Abstract

Background

Nilotinib has shown superiority over imatinib for treating pts with newly diagnosed CML-CP. Additionally, pts who are resistant or intolerant to imatinib can often achieve improved responses by switching to nilotinib. However, the value of switching pts to nilotinib due to molecular SoR on imatinib is not well characterized. The Study to Evaluate Nilotinib in CML pts with SubOptimal Response (SENSOR) was therefore conducted to evaluate the efficacy and safety of nilotinib 400 mg BID in pts with CML-CP with SoR to frontline imatinib. Here, we present results of a planned 12-mo interim analysis.

Methods

SENSOR (NCT01043874) is an open-label, multicenter, phase IV study. Adult pts with CML-CP in complete cytogenetic response but not in major molecular response (MMR; defined as BCR-ABL ≤ 0.1% on the International Scale [IS]) after ≥ 18 mo on frontline imatinib (SoR as defined by 2009 European LeukemiaNet criteria) were eligible to enroll and switch to nilotinib 400 mg BID. Molecular responses were assessed prior to enrollment, at 1, 2, and 3 mo and every 3 mo thereafter. Mutational analyses were performed at baseline (BL) and at end of study in all pts, every 3 mo in pts with BL mutations, and with any ≥ 5-fold increase in BCR-ABL from the lowest level in pts not in MMR. All of these assays were done at a single central laboratory. The primary endpoint was the rate of MMR at 12 mo. Planned enrollment was 45 pts in order to provide a ≥ 25% lower limit of the 95% CI with an expected MMR rate of 40%. Planned follow-up was 24 mo.

Results

Planned enrollment of 45 pts was completed between Dec 2009 and Feb 2012. Median age of pts was 47 years (range, 19-80). Pts had received imatinib for a median of 23.0 mo (range, 17.0-103.3) at a median daily dose of 400 mg (range, 297-628). Median BL BCR-ABL/ABL ratio was 0.24% (range, 0.11-3.49). At the cutoff date, 19 pts (42%) had completed the study (24 mo follow-up), and 21 (47%) had nilotinib treatment ongoing. Median nilotinib duration was 19.1 mo (range, 0.1-22.7) and median dose intensity was 733 mg/day (range, 183-800). Five (11%) pts discontinued from study treatment for the following reasons: adverse events (AEs; n = 2), disease progression (n = 1), withdrawal of consent (n = 1), and administrative problems (n = 1).

At 12 mo, the MMR rate was 51.1% and the median BCR-ABL/ABL ratio was 0.10% (range, ≤ 0.0032-1.62). The cumulative rate of MMR by 12 mo was 66.7%. Among 34 pts with MMR at any time, median time to first MMR was 2.28 mo. No pt who achieved MMR had confirmed loss of MMR (BCR-ABLIS > 0.1% with a ≥ 5-fold increase in BCR-ABL transcripts from the lowest level achieved on study in 2 consecutive samples) by the cutoff date (Table). Two pts (4.4%) achieved BCR-ABLIS ≤ 0.0032% at 12 mo.

Table 1
Nilotinib 400 mg BID (N = 45)
MMR at 12 mo, % (95% CI) 51.1 ( 35.8-66.3) 
Cumulative incidence of MMR, %  
 By 3 mo 42.2 
 By 6 mo 53.3 
 By 12 mo 66.7 
Progression-free survivala at 12 mo, % (95% CI)b 97.8 (85.3-99.7) 
Overall survival at 12 mo, % (95% CI)b 97.7 (84.9-99.7) 
Nilotinib 400 mg BID (N = 45)
MMR at 12 mo, % (95% CI) 51.1 ( 35.8-66.3) 
Cumulative incidence of MMR, %  
 By 3 mo 42.2 
 By 6 mo 53.3 
 By 12 mo 66.7 
Progression-free survivala at 12 mo, % (95% CI)b 97.8 (85.3-99.7) 
Overall survival at 12 mo, % (95% CI)b 97.7 (84.9-99.7) 
a

Defined as time from first dose of study drug to date of progression to AP/BC or death due to any cause.

b

Kaplan-Meier estimates using the standard error calculated with Greenwood's formula.

BCR-ABL mutations were detected at BL in 5 pts (E255K, E459K + exon 8/9 35 base pair insertion, Q252R, M244V, and exon 7 deletion), all of whom achieved MMR on nilotinib. Mutations were identified during treatment in 13 pts, 2 of whom had the same mutation at BL; 10 of these pts achieved MMR. One pt developed a T315I mutation, progressed at 5.4 mo, and died at 9.4 mo. These were the only reported events for progression-free survival and overall survival (1 each).

The safety profile of nilotinib was consistent with previous studies. Drug-related AEs (any grade) occurring in ≥ 20% of pts included hyperbilirubinemia (53.3%), increased ALT (28.9%), headache (28.9%), hypophosphatemia (26.7%), rash (26.7%), and increased lipase (24.4%). Grade 3/4 newly occurring/worsening abnormal hematology values were hemoglobin (6.7%), neutrophils (4.4%), platelet count (2.2%), and decreased total white blood cells (2.2%). Six pts had serious AEs (2 with suspected relation to study drug [anemia and erythema multiforme]).

Conclusions

After switching to nilotinib, MMR was rapidly achieved in the majority of pts. These results support the clinical benefit of switching to nilotinib in pts with molecular SoR to imatinib.

Disclosures:

Miyamura:Novartis: Speakers Bureau; JRC Nagoya 1st Hospital: Employment. Miyamoto:Kyushu University Hospital: Employment. Kurokawa:Celgene: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding. Yamamoto:Novartis: Honoraria, Research Funding. Taniwaki:Novartis: Honoraria. Kimura:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Ohyashiki:Novartis: Honoraria, Research Funding. Kawaguchi:Novartis: Honoraria. Matsumura:Bristol Myers Squibb: Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Tsurumi:Novartis: Honoraria. Hino:Novartis: Research Funding. Tadokoro:Novartis: Guest speaker in a scientific meeting sponsored by Novartis Other. Hyodo:Hiroshima University: Employment. Kubo:Aomori Prefectural Central Hospital: Employment; Novartis: Honoraria. Kondo:Novartis: Employment. Amagasaki:Novartis: Employment. Kawahara:Novartis: Employment. Yanada:Novartis: Consultancy.

Author notes

*

Asterisk with author names denotes non-ASH members.