The selective BCR::ABL1 inhibitor ELVN-001 produced major molecular responses in previously treated chronic-phase CML, including after asciminib progression.
ELVN-001, a novel, selective ATP-competitive inhibitor of BCR::ABL1, produced molecular responses in patients with previously treated chronic-phase chronic myeloid leukemia (CP-CML), according to updated data from the phase 1 ENABLE trial (NCT05304377) presented at the
At the optimal biological dose of 80 mg once daily, 61% of efficacy-evaluable patients in the phase 1b expansion portion (n = 49) achieved an overall major molecular response (MMR), with 48% of patients achieving an MMR by week 24. Additionally, a deep molecular response was achieved in 30% of patients. Responses were observed across lines of therapy, including in patients who had progressed on prior asciminib (Scemblix). With longer follow-up, ELVN-001 continued to show favorable safety and tolerability, a low rate of treatment discontinuation due to adverse effects (AEs), and no evidence of increased cardiovascular toxicity; no patients progressed to blast phase.
ELVN-001 was designed to address several unmet needs in CML, combining potent BCR::ABL1 inhibition with high selectivity for ABL1, with no inhibition of KIT, VEGFR2, PDGFR, or SRC. In profiling against approved TKIs, including imatinib (Gleevec), dasatinib (Sprycel), nilotinib (Tasigna), bosutinib (Bosulif), and ponatinib (Iclusig), ELVN-001 showed a narrower off-target inhibition footprint, which the investigators noted may translate to better tolerability.
ELVN-001 uses a unique P-loop folded-in binding mode and has shown activity against the BCR::ABL1 T315I mutation and an emerging class of mutations associated with resistance to allosteric inhibitors, such as asciminib. Notably, the agent is not a substrate or inhibitor of P-glycoprotein or breast cancer resistance protein. ELVN-001 is dosed once daily with or without food, with potential for concomitant use with CYP3A4 substrates or inhibitors and proton pump inhibitors.
ENABLE enrolled adult patients with CP-CML who had progressed on, were intolerant to, or were not candidates for available therapies known to be active against their disease, with typical or atypical BCR::ABL1 transcripts. The phase 1a dose-escalation (10-120 mg daily and 60-120 mg twice daily) and phase 1b dose-expansion portions of the trial in patients with non-T315I disease across 60 mg (n = 20), 80 mg (n = 20), and 120 mg (n = 21) daily cohorts are complete. Based on safety, tolerability, anti-CML activity, and pharmacokinetic/pharmacodynamic modeling, the optimal biological dose was identified as 80 mg daily, and an additional cohort of 40 patients is enrolling at that dose.
ENABLE Trial: Key Takeaways
As of the March 10, 2026, data cutoff, 161 dosing instances had occurred across 158 patients. Patients had a median age of 59 years (range, 19-82). Patients were heavily pretreated with a median of 4 prior lines of TKI therapy (range, 1-10) and 3 unique prior TKIs (range, 1-7). In total, 62% of patients had received prior asciminib, and 37% of patients had received prior ponatinib. Lack of efficacy (61%) and lack of tolerability (32%) were the most common reasons for discontinuing the last prior TKI.
Among all patients in the phase 1b portion, MMR rates by week 24 declined with greater pretreatment but remained meaningful across subgroups: 67% in patients with 1 to 2 prior TKIs (n = 27), 50% in those with 3 to 4 prior TKIs (n = 26), and 38% in those with 5 or more prior TKIs (n = 16), with all achieved responses maintained at 100%. Among patients who had progressed on asciminib, the MMR rates by week 24 were 67%, 41%, and 33%, respectively. Among patients evaluable for MMR by week 24 across the full cohort, molecular response category was stable or improved in all patients in the phase 1b portion. In the subgroup with a baseline BCR::ABL1 transcript above 10%, 59% of patients (n = 10/17) had an improved molecular response category.
Across all safety-evaluable patients (n = 158), any-grade treatment-emergent AEs (TEAEs) occurred in 90%, with grade 3 or higher TEAEs observed in 34%. At the 80-mg dose level (n = 62), these rates were 82% and 24%, respectively. The most common nonhematologic TEAEs of any grade in the overall population included increased lipase levels (22%), fatigue (18%), headache (15%), arthralgia and myalgia (14% each), nausea (12%), diarrhea (11%), and increased amylase levels (10%); hematologic TEAEs reported in at least 5% of patients included thrombocytopenia (15%) and neutropenia (7.0%).
The maximum tolerated dose was determined to be 80 mg twice daily, based on 2 dose-limiting toxicities at 120 mg twice daily (1 grade 3 hallucination in a patient with a prior history of hallucinations, and 1 grade 3 myalgia event). Arterial occlusive events occurred in 7 patients (4.4%), with 3 grade 3 events (1.9%), each in patients with cardiovascular disease or risk factors, including prior nilotinib or ponatinib exposure. Overall, 76% of patients remained on study, with treatment discontinuations most commonly due to lack of efficacy (13%) or AEs (6.2%). One death occurred and was attributed to a postoperative complication unrelated to ELVN-001.
The phase 3 ENABLE-2 pivotal trial is planned to be initiated in the second half of 2026 and will investigate ELVN-001 in the second-line and later setting.2
