ALBERT

Description: Abstract 2291 Background: Nilotinib is a potent and the most selective inhibitor of BCR-ABL. In the phase 3 ENESTnd trial, nilotinib demonstrated superior efficacy vs imatinib with higher and faster molecular responses and a significantly lower rate of progression on treatment to accelerated or blast phases of CML. Nilotinib has been previously shown to prolong the QT interval. The cardiac safety profile of nilotinib was previously described in pts with imatinib-resistant and -intolerant CML-CP enrolled in phase 2 clinical trials. Here, we report cardiac safety data on nilotinib 300 and 400 mg twice daily (bid), and imatinib, in pts with newly diagnosed CML-CP from the ENESTnd trial. Methods: A total of 836 pts were included in the safety analysis of ENESTnd (279, 277, and 280 pts in the nilotinib 300 mg bid, nilotinib 400 mg bid, and imatinib arms, respectively) with a median follow-up of 18 months. Pts were excluded from study participation if they had known uncontrolled or medically significant cardiac disease, left ventricular ejection fraction (LVEF) 〈 45%, or QTcF interval 〉 450 msec. Prospective cardiac monitoring was conducted throughout the study for QT prolongation (via electrocardiogram) and LVEF (via echocardiogram) at regular intervals. Results: QTcF increases of 〉 30 msec from baseline occurred in 26% of pts in each nilotinib arm and in 18% of pts in the imatinib arm. QTcF increases of 〉 60 msec from baseline were uncommon, occurring in 〈 1% of pts in all three arms (Table). The highest mean changes from baseline in QTcF interval were 10.4, 12.4, and 7.9 msec in nilotinib 300 mg bid, nilotinib 400 mg bid, and imatinib arms, respectively, which occurred between months 3–6 of therapy in all arms. Furthermore, there was a modest linear correlation between nilotinib serum concentration and QTcF change from baseline that was similar to previously reported results. No pt in any treatment arm demonstrated an absolute QTcF interval 〉 500 msec. Analysis was conducted to identify any potential case of clinically symptomatic QT prolongation. Only events of syncope were identified (1 pt in each arm with drug-related events) by this analysis and none of these could be attributed to QT prolongation; there were no episodes of torsades de pointes in any treatment arm. Additionally, there was no decrease from baseline in mean LVEF observed anytime on treatment in any arm (Table). No patient in any treatment arm had a LVEF of 〈 45% on treatment or an absolute reduction from baseline in LVEF of 〉 15%. Importantly, no pt discontinued therapy due to QT prolongation or LVEF change. An analysis of grouped adverse event terms was performed to identify cases consistent with ischemic heart disease (IHD) or left ventricular dysfunction. A total of 11 pts in all treatment arms experienced IHD events after median treatment duration of 18 months: 3 (1%) on nilotinib 300 mg bid, 6 (2%) on nilotinib 400 mg bid, and 2 (〈 1%) on imatinib. Of these 11 pts, 10 had preexisting cardiac disease or risk factors and only 1 pt discontinued treatment due to an IHD event. Nine pts reported angina pectoris. Two pts experienced myocardial infarction (MI) and 1 of these pts died during coronary artery bypass surgery (perisurgical MI). A total of 7 pts in all treatment arms with events consistent with left ventricular dysfunction were identified: 1 (〈 1%) on nilotinib 300 mg bid, 4 (1%) on nilotinib 400 mg bid, and 2 (〈 1%) on imatinib. Of these 7 pts, 4 pts experienced reduction in LVEF (3 were asymptomatic grade 1/2) and 3 pts experienced cardiac failure/congestive failure; 5 of these 7 pts had prior history of cardiovascular disease and/or preexisting cardiovascular risk factors. None of these 7 pts discontinued treatment due to events with left ventricular dysfunction. There were no sudden deaths reported on study. Conclusions: Overall, QT prolongation, changes in LVEF, and clinical cardiac events were uncommon in all arms and seldom led to discontinuation. There was no cumulative effect of nilotinib exposure on cardiac safety with a median of 18 months follow-up. Nilotinib at both doses had a favorable cardiac safety profile that was similar to imatinib in pts with newly diagnosed CML-CP. Disclosures: Larson: Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Hochhaus: Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Saglio: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Rosti: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Roche: Speakers Bureau. Lopez: Novartis: Consultancy; Bristol Myers Squibb: Consultancy. Goldberg: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Gallagher: Novartis Pharma AG: Employment, Equity Ownership. Hoenekopp: Novartis: Employment. Ortmann: Novartis: Employment. Hughes: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria. Kantarjian: Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding.

