Switching To Nilotinib In Patients (pts) With Chronic Myeloid Leukemia In Chronic Phase (CML-CP) With Suboptimal Cytogenetic Response (CyR) On Imatinib: First Results Of The LASOR Trial
Authors: Cortes Jorge E. , Antonio De Souza Carmino , Lopez Jose Luis , Ayala Manuel , Bullorsky Eduardo , Huang Xiaojun , Shah Sandip , Babu K. Govind , Sacha Tomasz , Bendit Israel , Liang Zhizhou , Owugah Tina , Nidamarthy Prasanna Kumar , Szczudlo Tomasz , Piccolo Carmen , le Coutre Philipp D. 
Published: October 2019

Abstract

Introduction
The phase 3 LASOR trial is the only randomized trial that compares the effects of imatinib dose escalation with those of switching to nilotinib in pts with Philadelphia chromosome–positive (Ph+) CML-CP who experience suboptimal response to frontline imatinib. Suboptimal response has been associated with inferior long-term outcomes in several landmark analyses and was observed in 13% of pts randomized to the imatinib arm of ENESTnd by 12 mo (vs 4% in each nilotinib arm).

Methods
Adults (N = 191) with CML-CP with suboptimal CyR to frontline imatinib 400 mg once daily (QD) were randomized 1:1 to nilotinib 400 mg twice daily (BID; n = 96) or imatinib 600 mg QD (n = 95). Suboptimal CyR was defined according to 2009 European LeukemiaNet (ELN) criteria as: no CyR ≥ 3 to < 6 mo (Ph+ > 95%), no partial CyR (PCyR) ≥ 6 to < 12 mo (Ph+ 36%-95%), or no complete CyR (CCyR) ≥ 12 to <18 mo (Ph+ 1%-35%) after starting imatinib. All pts had complete hematologic response at study entry. The primary endpoint was CCyR (Ph+ 0%) at 6 mo after randomization. The key secondary endpoint was major molecular response (MMR; BCR-ABLIS ≤ 0.1%) at 12 mo. Crossover to the alternate treatment arm was allowed for pts who failed to achieve CCyR by 6 mo or had intolerance or loss of response at any time.

Results
Baseline characteristics were well balanced between arms, with most pts entering study for not having PCyR at 6 mo or CCyR at 12 mo (Table). The primary endpoint, CCyR at 6 mo after randomization, was observed in 47 (49.0%) and 40 (42.1%) pts in the nilotinib and imatinib arms, respectively (P = .3844). Crossover was more common in pts randomized to the imatinib arm. Crossover occurred before the primary endpoint analysis at 6 mo in 6 pts in the nilotinib arm (5 for intolerance; 1 for lack of efficacy) and 15 pts in the imatinib arm (13 for intolerance; 1 for lack of efficacy; 1 for loss of response). Median time to crossover was 3.9 and 3.6 mo in the nilotinib and imatinib arms, respectively. None of the nilotinib pts who crossed over to imatinib vs 6 of the 15 imatinib pts who crossed over to nilotinib achieved CCyR at the primary analysis time point 6 mo after randomization. Ten pts in the nilotinib arm and 7 in the imatinib arm had neither samples evaluable for CyR at 6 mo nor had crossed over to the alternate treatment arm. Excluding these pts (evaluable population) and counting crossed-over pts as non-responders, 47 of 86 pts (54.7%) in the nilotinib arm and 34 of 88 (38.6%) in the imatinib arm achieved CCyR at 6 mo. Analyses of molecular response at 6 mo after randomization suggested higher rates in the nilotinib arm for BCR-ABLIS ≤ 1% (CCyR equivalent) and ≤ 0.1% (MMR) compared with the imatinib arm (52.1% vs 29.5% and 31.3% vs 11.6%, respectively). The safety profile for both drugs was consistent with prior reports of pts who switched therapy after inadequate responses to imatinib.

Conclusions
Patients with suboptimal CyR to imatinib (today classified by ELN as warning/failure) represent a significant unmet need in the treatment of CML-CP. This important study is the only randomized evaluation of imatinib dose escalation vs switch to the more potent BCR-ABL tyrosine kinase inhibitor nilotinib in this population. Although the primary endpoint was not met, sensitivity analyses accounting for crossover and more sensitive molecular monitoring demonstrated higher rates of response with switch to nilotinib vs imatinib dose escalation in pts with suboptimal response to frontline imatinib.

Disclosures:
Cortes: Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Teva: Consultancy, Research Funding. Bullorsky:Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Sacha:Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Owugah:Novartis Pharmaceuticals Corporation: Employment. Kumar Nidamarthy:NOVARTIS HEALTH CARE Pvt Ltd: Employment. Szczudlo:Novartis: Employment, Equity Ownership. Piccolo:Novartis: Employment. le Coutre:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria.