Nilotinib is Superior to Imatinib as First-line Therapy of Chronic Myeloid Leukemia: The ENESTnd Study

Francis J Giles; Gianantonio Rosti; Photis Beris; Richard E Clark; Philipp le Coutre; Francois-Xavier Mahon; Juan-Luis Steegmann; Peter Valent; Giuseppe Saglio


Expert Rev Hematol. 2010;3(6):665-673. 

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Nilotinib binds to the inactive conformation of the ABL1 tyrosine kinase, causing P-loop folding over the ATP-binding site and activation loop blockade of the substrate-binding site. These events disrupt ATP/substrate binding and inhibit the catalytic activity of the enzyme. The structural similarities of both imatinib and nilotinib result in a very similar limited profile of protein kinase targets. In imatinib-sensitive CML cell lines, nilotinib is up to 60-fold more potent a growth inhibitor than imatinib. Nilotinib retains activity against a broad spectrum of abl mutations that are associated with resistance to imatinib, with the exception of the E255K/V, F359C/V, T315I and Y253H mutated phenotypes.[3] Other protein kinase targets of nilotinib include TEL-PDGFRβ, FIP1L1-PDGFRα and KIT. Pharmacokinetic data are available from a Phase I dose escalation study reported by Kantarjian and Giles et al. in 2006.[4] Nilotinib was administered orally at doses of 50–1200 mg once daily and at doses of 400 or 600 mg twice daily. All trough serum concentrations exceeded the IC50 values for cellular phosphorylation of BCR–ABL1, including the great majority of BCR–ABL1 mutants. Peak serum concentrations and AUC values increased with once-daily doses of 50–400 mg, but at higher doses these values began to plateau, probably reflecting saturation of gastrointestinal absorption. At the regulatory approved second-line (post-imatinib failure) dose of nilotinib 400 mg twice daily, mean peak and trough serum drug concentrations were, respectively, 3.6 µmol/l and 1.7 µmol/l at 3 h. The apparent elimination half-life of nilotinib was close to 17 h, with more than 90% eliminated in the feces within 7 days and 70% of the dose is accounted for by the parent drug. Coadministration of nilotinib with ketoconazole in healthy volunteers resulted in a threefold increased systemic exposure to nilotinib, indicating that nilotinib metabolism is influenced by cytochrome P450 (CYP) 3A4 inhibition. In the same analysis, coadministration of nilotinib with midazolam resulted in a 30% increase in midazolam exposure, implying that nilotinib may be a weak inhibitor of CYP3A4. Therefore, concomitant use of both CYP3A4 inhibitors (e.g., azole antifungals, clarithromycin, atazanavir and ritonavir) and CYP3A4 inducers (e.g., dexamethasone, phenytoin and carbamazapine) should be avoided. Based on embryo–fetal developmental studies in pregnant rats and rabbits, nilotinib is not considered to be teratogenic; however, there are no well-controlled studies with nilotinib in pregnant women taking the drug and strict adherence to the contraception advice contained in the approved product insert is very strongly advised. A pharmacogenetic analysis of 97 patients evaluated polymorphisms of UGT1A1 and the potential for hyperbilirubinemia in this group. The (TA)7/(TA)7 genotype was associated with a statistically significant increase in the risk of indirect, clinically insignificant, hyperbilirubinemia relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes.[5]