Description: Abstract 3768 Background: Data from the phase 3, randomized multicenter ENESTnd trial have demonstrated the superiority of nilotinib over imatinib after 24 months (mo) of follow-up, with significantly higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR), and significantly lower rates of progression to accelerated phase/blast crisis (AP/BC). The current subanalysis evaluated the efficacy and safety of nilotinib 300 mg twice daily (Nil300) and nilotinib 400 mg twice daily (Nil400) in older (≥ 65 years [yrs] at study entry) patients (pts) with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) with a minimum follow-up of 24 mo. Methods: In ENESTnd, 846 pts stratified by Sokal risk score were randomized 1:1:1 to Nil300 (n = 282), Nil400 (n = 281), or imatinib 400 mg once daily (n = 283). Pts with impaired cardiac function or ECOG performance status 〉 2 were excluded. Rates of CCyR and MMR by 24 mo, progression to AP/BC on treatment, and safety were evaluated according to age group (〈 65 vs ≥ 65 yrs) in the 2 nilotinib arms. Safety data are reported for any pt who received ≥ 1 dose of nilotinib (n = 279, Nil300; n = 277, Nil400). Results: 36 pts (13%) and 28 pts (10%) were ≥ 65 yrs old in the Nil300 and Nil400 arms, respectively. Of the pts aged ≥ 65 yrs, 51/64 (80%) had an ECOG performance status of 0 at baseline and 60/64 (94%) had intermediate or high Sokal risk scores. Of the older pts, 8 (22%) on Nil300 and 6 (21%) on Nil400 had type 2 diabetes at baseline. CCyR rates by 24 mo were 83% and 68% among older pts treated with Nil300 and Nil400, respectively, and 87% for pts aged 〈 65 yrs in each nilotinib arm. By 24 mo, MMR was achieved by 72% and 61% of older pts on Nil300 and Nil400, respectively; in pts aged 〈 65 yrs, the respective rates were 71% and 67%. All 5 pts who progressed to AP/BC on treatment (2 on Nil300 and 3 on Nil400) were aged 〈 65 yrs. The frequency of grade 3/4 hematologic adverse events (AEs) was low in older pts; no pts had grade 3/4 neutropenia and only 1 older pt reported grade 3/4 thrombocytopenia in each nilotinib arm (Table). Transient, asymptomatic lipase elevations were reported in 11% and 16% of older pts treated with Nil300 and Nil400, and 7% of younger pts in each arm. Hyperglycemia occurred in 23% and 16% of older pts on Nil300 and Nil400, respectively, and 4% of younger pts in each arm; regardless of age, no pt discontinued study due to hyperglycemia. Among the 12 older pts with grade 3/4 hyperglycemia (8 on Nil300; 4 on Nil400), 9 pts had type 2 diabetes at baseline. There were no QTcF increases of 〉 60 msec from baseline in older pts and 3 in nilotinib-treated pts 〈 65 yrs old (1 on Nil300; 2 on Nil400). QTcF prolongation of 〉 500 msec did not occur in any pt treated with nilotinib on study. Periodic echocardiograms were done, and there were no decreases of 〉 15% in left ventricular ejection fraction from baseline in any pt treated with nilotinib on study. There were 4 cases of ischemic heart disease reported in older pts (1/35 [3%] on Nil300; 3/25 [12%] on Nil400) and 7 cases in pts 〈 65 yrs of age (4/244 [2%] on Nil300; 3/252 [1%] on Nil400). No sudden deaths occurred on study. Discontinuation occurred in approximately 25% of older and younger pts with Nil300, of which, 6% and 9%, respectively, were due to AEs/lab abnormalities. Discontinuation from study with Nil400 was 46% in older pts and 19% in younger pts; of which, 36% and 10% were due to AEs/lab abnormalities. Conclusions: Older pts treated with nilotinib demonstrated high rates of cytogenetic and molecular responses and low rates of progression. Nilotinib was generally well tolerated by older pts. In older pts, Nil300 had numerically higher rates of CCyR and MMR and was generally better tolerated (as evidenced by fewer AEs and discontinuations) vs Nil400. These data support the use of Nil300 in older pts with newly diagnosed CML-CP. Disclosures: Larson: Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Bunworasate:Novartis Pharmaceutical: Research Funding. Turkina:Novartis: Consultancy, Honoraria; BMS: Honoraria. Goldberg:Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding. Dorlhiac-Llacer:Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding. Saglio:Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis Pharmaceutical: Consultancy, Speakers Bureau; Pfizer: Consultancy. Hochhaus:Ariad: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Yu:Novartis: Employment, Equity Ownership. Gallagher:Novartis: Employment, Equity Ownership. Clark:Bristol Myers Squibb: Honoraria, Research Funding; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau. Hughes:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Abstract LBA-1 Background: Nilotinib is a highly potent and the most selective inhibitor of BCR-ABL, the only proven molecular target for CML therapy. ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) is a phase 3, randomized, open-label, multicenter study comparing the efficacy and safety of 300 or 400 mg bid nilotinib with 400 mg qd imatinib in patients (pts) with newly diagnosed Ph+ CML in chronic phase (CML-CP). Methods: 846 pts with newly diagnosed Ph+ CML-CP, diagnosed within 6 mos, and stratified by Sokal risk score, were randomized 1:1:1 to nilotinib 300 mg bid (n=282), nilotinib 400 mg bid (n=281), and imatinib 400 mg qd (n=283) arms. The primary endpoint was rate of major molecular response (MMR) at 12 months (mos). All pts had a minimum of 12 mos of treatment or discontinued early; median follow-up was 14 mos. MMR was defined as a value of ≤ 0.1% of BCR-ABL/ABL ratio on the International Scale. Molecular response was assessed by RQ-PCR at baseline, monthly for 3 mos and every 3 mos thereafter. Samples were analyzed at a central PCR laboratory. The major secondary endpoint was rate of complete cytogenetic response (CCyR) by 12 mos based on bone marrow cytogenetics. Results: Baseline demographics, disease characteristics, and Sokal scores were well balanced among the 3 arms; pts with high-risk Sokal scores were 28% in all arms. Median dose intensities of nilotinib delivered were 592 mg/day for 300 mg bid and 779 mg/day for 400 mg bid; imatinib dose intensity was 400 mg/day. Overall, 84%, 82%, and 79% of pts remained on the study for 300 mg bid nilotinib, 400 mg bid nilotinib, and 400 mg qd imatinib, respectively. Rates of MMR at 12 mos (Table) were superior for nilotinib 300 mg bid compared with imatinib 400 mg qd (44% vs. 22%,P 〈 .0001) and also for nilotinib 400 mg bid compared with imatinib 400 mg qd (43% vs. 22%,P 〈 .0001). Median time to MMR among pts who achieved MMR was faster for nilotinib 300 mg bid (5.7 mos) and nilotinib 400 mg bid (5.8 mos) compared with imatinib 400 mg qd (8.3 mos). Rates of CCyR by 12 mos were significantly higher for both nilotinib at either 300 mg bid compared with imatinib 400 mg qd (80% vs. 65%,P 〈 .0001) and for nilotinib 400 mg bid compared with imatinib 400 mg qd (78% vs. 65%,P = .0005). Overall, progression to advanced disease was lower for nilotinib 300 mg bid (2 pts) and nilotinib 400 mg bid (1 pt) compared with imatinib 400 mg qd (11 pts). Overall, both drugs were well-tolerated. Rates of discontinuation due to adverse events or laboratory abnormalities were 7% for nilotinib 300 mg bid, 11% for nilotinib 400 mg bid, and 9% for imatinib 400 mg qd. Pts were monitored for QT prolongation and LVEF. No patients in any treatment arm showed a QTcF interval 〉 500 msec. There was no decrease from baseline in mean LVEF anytime during treatment in any arm. The study is ongoing. Conclusions: Nilotinib at both 300 mg bid and 400 mg bid induced significantly higher and faster rates of MMR and CCyR compared with imatinib 400 mg qd, the current standard of care in pts with newly diagnosed CML. Nilotinib was effective across all Sokal scores. After only one year of treatment, both nilotinib arms resulted in a meaningful clinical benefit compared to imatinib, with reduction of transformation to AP/BC. Nilotinib exhibited a favorable safety and tolerability profile. The superior efficacy and favorable tolerability profile of nilotinib compared with imatinib suggests that nilotinib may become the standard of care in newly diagnosed CML. Disclosures: Saglio: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Off Label Use: Nilotinib is not currently approved for first-line treatment of CML. The presentation will report the results from a randomized study of imatinib