and improves overall survival, as assessed at more than three years of follow-up in T315I-mutated CP-CML patients.
The oral presentation titled “Analysis of the Sub-Clonal Origins of Compound Mutations in Patients with Refractory Ph+ Malignancies Treated with Ponatinib” (#93238) described the results of a sequencing strategy that combined several sequencing methods to predict sub-clonal mutations to Iclusig from the PACE study.
The researchers found that clonal mutation status (BCR-ABL) does not predict intrinsic resistance to Iclusig. However, compared to patients with CP-CML, those with blastic phase CML (BP-CML)/Ph+ ALL are more likely to relapse on Iclusig with acquired mutations in BCR-ABL1.
“The data presented at ASH include the final report from the Phase 1 trial of ponatinib, with maximum follow-up of more than 7.5 years and median follow-up approaching five years that demonstrated ongoing cytogenetic and molecular responses,” Timothy P. Clackson, PhD, Ariad’s president of research and development and chief scientific officer, said in a press release.
“A separate study of CP-CML patients with the T315I mutation demonstrated a 72 percent probability of overall survival at 4.5 years among these patients who, prior to ponatinib, had no approved targeted treatment options and had a median survival of less than two years,” Clackson added. “In addition, an oral presentation on studies in Ph+ ALL patients provides important new data on the molecular basis for Iclusig’s activity in these patients.”