Nilotinib has significant activity in all phases of CML in patients who have failed prior imatinib therapy.[6–8] In these studies, as in Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Newly Diagnosed Patients (ENESTnd), definitions of remission and response to imatinib are based on those proposed by the European Leukemia Network for CML (Table 1).[9] In addition to patients with newly-diagnosed CML, nilotinib is currently approved by the US FDA for the treatment of imatinib-resistant or -intolerant patients who are in CP or AP. As a very important reflection of the importance of true targeting with kinase inhibitors, there is minimal, if any, cross-intolerance to nilotinib in imatinib-intolerant patients with CML, although nilotinib shares approximately 50% structural similarity to imatinib.[6] An application for regulatory approval for nilotinib in patients with CML BP who have failed imatinib therapy has not been submitted. Data presented at the 2010 European Hematology Association (EHA) meeting on the 24-month follow-up of a cohort of 136 patients in this clinical situation would indicate that nilotinib is at least as effective as dasatinib or any other current nontransplantation therapy for these patients with a 40% 12-month survival rate (Figure 1).[10] We hope that a regulatory application will be submitted in the near future – options for these patients are currently extremely limited. Nilotinib is also active in patients who have failed prior therapy with both imatinib and dasatinib, with a 12-month survival rate of over 90% in patients with CP disease (Figure 2).[11] Dasatinib is a multitargeted kinase inhibitor which has significant activity in imatinib-resistant or -intolerant patients.[12] Dasatinib is currently approved by the FDA for the treatment of imatinib-resistant or -intolerant patients who are in CP, AP or BP. Dasatinib is not currently approved for patients with newly diagnosed CML. Dasatinib has been studied in the frontline setting, both in a Phase II study and in a prospective randomized study versus imatinib therapy.[13,14] In the latter study, dasatinib attained significantly higher rates of CCyR and MMR by 12 months than imatinib. Dasatinib and imatinib, however, had comparable rates of transformation to AP/BP and dasatinib was associated with significantly more myelosuppression than imatinib.[14] No patient with progression to AP or BP had a prior MMR.

Figure 1.

Overall survival of patients with chronic myeloid leukemia blastic phase treated with nilotinib.
Cen: Censored; Evt: Evaluated; LBC: Lymphoid blastic crisis; MBC: Myeloid blastic crisis; Pt: Number of patients.
Adapted from [10].

Figure 2.

Overall survival: nilotinib in imatinib and dasatinib failure.
AP: Accelerated phase; BC: Blast crisis; CP: Chronic phase.
Adapted from [11].

Nilotinib has been reported to be effective and safe in two Phase II studies conducted in patients with newly diagnosed CML.[15,16] Rosti et al. reported on a GIMEMA study in a cohort of 73 patients treated with nilotinib 400 mg twice daily.[15] This study was registered at as NCT00481052.[101] The primary study end point was the CCyR rate at 1 year, which, at a median follow-up of 15 months, was 96%, with a MMR rate of 85%. Responses occurred rapidly, with 78% CCyR and 52% MMR rates documented at 3 months follow-up (Table 2 & Figure 3). During the first year, the treatment was interrupted at least once in 38 patients (52%). The mean daily dose ranged between 600 and 800 mg in 74% of patients, 400 and 599 mg in 18% of patients, and was less than 400 mg in 8% of patients. Dose interruptions were usually very brief and mainly attributable to biochemical abnormalities with minimal myelosuppression being noted. One patient progressed to BP after 6 months; another went off treatment for lipase elevation which was not associated with pancreatitis. These data from the GIMEMA group indicated that nilotinib was both safe and very active in early CP CML and generated cytogenetic and molecular response rates that appeared considerably superior to those seen with imatinib. Cortes et al. reported on a cohort of 51 newly diagnosed patients with CML CP who were treated with nilotinib 400 mg twice daily.[16] This study was registered at as NCT00129740.[102] A total of 50 (98%) patients achieved CCyR and 76% achieved MMR. Responses occurred rapidly, with 96% of patients achieving CCyR by 3 months and 98% achieving CCyR by 6 months. The projected event-free survival at 24 months was 90%, with all patients alive after a median follow-up time of 17 months. Nonhematologic toxicity was usually grade 1/2. The actual median nilotinib dose at 12 months was 800 mg (range: 200–800 mg). This group also concluded that nilotinib was an effective initial therapy of CML CP.

Figure 3.

GIMEMA: nilotinib first-line: major molecular response <0.1%.
MMR: Major molecular response; NE: Not evaluated.
Adapted from [15].


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