versus nilotinib in patients with newly diagnosed Ph+ CML-CP. Kim:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. le Coutre:Novartis: Honoraria, Research Funding; BMS: Honoraria. Reiffers:Novartis: Research Funding. Pasquini:Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees; Schering: Membership on an entity’s Board of Directors or advisory committees. Clark:Novartis: Honoraria, Research Funding, Speakers Bureau. Hughes:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Hochhaus:Novartis: Research Funding. Gallagher:Novartis: Employment, Equity Ownership. Hoenekopp:Novartis: Employment. Dong:Novartis: Employment, Equity Ownership. Haque:Novartis: Employment. Larson:Novartis:

Description: Background: Nilotinib is a rationally designed, potent and highly selective BCR-ABL kinase inhibitor with significant clinical efficacy in the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia patients in chronic (CML-CP) or accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. This subanalysis of the phase 2 registration study of nilotinib was designed to examine the occurrence of cross-intolerance to nilotinib in patients with prior intolerance to imatinib. Methods: Imatinib intolerance was defined as discontinuation of imatinib due to grade 3/4 adverse events (AEs) or persistent (〉1 month) or recurrent (recurred 〉3 times) grade 2 AEs despite optimal supportive care. Additionally, patients with major cytogenetic response (MCyR) at baseline were excluded from the trial. Cross-intolerance between nilotinib and imatinib was defined as treatment with nilotinib and occurrence (regardless of causality) of grade 3/4, or persistence or recurrent grade 2, of the same AE(s) that previously led to discontinuation of imatinib therapy. Nilotinib was dosed at 400mg twice daily with the option to escalate to 600 mg twice daily for lack of response. Results: Ninety-five of 321 (30%) CML-CP patients and 27 of 138 (20%) CML-AP patients were included in this subanalysis of cross-intolerance following imatinib intolerance. Patients experiencing multiple reasons for imatinib intolerance were counted for each AE category and these included patients (8 CML-CP, 3 CML-AP) with unusual symptoms during imatinib therapy, none of these patients discontinued nilotinib due to the same AE. Median dose intensity for nilotinib (CML-CP 688mg/day, range 151–800; CML-AP 769mg/day range 184–1149) closely approximated the planned dose of 800mg/day. Among these patients, 64% of CML-CP and 52% of CML-AP patients experienced dose interruptions, however, the median cumulative duration of dose interruptions were short (CML-CP 24 days, range 1–301; CML-AP 17 days, range 4–234). Of the 72 patients (57 CML-CP, 15 CML-AP) who discontinued imatinib due to non-hematologic AEs, 3/72 (4%) experienced same persistent grade 2 AEs, only 1 patient (1%) experienced a recurrence of same grade 3/4 AE during nilotinib therapy, and none discontinued nilotinib due to cross intolerance. Approximately one-third of patients were imatinib intolerant due to hematologic AEs. Of 39 patients (30 CML-CP, 9 CML-AP) with hematologic intolerance to imatinib, 3/39 (8%) experienced same persistent grade 2 hematologic AEs, 20/39 (51%) of patients experienced a recurrence of same grade 3/4 AEs during nilotinib therapy, however, only 7 (18%) discontinued nilotinib and all occurred in CML-CP patients due to thrombocytopenia. Nilotinib therapy exhibited significant efficacy in imatinib-intolerant patients. Among the imatinib-intolerant patients included in this subanalysis who did not have complete hematologic response (CHR) at baseline, 90% of patients with CML-CP and 37% with CML-AP achieved a CHR on nilotinib therapy. Among all imatinib-intolerant patients included in this subanalysis, MCyR was achieved by 63% and 32% of patients with CML-CP and CML-AP, respectively; CCyR was achieved by 49% of CML-CP and 19% of CML-AP patients. Conclusions: These results confirm that there is minimal cross-intolerance with nilotinib in imatinib-intolerant CML-CP and CML-AP patients. Thrombocytopenia was the only laboratory abnormality leading to imatinib intolerance that has recurred with any significant frequency during nilotinib therapy.

