Abstract

Background

In global clinical trials, nilotinib has shown superior efficacy vs imatinib for treating patients (pts) with CML-CP. The Evaluating Nilotinib Efficacy and Safety in Clinical Trials–China (ENESTchina) study is assessing the efficacy and safety of frontline nilotinib vs imatinib in Chinese pts with CML-CP.

Methods

ENESTchina (NCT01275196) is a multicenter, open-label, phase 3 study of Chinese adults with newly diagnosed (≤ 6 mo) CML-CP. Pts were randomized to nilotinib 300 mg BID (n = 134) or imatinib 400 mg QD (n = 133). The primary endpoint was the rate of major molecular response (MMR; ≤ 0.1% BCR-ABL on the international scale) at 12 mo. Molecular assessments were performed at a central laboratory. This analysis was conducted when all randomized pts had ≥ 12 mo of follow-up or discontinued early.

Results

Baseline characteristics were similar between the arms (Table). Most pts (nilotinib, 93%; imatinib, 95%) remained on treatment at the data cutoff. Median actual dose intensities were nilotinib 565 mg/day (range, 167-600 mg/day) and imatinib 393 mg/day (range, 204-550 mg/day). Sixteen pts (nilotinib, n = 9; imatinib, n = 7) discontinued, mainly due to adverse events (AEs; nilotinib, n = 3; imatinib, n = 1), withdrawal of consent (nilotinib, n = 3; imatinib, n = 1), or disease progression (nilotinib, n = 2; imatinib, n = 2).

Table
 Nilotinib n = 134 Imatinib n = 133 
Age, median (range), y 41 (18-76) 39 (19-74) 
Male, % 68 61 
Prior iterferon, % 
Sokal risk, %   
Low 51 52 
Intermediate 33 32 
High 16 16 
MMR at 12 mo, % (95% CI) 52 (43-61) 28 (20-36) 
MMR at 12 mo by Sokal risk, %   
Low 64 32 
Intermediate 41 30 
High 38 10 
MMR by 12 mo, % (95% CI) 56 (47-65) 31 (23-39) 
CCyR, % (95% CI)   
By 6 mo 66 (58-74) 57 (48-66) 
 By 12 mo 77 (69-84) 77 (69-84) 
AEs in ≥ 10% of pts in either arm (all grades, regardless of relationship to study drug, excluding system organ class investigations), %a 
 Rash 35 11 
 Myalgia 12 
 Nasopharyngitis 16 
 Fluid retentionb 31 
Newly occurring/worsening grade 3/4 hematologic and biochemical abnormalities in ≥ 5% of pts in either arm, %a 
 Thrombocytopenia 26 29 
 Neutropenia 20 20 
 Leukopenia 10 17 
 Lymphopenia 
Anemia 
 Elevated lipase 13 
 Nilotinib n = 134 Imatinib n = 133 
Age, median (range), y 41 (18-76) 39 (19-74) 
Male, % 68 61 
Prior iterferon, % 
Sokal risk, %   
Low 51 52 
Intermediate 33 32 
High 16 16 
MMR at 12 mo, % (95% CI) 52 (43-61) 28 (20-36) 
MMR at 12 mo by Sokal risk, %   
Low 64 32 
Intermediate 41 30 
High 38 10 
MMR by 12 mo, % (95% CI) 56 (47-65) 31 (23-39) 
CCyR, % (95% CI)   
By 6 mo 66 (58-74) 57 (48-66) 
 By 12 mo 77 (69-84) 77 (69-84) 
AEs in ≥ 10% of pts in either arm (all grades, regardless of relationship to study drug, excluding system organ class investigations), %a 
 Rash 35 11 
 Myalgia 12 
 Nasopharyngitis 16 
 Fluid retentionb 31 
Newly occurring/worsening grade 3/4 hematologic and biochemical abnormalities in ≥ 5% of pts in either arm, %a 
 Thrombocytopenia 26 29 
 Neutropenia 20 20 
 Leukopenia 10 17 
 Lymphopenia 
Anemia 
 Elevated lipase 13 

aAmong pts who received ≥ 1 dose of study drug (nilotinib, n = 133; imatinib, n = 132).

bIncluding eyelid edema.

The primary endpoint was met, with a significantly higher rate of MMR at 12 mo in the nilotinib arm vs the imatinib arm (52% vs 28%, respectively; P < .0001). The MMR rate at 12 mo was higher in the nilotinib arm vs the imatinib arm across all Sokal risk groups (Table). The rate of complete cytogenetic response (CCyR) by 6 mo was higher in the nilotinib arm vs the imatinib arm, but by 12 mo CCyR rates were similar in both arms. By the cutoff date, 2 pts (1.5%) in each arm had progressed to accelerated phase/blast crisis (AP/BC) on treatment. Three deaths were reported (all ≥ 28 days after discontinuing treatment), 2 in the nilotinib arm (due to cerebral hemorrhage [n = 1] and study indication [n = 1]) and 1 in the imatinib arm (due to recurrent non-Hodgkin lymphoma).There was no difference between the arms in time to progression to AP/BC on treatment or overall survival.

Both drugs were well tolerated, with safety profiles similar to those reported in prior studies. The most common AEs on nilotinib were rash and myalgia; on imatinib, fluid retention and nasopharyngitis were most common (Table). One pt in the imatinib arm had a grade 1 increase in creatine phosphokinase-MB with no clinical signs indicative of ischemic heart disease. No cases of peripheral arterial occlusive disease, ischemic cerebrovascular events, or QTcF > 480 ms were observed in either arm. Newly occurring/worsening grade 3/4 thrombocytopenia and neutropenia occurred at similar rates in both arms, while leukopenia, lymphopenia, and anemia were more frequent in the imatinib arm. The most common newly occurring/worsening grade 3/4 biochemical abnormality in both arms was elevated lipase.

Conclusions

In Chinese pts with newly diagnosed CML-CP, nilotinib was well tolerated and demonstrated superior efficacy over imatinib, as shown by higher rates of MMR in all Sokal risk groups, despite similarly high rates of CCyR after 1 y with both drugs. These results highlight the utility of MMR as a more sensitive efficacy endpoint for differentiating tyrosine kinase inhibitors in pts with CML-CP and provide the first evidence-based, prospective confirmation of the superiority of nilotinib over imatinib observed in the ENESTnd trial.

Disclosures:

Wang:Novartis: Employment; Bristol Myers Squibb: Consultancy. Baccarani:Ariad: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Jevtic:Novartis: Employment, Equity Ownership. Ortmann:Novartis: Employment. Yuan:Novartis: Employment. Menssen:Novartis: Employment. Saglio:ARIAD: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

Author notes

*

Asterisk with author names denotes non-ASH members.