Treatment-Free Remission (TFR) after Two Different Durations of Nilotinib Consolidation in Patients with Chronic Myeloid Leukemia (CML) Previously Treated with Imatinib: Enestpath Study Results
Authors: Rea Delphine , Kyrcz-Krzemien Slawomira , Sportoletti Paolo , Mayer Jiří , Illes Arpad , Angona Anna , Kiani Alexander , Charbonnier Aude , Marinakis Theodoros , Stenke Leif , Weltermann Ansgar , Shah Seema , Supekar Sharon , Di Caprio Luigi , Baccarani Michele 
Published: November 2021

Abstract
Background
TFR following cessation of tyrosine kinase inhibitor (TKI) therapy is increasingly regarded as a feasible objective for many patients (pts) with CML in chronic phase (CML-CP) who achieve a sustained deep molecular response (DMR). In Evaluating Nilotinib Efficacy and Safety in clinical Trials (ENEST)-complete molecular response (ENESTcmr), pts unable to achieve DMR on imatinib (IM) were able to reach deeper levels of MR by switching to nilotinib (NIL) 400 mg twice daily (BID) vs continuing IM (Hughes et al. 2017). Recent long-term analysis from ENESTop illustrated the durability and safety of TFR for pts who achieved sustained DMR only after switching from IM to NIL 400 mg (Hughes et al. 2021). European LeukemiaNet guidelines allow discontinuation of TKI therapy following &gt;2 years of DMR (MR 4.0 or better) (Hochhaus et al. 2020). However, the optimal duration of NIL consolidation (CONS) to increase the chances for successful TFR is not yet known.
Objectives
The ENESTPath study was designed to evaluate the impact of 12 or 24 months (mos) of NIL 300 mg BID CONS, on the TFR rate in pts who had not achieved sustained DMR with IM.
Methods
ENESTPath (NCT01743989) is a prospective, randomized, open-label, two-arm phase 3 study that enrolled pts with CML-CP who achieved a complete cytogenetic response (CCyR), but not MR 4.0, after ≥24 mos of IM. After enrollment, pts received NIL 300 mg BID for 12 mos each of induction (IND) and CONS. Pts with sustained DMR for at least the last 12 mos (≥MR 4.0; BCR-ABL1IS ≤0.01% in 4 of the 5 preceding quarterly assessments and ≥MR 4.0 in the last assessment) were randomized (1:1) either to enter the TFR phase (Arm 1) or to continue NIL for an additional 12 mos CONS, before entering TFR (Arm 2) if eligibility criteria were still met, resulting in a 36- or 24- mos TFR phase, respectively (Figure 1). The primary endpoint was the number of pts who remained in TFR (≥MR 4.0) without molecular relapse 12 mos after entering TFR. Molecular relapse was defined as loss of major molecular response (loss of MMR, BCR-ABL1IS &gt;0.1%) or the confirmed loss of MR 4.0 (3 tests &lt;MR 4.0 assessed at 3 consecutive visits).
Results
Overall, 620 pts were enrolled. In the full analysis set (FAS, N=619), 238 pts were randomized after 24 mos of NIL, 381 patients were not randomized and followed for survival, and one pt was excluded from FAS due to major protocol deviation. Baseline characteristics were well balanced between Arm 1 (N=120) and Arm 2 (N=118): 49.5 and 49.0 years median age; 60.0% and 58.5% male; 56.11 vs 57.97 mos median time since initial diagnosis; 54.08 vs 57.99 mos median prior exposure to IM, respectively. The number of pts in the FAS entering TFR was 119 in Arm 1 and 104 in Arm 2. There was no significant difference in the primary endpoint of MR 4.0 rate at 12 mos of TFR between arms (Arm 1, 31.9% [95% CI: 23.7 - 41.1]; Arm 2, 37.5% [95% CI: 28.2 - 47.5]; P=0.383) (Table 1). Median time to treatment-free survival event (TFS; defined as loss of MMR, confirmed loss of MR 4.0, re-start of NIL for any reason, progression to accelerated phase/blast crisis, or death from any cause) was 4.1 (95% CI: 3.7 - 5.5) mos in Arm 1 and 4.2 (95% CI: 3.7 - 19.7) in Arm 2 (Figure 2). Among the 129 pts who relapsed during TFR and were re-treated with NIL, the majority regained MMR and MR 4.0 by 3 mos (Table 2). In the 619 pts who received NIL during IND/CONS, the raw cumulative rate of MR 4.0 and MR 4.5 was 64.3% and 36.8% by 12 mos and 72.4% and 48.0% by 24 mos, respectively. The proportion of pts who achieved MR 4.0 and MR 4.5 was 48.0% and 25.0% at 12 mos, and 44.1% and 24.9% at 24 mos, respectively. During IND/CONS before randomization, 87.7% (543/619) pts experienced an adverse event (AE), 18.1% (112/619) serious AEs (SAEs), 9.7% (60/619) cardiovascular AEs, and 12.1% (75/619) discontinued study treatment due to AEs. In the TFR phase, 63.2% (141/223) pts experienced AEs, and 6.7% (15/223) pts SAEs (Table 3); and three patients had SAEs suspected to be related to study drug (all in Arm 1): one cerebrovascular accident, one peripheral artery stenosis, and one Grade 3/4 myocardial infarction.
Conclusions
ENESTPath results suggest there is no significant incremental benefit in terms of TFR success from an additional year of NIL CONS for pts with CML-CP who achieved sustained DMR after 2 years on NIL following a switch from IM. The efficacy of NIL at a dose of 300 mg BID in achieving MR in pts unable to reach sustained DMR with first-line IM for ≥24 mos was confirmed. No new safety signals were observed.
Figure 1 Figure 1.

Disclosures
Rea: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Mayer: Principia: Research Funding. Illes: Novartis, Janssen, Pfizer, Roche: Other: Travel, Accommodations, Expenses; Takeda, Seattle Genetics: Research Funding; Janssen, Celgene, Novartis, Pfizer, Takeda, Roche: Consultancy. Kiani: Novartis Pharma GmbH: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Charbonnier: Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Marinakis: Novartis: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Stenke: Incyte: Membership on an entity's Board of Directors or advisory committees. Shah: Cognizant technology Solutions: Current Employment. Supekar: Novartis Farma: Current Employment. Di Caprio: Novartis Pharma: Current Employment. Baccarani: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.