Description: Abstract 3431 Background: In the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Pts) trial, nilotinib demonstrated superior efficacy vs imatinib in newly diagnosed pts. Here, we examined the kinetics of molecular response and BCR-ABL mutation status in pts from ENESTnd. Methods: Pts with CML-CP were randomized to receive nilotinib 300 mg twice daily (bid) (n = 282), nilotinib 400 mg bid (n = 281), or imatinib 400 mg once daily (qd) (n = 283). BCR-ABL transcripts were quantified at baseline (BL) and every 3 months (mos); MMR was defined as ≤ 0.1% BCR-ABL on the International Scale (IS). Mutational testing of BCR-ABL was performed by direct sequencing at BL and at the occurrence of: (i) 5-fold increase in PCR levels, (ii) failure to achieve MMR at 12 mos, (iii) loss of MMR (≥ 0.1% BCR-ABLIS confirmed by a subsequent sample in association with a ≥ 5-fold rise in BCR-ABL from the lowest value achieved on study treatment), and (iv) end of treatment. Median follow-up was 18 mos. Results: During therapy, a more rapid decline in BCR-ABL levels was demonstrated in the nilotinib arms vs imatinib (Table). The median BCR-ABL levels for pts on nilotinib at 6 mos (both arms) were similar to those on imatinib at 18 mos. The median time to MMR among responders was also shorter on nilotinib (6, 8, and 10 mos in the nilotinib 300 mg bid, 400 mg bid, and imatinib arms, respectively). Loss of MMR occurred in 14 (2%) pts (6 [2%], 5 [2%], and 3 [1%] in the nilotinib 300 mg bid, 400 mg bid, and imatinib arms). Of the 14, none progressed to accelerated phase/blast crisis (AP/BC); only 1 of these pts showed a BCR-ABL mutation (M244V) in the imatinib arm, and 1 pt in the nilotinib 300 mg bid arm lost CCyR. Overall, 9 of 14 (64%) pts, including 8 of 11 on nilotinib, regained MMR within 6 mos on their assigned therapy. In 3 of these 9 pts who regained MMR, loss of MMR was concurrent with dose reduction, and MMR was regained at the time of dose re-escalation. Poor compliance may have contributed to fluctuations in BCR-ABL levels in some pts. At BL, no BCR-ABL mutations were found; 60 pts had polymorphisms which were equally distributed among the 3 arms. Mutational testing was triggered on therapy in 164, 171, and 199 pts in the nilotinib 300 mg bid, 400 mg bid, and imatinib arms, respectively, most commonly due to lack of MMR at 12 mos. Approximately twice as many BCR-ABL mutations (16 [6%]) developed in the imatinib arm vs nilotinib arms (8 [3%] and 5 [2%] for 300 mg bid and 400 mg bid), and most of these were detected within the first 12 mos. The majority of mutations in the nilotinib arms were less sensitive (Y253H, E255K, F359V) or resistant (T315I) to nilotinib, while both nilotinib-sensitive and insensitive mutations were detected in the imatinib arm (Table). The T315I mutation emerged in 5 pts: 2 on nilotinib 300 mg bid, 1 on nilotinib 400 mg bid, and 2 on imatinib; two of these 5 pts discontinued therapy. Overall, 6 of 16 pts with mutations on imatinib progressed to AP/BC vs only 1 of 13 pts on nilotinib (Table). Minimum 24 month follow-up data for all pts will be presented. Conclusions: Pts treated with nilotinib had faster and deeper molecular responses compared with imatinib. The incidence of new mutations was highest for imatinib, and most pts with mutations on nilotinib have not progressed with 18 mos of median follow-up. Loss of MMR was infrequent and was regained in the majority of cases without a change in therapy, and was not typically associated with subsequent treatment failure or the emergence of new mutations. Therefore, loss