Paper Details

ABSTRACT

Purpose: Outcomes for patients with chronic phase chronic myeloid leukemia (CP-CML) remain suboptimal despite availability of tyrosine kinase inhibitor (TKI) therapies. An earlier report from the phase 1/2 CARDINAL study (NCT06163430) of the investigational, highly selective, oral, allosteric BCR::ABL1 inhibitor MK-4208 (formerly TERN-701) showed that MK-4208 had promising activity with manageable safety in participants (pts) with previously treated CP-CML. Two doses (320 mg and 500 mg) were recommended for the randomized dose expansion phase. Reported here are updated data from this ongoing study. 

Methods: In this 2-part study, eligible pts aged ≥18 years with BCR::ABL1-positive CP-CML previously treated with at least 1 prior TKI, received MK-4208 once-daily in continuous 28-day cycles. The study comprised a dose escalation phase (Part 1) followed by a dose expansion phase (Part 2) where pts were randomized 1:1 to either 320 mg or 500 mg. Endpoints include incidence of adverse events (AEs) and serious AEs, and major molecular response (MMR) by 24 weeks (wks) as measured by BCR::ABL1 transcripts centrally assessed using RT-qPCR. Pts with T315I or myristoyl pocket mutations were not included in the efficacy evaluable population. Pts were evaluable for MMR by 24 wks, per protocol, if they had ≥1 post-baseline molecular response assessment and met at least one of the following: had response assessment at 24 wks, achieved MMR prior to 24 wks (if no MMR at baseline), maintained MMR for >24 wks (if in MMR at baseline), or discontinued treatment for any reason prior to 24 wks.

 Results: As of Apr 03, 2026, 128 pts were treated with MK-4208. A total of 104 (81%) pts were ongoing and 24 (19%) had discontinued treatment. The most common reasons for discontinuation were treatment failure (n = 8), physician/pt withdrawal (n = 6), and adverse events (n = 4). Among 113 pts treated at ≥320 mg, the median age was 55 years (range, 23-82), and 67 (59%) were male. Pts had a median of 3 prior TKIs (range, 1 – 7), 31 (27%) had ≥4 prior TKIs, 42 (37%) with prior asciminib, 28 (25%) with prior ponatinib, and 11 (10%) with prior investigational TKI (olverembatinib/ELVN-001); 57 (50%) had baseline BCR::ABL1 >1%, with 45 (40%) having baseline BCR::ABL1 >10%; and 18 (16%) with BCR::ABL1 mutations including T315I (10%). A total of 75 (66%) and 31 (27%) pts had lack of efficacy (per ELN 2020), and lack of tolerability to last TKI, respectively. At data cut-off, the median duration of exposure was 21.8 weeks (range, 0.14-104). Treatment-emergent AEs (TEAEs) were mostly low-grade and occurred in 108 (84%) pts (grade ≥3 TEAEs, 39 [31%]). The most common TEAEs were headache (18%) and diarrhea (17%). Three pts had a grade 5 TEAE. Serious TEAEs occurred in 16 (13%) pts. Among 58 efficacy-evaluable pts treated with ≥ 320 mg, the MMR rate in all pts (regardless of MMR status at study entry) was 60% (35/58) by 24 wks. The rate of pts achieving MMR (not in MMR at study entry) was 54% (27/50) by 24 wks. All pts in MMR at time of enrollment maintained MMR (8/8). 

Conclusion: In this updated analysis, MK-4208 continued to provide encouraging efficacy and manageable safety in a population heavily pretreated with approved and investigational active-site and allosteric TKIs. The study is currently enrolling.