Bold claim: TERN-701 can trigger deep, meaningful responses even in patients who have endured extensive prior therapy for CP-CML. That’s the takeaway from the CARDINAL phase 1 study, which explored the highly selective allosteric BCR-ABL1 inhibitor TERN-701 and its performance in heavily pretreated chronic phase CML patients, with results shared at ASH 2025.
At a recommended phase 2 dose (RP2D) of at least 320 mg once daily, efficacy evaluable patients with more than 24 weeks of follow-up (n = 30) achieved an overall 24-week major molecular response (MMR) rate of 80% (95% CI, 61.4%-92.3%). Among participants entering without an MMR (n = 24), the MMR rate reached 75% (95% CI, 53.3%-90.2%). For those who began with an existing MMR (n = 6), MMR was maintained in 100% of cases (95% CI, 54.1%-100.0%). The deep molecular response rates (MR4 or MR4.5) reached 36% (95% CI, 18.6%-55.9%) across 28 efficacy-evaluable patients. Importantly, among patients not in CCyR at entry (n = 13), 62% achieved MR2 (BCR-ABL1 <1%) or better with TERN-701.
Lead investigator Elias Jabbour, MD, from MD Anderson, noted a dose–response pattern: higher MMR achievement at and above the 320 mg RP2D, with most treatment-emergent adverse effects (TEAEs) being low grade and no clear dose relationship for cytopenias. Rates of grade 3 or higher thrombocytopenia and neutropenia were generally below 10%, and most non-hematologic AEs were grade 2 or lower.
Study design and patient population
TERN-701 targets the myristate pocket of BCR-ABL1, an approach that yields markedly greater selectivity—about 10,000-fold—compared with active-site TKIs, according to Jabbour. This targeting excludes patients with resistance mutations at that binding site from CARDINAL. The phase 1 trial employed a dose-escalation phase followed by a dose-expansion phase. By the data cutoff of September 13, 2025, 63 patients had enrolled in the escalation portion, receiving 4 once-daily doses from 160 mg to 500 mg. Of these, 53 received either 320 mg or 500 mg daily.
In April 2025, a dose-expansion arm opened to evaluate the two larger escalation doses. In this portion, patients are randomized to receive either 500 mg or 320 mg, with a planned enrollment of 40 patients at each dose. Enrollment for the expansion arm is ongoing.
Efficacy signals across the CARDINAL cohort
In heavily pretreated CP-CML, TERN-701 at the RP2D produced substantial MMR and deep molecular responses. At ≥320 mg, MMR was 75% (n = 24 without baseline MMR) and maintained MMR was 100% for those already in MMR at baseline; overall deep molecular responses (MR4/MR4.5) occurred in 36% of evaluable patients. Across all dose levels, MMR and deep molecular response rates were 64% and 29%, respectively.
Among all participants, the median age was 57 years (range 29–86). The median number of prior TKIs was 3 (range 1–6), with the majority having three or more prior TKIs (60%), including prior asciminib (38%) and ponatinib (22%). Baseline BCR-ABL1 transcripts were above 1% in 57% of patients, and above 10% in 44%; 82% entered without prior MMR. The most common resistance mutations included T315I (10%), F317L (3%), and E255K (2%), with no compound mutations reported.
Primary reasons for previous TKI discontinuation were lack of efficacy (64%), tolerability issues (29%), and other reasons (8%). For asciminib, lack of efficacy accounted for 75% of discontinuations and tolerability for 25%; for ponatinib, lack of efficacy was 79% and tolerability 21%.
For the RP2D cohort (n = 21), the median age was 57 (range 30–82). Baseline BCR-ABL1 levels above 0.1% were present in 86% of patients, with 47% above 10%. Prior discontinuation was mainly due to lack of efficacy (68%), tolerability (23%), and other factors (9%). The median number of prior therapies was 3 (range 1–6), with 60% having three or more prior treatments. Notably, 21% had prior ponatinib and 38% had prior asciminib. Fifteen percent carried a BCR-ABL1 resistance mutation.
Safety was the primary endpoint, followed by efficacy and pharmacokinetics. Efficacy was assessed by maintaining or achieving MMR for 24 weeks, depending on baseline status.
Additional efficacy signals and pharmacology
Pharmacokinetics showed linear, dose-proportional increases in plasma concentration across the escalation doses, and target coverage above the efficacy threshold in a KCL22 xenograft mouse model. No food effect on exposure was observed.
At a median follow-up of 6.1 months (range 0.2–19), all patients with evaluable data showed improvement from baseline, with no one experiencing a worsening response.
In 38 efficacy-evaluable patients without atypical transcripts across all dose levels, the overall MMR rate was 74% (95% CI, 56.9%-86.6%). For those entering without an existing MMR, MMR was 64% (95% CI, 44.1%-81.4%). For those entering with prior MMR, maintenance was 100% (95% CI, 69.2%-100.0%). Deep molecular response (MR4 and MR4.5) rates were 29% and 27%, respectively.
Baseline disease burden mattered: among patients with BCR-ABL1 above 10% at baseline (n = 11), MMR was 45%; for those with 1–10% (n = 6), MMR was 83%; and all patients with 0.1%–1% at baseline (n = 11) achieved MMR. Among those without CCyR at entry (n = 17), 59% achieved MR2.
Prior TKI resistance or tolerability issues influenced outcomes: MMR was 63% in those with prior lack of efficacy (n = 19) and 71% in those with prior tolerability issues (n = 7). Among those who had prior asciminib (n = 7), MMR was 43%; in patients with prior asciminib, ponatinib, or an investigational TKI (ELVN-001; n = 8), MMR was 50%.
Safety snapshot
By the data cutoff, 87% of patients remained on treatment. Discontinuations were due to treatment failure (n = 4), other reasons (n = 2), physician decision (n = 1), and adverse events (n = 1). Some AEs—diarrhea, fatigue, and joint pain—had been reported with prior TKIs as well.
Across all dose levels (n = 63), any-grade treatment-emergent AEs occurred in 81% of patients. Grade 3 or higher TEAEs occurred in 32% of patients, with no dose-limiting toxicities identified in the dose-escalation phase and no maximum tolerated dose reached.
The most common all-grade AEs were diarrhea (21%), headache (19%), nausea (19%), thrombocytopenia (16%), fatigue (14%), neutropenia (13%), abdominal pain (13%), and myalgia (13%). The most frequent grade 3+ AEs were thrombocytopenia (8%), neutropenia (8%), with other grade 3+ events each at or below 2%. Importantly, there were no clinically meaningful changes in blood pressure, no pancreatitis, and no symptomatic lipase elevations observed.
Bottom line
TER N-701 demonstrates meaningful activity in a difficult-to-treat CP-CML population, with a notable dose–response signal at 320 mg and higher and an overall tolerability profile that appears manageable in the early phase of development. While these early phase results are encouraging, confirmation in larger, controlled trials will be essential to determine its role alongside or after prior TKIs and specifically among patients with resistant mutations.
References
1. Jabbour E, Hughes T, Van Etten R, et al. CARDINAL: A phase 1 study of TERN-701, a novel investigational allosteric BCR::ABL1 inhibitor for patients with previously treated CML. Blood. 2025;146(Suppl 1):901.
2. Terns highlights additional positive phase 1 data supporting TERN-701’s best-in-disease potential in relapsed/refractory CML at the 67th ASH Annual Meeting. News release. Terns Pharmaceuticals. December 8, 2025.
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