of MMR may not be an indicator for adjusting therapy, although close monitoring for further loss of response is warranted and mutation testing may be considered. Disclosures: Hochhaus: Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Saglio:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Larson:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Kim:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Flinn:Novartis: Research Funding. Goh:Novartis: Honoraria, Research Funding; Janssen Ciliag: Honoraria, Research Funding; Celgene: Honoraria; Bristol Myers Squibb: Honoraria. Dorlhiac-Llacer:Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Wyeth: Research Funding. Porkka:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Kurokawa:Novartis: Consultancy; Shionogi & Co., Ltd.: Consultancy. Shou:Novartis: Employment. Gallagher:Novartis Pharma AG: Employment, Equity Ownership. Haque:Novartis: Employment. Kantarjian:Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding. Hughes:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria.

Description: Background: Nilotinib is a rationally designed, potent and highly selective BCR-ABL kinase inhibitor, and binds to ABL with higher affinity and improved topological fit compared to imatinib. Nilotinib is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myeloid leukemia pts in chronic (CML-CP) or accelerated phase (CML-AP) resistant or intolerant to prior therapy including imatinib. Methods: This open-label, single-arm, phase 2 study was designed to evaluate the efficacy and safety of nilotinib in CML-AP pts who are resistant or intolerant to imatinib. Nilotinib was dosed at 400 mg twice daily with the option to dose escalate to 600 mg twice daily for lack of response. The primary endpoint was confirmed hematologic response (HR). Complete hematologic response (CHR) was defined as meeting all of the following criteria: myeloblast count

Description: Abstract 1129 Poster Board I-151 Background Nilotinib is a selective and potent BCR-ABL inhibitor, developed through structure-based drug design, indicated for the treatment of Philadelphia chromosome positive (Ph+) CML patients in CP or accelerated phase (AP) resistant or intolerant to prior therapy including imatinib. Recently, 24-month follow-up data from the pivotal nilotinib 2101 study demonstrated achievement of rapid and durable cytogenetic responses in the majority of patients and an excellent overall survival (OS) rate of 87%. The current update focuses on the major molecular response (BCR-ABL transcript levels ≤ 0.1% according to the international scale; MMR) of patients treated with nilotinib. Methods Imatinib-resistant and -intolerant CML-CP patients (n=321) were treated with nilotinib 400 mg twice daily and followed for at least 24 months. In this report, the efficacy parameters studied were: rate of MMR, rate of major and complete cytogenetic response (MCyR, CCyR), time to and duration of response, time to progression (TTP), and OS. Efficacy parameters were also analyzed based on the presence or absence of a CHR at study entry. Results The median duration of exposure to nilotinib was 18.7 months (〈 1.0–36.5), with 62% of patients on therapy for at least 12 months and 42% on therapy for ≥ 24 months. Median dose intensity of nilotinib was 788.5 mg/day, very close to planned dosing. Overall, 58% of patients required dose interruption (defined conservatively ≥ 1 day of interruption regardless of reason) with a median cumulative duration of interruption of 20 days (4% of days of exposure). Importantly, 73% of patients