Nilotinib Exposure-Response Analysis In Patients with Imatinib-Resistant or -Intolerant Chronic Myeloid Leukemia (CML)

Nilotinib is a highly selective and potent BCR-ABL inhibitor, approved for the treatment of patients with newly diagnosed Ph+ CML in chronic phase (CP) and CML patients who fail imatinib. The long-term clinical outcome of nilotinib therapy in patients with imatinib-resistant or -intolerant CML has been reported recently in a 24-month follow-up. In contrast to imatinib, the cellular uptake of nilotinib is independent of active transporter expression, so that systemic exposure is likely to be more closely related to patient response. The purpose of this analysis is to evaluate the population pharmacokinetics (PK) of nilotinib and its potential relationship to efficacy and safety in patients with imatinib-resistant or -intolerant CML.

A non-linear mixed effects modeling analysis was performed to determine nilotinib PK. Serum-concentration data from 495 CML patients in CP (n=235), accelerated phase (AP, n=135) or blast crisis (BC, n=125) from Ph I and II studies was used. An exposure-efficacy analysis was performed in patients with CML-CP in Ph II, where the steady-state trough concentrations (Cmin) of nilotinib were computed for individual patients, and then correlated to efficacy measures, including CCyR at 12 months, MMR at 12 and 24 months, time to CCyR, time to MMR, and time to progression (TTP). Patients with baseline T315I mutations or those who had dose escalation to nilotinib 600 mg twice daily prior to the efficacy endpoints were excluded from the analysis. Baseline prognostic factors and mutation status that were previously suggested to affect the clinical benefit of nilotinib therapy were also investigated as potential covariates in the exposure-efficacy analysis, according to Akaike Information Criteria (Kantarjian et al, ASH abstract 2009). The prognostic score was defined as follows: 0 when the patient had baseline HGB >120 g/L, baseline basophils < 4% and no insensitive mutation; 1 if the patient did not satisfy one of the criteria; and 2 if the patient did not satisfy 2 of the criteria. The relationship between nilotinib Cmin, UGT genotype, and total bilirubin levels over 24 months was assessed in all patients from Ph I and II studies.

Nilotinib PK was found to be similar in patients with CML-CP, -AP or -BC. Patient age, body weight, ethnicity, and racial group did not significantly affect nilotinib PK. Overall, patients with lower nilotinib Cmin (quartile Q1) tended to have lower CCyR at 12 months, lower MMR at 12 and 24 months, longer time to achieve CCyR and MMR, and shorter TTP compared with patients with higher nilotinib Cmin (quartiles Q2-Q4, Table). Logistic regression of CCyR at 12 months and Cox proportional hazard analysis of TTP demonstrated that in addition to nilotinib Cmin, baseline prognostic scores also significantly affected CCyR (57% and 21% for patients with prognostic scores of 0–1 and 2, respectively) and TTP (27.9 and 18.7 months for patients with prognostic scores of 0–1 and 2, respectively). Both nilotinib Cmin and UGT genotype were significantly associated with the occurrence of total bilirubin abnormality (both p<0.1). Patients with nilotinib C_min in Q1 (<422 ng/ml, n = 122) had a lower incidence of grade 3/4 bilirubin abnormalities (5.7%) than patients with nilotinib Cmin in Q2 ([422,610) ng/mL, n=120, 9.2%), Q3 ([610,842) ng/mL, n=121, 10.9%), and Q4 (>=842 ng/mL, n = 121, 14.1%), respectively. The occurrence of grade 3/4 bilirubin abnormalities was 6%, 12% and 48% for patients with TA(6)/TA(6), TA(6)/TA(7), and TA(7)/TA(7) UGT genotypes, respectively.

Patients with lower nilotinib Cmin and higher baseline prognostic risk score showed a higher risk of progression as well as a trend of poorer response. These data suggest that adherence to nilotinib dose in order to maintain sufficient Cmin is important in maximizing the clinical efficacy of nilotinib therapy.

Giles:Novartis: Consultancy, Honoraria. Yin:Novartis : Employment, Equity Ownership. Chia:Novartis: Employment, Equity Ownership. le Coutre:Novartis: Research Funding, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Woodman:Novartis: Employment. Ottmann:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Baccarani:Novartis, Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kantarjian:Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding.