Impact of Prior Therapy and Suboptimal Response to Imatinib On the Efficacy and Safety of Nilotinib Among 1,422 Patients with Imatinib-Resistant or —Intolerant Chronic Myeloid Leukemia (CML) in Chronic Phase (CP): Sub-Analyses of the ENACT (Expanding Nilotinib Access in Clinical Trials) Study.

Nilotinib, a potent and highly selective BCR-ABL tyrosine kinase inhibitor (TKI), is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CP) and accelerated phase (AP) who are resistant or intolerant to prior therapy, including imatinib. The ENACT study is a Phase IIIb, open-label, multicenter study that evaluated the efficacy and safety of nilotinib 400 mg twice daily in 1,422 pts with CP who were resistant and/or intolerant to imatinib. It is the largest single source of efficacy and safety information of any available TKI in CML. Study results are presented for all CP pts as well as 2 subpopulations: (1) 2nd-line pts who received imatinib as the only prior CML therapy with no prior exposure to other therapy including interferon (IFN), busulfan and ara-c; and (2) pts with 6- and 12-month suboptimal cytogenetic response (SoR) to prior imatinib therapy.

In addition to all CP pts, ENACT study results are presented for 2 subpopulations, defined as follows. (1) Pts who received nilotinib as 2nd-line therapy received only imatinib (hydroxycarbamide was allowed) prior to nilotinib. Pts with any other therapy, including interferon, busulfan and ara-c were excluded. (2) Pts with 6- or 12-month cytogenetic SoR to imatinib were identified as: a) received imatinib as 1st-line therapy within 12 months of CML diagnosis; b) did not have imatinib resistance; and c) met ELN criteria for cytogenetic SoR (<PCyR at month 6 or <CCyR at month 12.)

A total of 1,422 CP pts were enrolled in the ENACT study between Jan. 2006 and Oct. 2008 from 293 study sites worldwide. The median age of pts was 52 years. At study completion, 857 (60%) pts were continuing on nilotinib. Median (range) duration of nilotinib exposure was 266 (1 - 807) days; median average dose intensity was 783 mg/day. The main reasons for treatment discontinuation were inadequate response (16%), AEs (14%) and other (10%). The majority of grade 3/4 AEs suspected of being study drug related were hematologic and the most common hematologic toxicities were thrombocytopenia (22%) and neutropenia (14%). Nonhematologic AEs were mostly grade 1/2. Grade 3/4 nonhematologic AEs were infrequent and included rash (<3%), headache and nausea. Overall major cytogenetic response (MCyR) rates were consistent with those observed in earlier Phase 2 trial at 45.1%. Likewise, complete hematologic response (CHR) rate was 43.0%. (1) A total of 584 CP pts received nilotinib as 2nd-line therapy. The proportion of pts with dose interruptions and reductions lasting >5 days was similar between these pts and overall (interruption: 39% and 41%; reduction: both 5%), as was the median dose intensity for nilotinib (788 and 783 mg/day). MCyR and CHR rates were also similar between 2nd-line therapy pts and overall (MCyR: 47% and 45%; CHR: both 43%). (2) 12 pts were identified with cytogenetic SoR to prior imatinib therapy; 11 pts were 6-month cytogenetic SoR, 1 pt was 12-month cytogenetic SoR. The median duration of nilotinib exposure for these pts was higher than overall at 344 days (vs. 266) while their median dose intensity was slightly lower than overall at 741 mg/day (vs. 783). Of pts with cytogenetic SoR to imatinib, 75% (9) achieved MCyR, 50% (6) achieved CCyR and 67% (8) achieved CHR, compared to 45%, 34% and 43% for overall, respectively. MCyR and CCyR rates among pts with hematologic response were 60% and 80%, respectively. Median time to achieving MCyR and CHR among cytogenetic SoR pts was 3.8 and 3.4 months, respectively, faster than in the overall study (MCyR: 6.1 months; CHR: 4.9).

This analysis further demonstrates that nilotinib is well tolerated in heavily pretreated pts with CML-CP with the efficacy and safety profile reported in ENACT being similar to that observed in the pivotal phase II registration study. The first sub-analysis of CP pts showed that prior exposure to therapeutic agents including IFN, busulfan and ara-c in addition to imatinib does not affect nilotinib dose intensity or response rates. The second sub-analysis demonstrates that pts with 6- or 12-month cytogenetic SoR experience higher CHR, MCyR and CCyR rates, and faster time to CHR and MCyR than pts who were imatinib failures, suggesting that nilotinib may be a suitable treatment option in pts with cytogenetic SoR on imatinib therapy. Studies are ongoing with nilotinib in suboptimal imatinib responders.

Nicolini:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chemgenex: Honoraria, Speakers Bureau. Kim:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Ceglarek:Novartis Pharmaceuticals: Honoraria. Turkina:Novartis Pharmaceuticals: Honoraria. Shen:Novartis Pharmaceuticals: Honoraria. Smith:Novartis Pharmaceuticals: Honoraria. Rizzieri:Novartis: Honoraria, Research Funding, Speakers Bureau. Szczudlo:Novartis: Employment. Berton:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Employment. Bieri:Novartis Oncology: Research Funding. le Coutre:Novartis : Honoraria, Research Funding; Bristol Myers Squibb: Honoraria.