that required treatment interruptions resumed treatment after interruption at the planned dose. The achievement of MMR in imatinib-resistant and -intolerant CML-CP patients who had BCR-ABL transcript levels available post-baseline (n=294) were included in this efficacy analysis (Table). Of these patients, 105/294 (36%) entered the study with a CHR and 189/294 (64%) did not have a CHR at study entry. The overall MMR rate was 28%; MMR was higher in patients with CHR at study entry (38% vs. 22%). Overall, CCyR was achieved in 46% of patients, among whom 56% achieved MMR. Median time to MMR was 5.6 months. Overall, 77% and 84% of responding patients maintained MCyR and CCyR at 24 months, respectively. Overall (n=321), the estimated rate of progression-free survival (PFS), defined as progression to AP/BC or discontinuation due to progression or death, at 24 months was 64%, however, only 9 patients (3%) progressed to AP/BC based on actual laboratory values. PFS rate at 24 months was higher for patients with baseline CHR (77%) compared with patients without CHR at study entry (56%). OS at 24 months is 87% for the entire patient population. The safety profile of nilotinib remains unchanged at 24 months of follow-up. The majority of first episodes of grade 3/4 bilirubin and lipase elevations occurred within the first month of therapy and were brief in duration (median duration 15 days). The incidences of hepatic and pancreatic disorders on nilotinib were 1.3 and 1.7 per 100-patient years of therapy and no cumulative risk of hepatic and pancreatic events was observed in this population with longer follow-up. Importantly, discontinuations due to hepatobiliary adverse events were uncommon (n=2; 〈 1.0%). Conclusions Nilotinib therapy led to the achievement of MMR in a majority of patients with CCyR, and in 38% of patients with CHR at study entry. Furthermore, the response and outcomes of patients treated with nilotinib was higher in patients with CHR at baseline suggesting that patients with imatinib resistance and intolerance who lost cytogenetic response but not hematologic response have a more favorable response compared to those patients who have lost hematologic response when switched to nilotinib. Overall, the safety profile of nilotinib remains well-tolerated with long-term follow-up. At 24 months, nilotinib therapy remains an effective and tolerable therapy for patients with imatinib-resistant or -intolerant CML. Disclosures Kantarjian: Novartis: Research Funding. Giles:Novartis: Consultancy, Research Funding; BMS: Research Funding; Merck: Research Funding; Clavis: Research Funding. Bhalla:Novartis: Honoraria, Research Funding; Merck: Honoraria. Pinilla-Ibarz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Larson:Novartis: Consultancy, Honoraria, Research Funding. Gattermann:Novartis, Celgene: Honoraria, Participation in Advisory Boards on deferasirox clinical trials, Research Funding. Ottmann:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Hochhaus:Novartis: Research Funding. Radich:Novartis: Consultancy, Honoraria, Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Martinelli:Novartis: Research Funding. Kim:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Shou:Novartis: Employment. Gallagher:Novartis: Employment, Equity Ownership. Wang:Novartis: Employment. Cortes-Franco:Novartis: Honoraria, Research Funding, Speakers Bureau; Wyeth: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau. Baccarani:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau. le Coutre:Novartis: Honoraria, Research Funding; BMS: Honoraria.

Description: Abstract 114 Background: In ENESTnd, nilotinib demonstrated superior efficacy vs imatinib in pts with newly diagnosed CML-CP, including a significantly reduced rate of progression to AP/BC on treatment and a lower rate of SoR/TF. Pts in ENESTnd with SoR/TF on nilotinib 300 mg BID or imatinib could discontinue core study and enter an extension study; entrance was not allowed for intolerance. Here, we report the efficacy and safety of 49 such pts. Methods: 31 pts initially randomized to imatinib 400 mg QD (IM group) and 18 pts to nilotinib 300 mg BID (NIL group) in ENESTnd discontinued due to SoR/TF and received nilotinib 400 mg BID in this study. Progression and deaths in the extension study and after discontinuation of extension treatment have been previously reported as progression events after discontinuation of core ENESTnd treatment and in the OS analysis of ENESTnd. Results: Median time on extension treatment was 6 months (mo) for both groups (range, IM 0.2–24; NIL 1–14); 35/49 pts (71%) remain on study. Median nilotinib dose during extension treatment was equal to planned dose (800 mg/day). In the IM group, 65% of pts escalated imatinib to 400 mg BID prior to extension; 12 pts (46%) not in CCyR at extension entry and 7 pts (23%) not in MMR achieved these responses on extension treatment (table). Of these responders, 7/12 pts (58%) who achieved CCyR and 4/7 pts (57%) who achieved MMR had escalated imatinib to 400 mg BID on core study. In the NIL group, 1 pt (17%) not in CCyR at extension entry and 5 pts (29%) not in MMR, achieved this response on extension treatment. Overall, 4 pts in the IM group progressed to AP/BC (2 on extension treatment, 1 within 1 mo and the other 〉 12 mo after discontinuation). All 4 pts discontinued core study for TF. Overall, 1 pt in the NIL group progressed to AP/BC (〈 1 mo after discontinuation of extension treatment); pt discontinued core study for SoR. The safety of nilotinib 400 mg BID was similar to that in the core study. Grade 3/4 AEs and drug-related AEs leading to discontinuation were reported in 52% and 10% of pts in the IM group. Higher rates of AEs in the first few mo of starting nilotinib in pts previously treated with imatinib were not unexpected as common AEs occur early following initial exposure. In the NIL group, grade 3/4 AEs were reported in 28% of pts and no pt discontinued due to drug-related AEs. No deaths were reported on extension treatment or ≤ 28 days of discontinuation; 4 deaths occurred 〉 28 days after discontinuation of treatment: 3 were CML-related (2 and 1 deaths in the IM and NIL groups, respectively) and occurred 8–10 mo after discontinuation. Conclusions: Results confirm the efficacy of nilotinib 400 mg BID for pts with CML-CP who had SoR/TF on imatinib, even after imatinib dose escalation. These results suggest that nilotinib 400 mg BID may be efficacious in pts with CML-CP with SoR/TF on nilotinib 300 mg BID, although longer follow-up is required. Whereas dose escalation of imatinib may overcome OCT-1 transporter activity in pts with correspondingly low imatinib plasma levels, nilotinib is not a substrate for OCT-1. The modest (∼16%) increase in nilotinib systemic exposure by dose escalation from 300 to 400 mg BID may benefit some patients with SoR/TF, but requires further evaluation. Currently, dose escalation of nilotinib from 300 to 400 mg BID appears safe with no additional safety signals. The extension study is ongoing and additional follow-up will provide more information moving forward. Disclosures: Hochhaus: Ariad: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Ossenkoppele:Bristol Myers Squibb: Consultancy, Honoraria; Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding. Gattermann:Novartis: Honoraria, Research Funding. Hughes:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Saglio:Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis Pharmaceutical: Consultancy, Speakers Bureau; Pfizer: Consultancy. Larson:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Gallagher:Novartis: Employment, Equity Ownership. Yu:Novartis: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Kantarjian:Pfizer: Research Funding; Novartis: Research Funding; Novartis: Consultancy; BMS: Research Funding.

Description: Nilotinib is a potent selective inhibitor of the BCR-ABL tyrosine kinase approved for use in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP), and in CML-CP and CML-accelerated phase after imatinib failure. Nilotinib (400 mg twice daily) was approved on the basis of the initial results of this phase 2 open-label study. The primary study endpoint was the proportion of patients achieving major cytogenetic response (CyR). All patients were followed for ≥ 24 months or discontinued early. Of 321 patients, 124 (39%) continue on nilotinib treatment. Overall, 59% of patients achieved major CyR; this was complete CyR (CCyR) in 44%. Of patients achieving CCyR, 56% achieved major molecular response. CyRs were durable, with 84% of patients who achieved CCyR maintaining response at 24 months. The overall survival at 24 months was 87%. Adverse events were mostly mild to moderate, generally transient, and easily managed. This study indicates that nilotinib is effective, with a manageable safety profile, and can provide favorable long-term benefits for patients with CML-CP after imatinib failure. This trial was registered at www.clinicaltrials.gov as #NCT00109707.