Bold claim: TERN-701 is delivering deep, meaningful responses in patients who have exhausted many prior therapies in chronic phase CML. But here’s where it gets controversial: the full picture still requires careful interpretation of early-phase data and broader applicability.
TERN-701, a highly selective allosteric inhibitor of BCR-ABL1, showed a notable response rate with deep molecular remissions in a cohort of heavily pretreated chronic phase CML patients, according to findings from the phase 1 CARDINAL study (NCT06163430) presented at the 2025 ASH Annual Meeting and Exposition. These results suggest robust activity even in patients who progressed on prior TKIs, including asciminib and ponatinib.
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 those who entered without an existing MMR (n = 24), the MMR rate with TERN-701 was 75% (95% CI, 53.3%-90.2%). For patients who started with an existing MMR (n = 6), MMR was maintained at 100% with TERN-701 (95% CI, 54.1%-100.0%). The deep molecular response rate (MR4 or MR4.5) among 28 efficacy-evaluable patients was 36% (95% CI, 18.6%-55.9%). Notably, among those not in cytogenetic complete response at baseline (n = 13), 62% achieved an MR2 or better with TERN-701.
Lead investigator Elias Jabbour, MD, from The University of Texas MD Anderson Cancer Center, highlighted a dose–response relationship: higher MMR achievement at the RP2D and above. He noted that most treatment-emergent adverse effects (TEAEs) were low grade with no clear dose relationship, cytopenias were uncommon (fewer than 10% had grade 3 thrombocytopenia or neutropenia), and most non-hematologic AEs were grade 2 or lower.
Study design and patient characteristics
TERN-701 targets the myristate pocket of BCR-ABL1, delivering an exceptionally high selectivity—about 10,000-fold greater than first-site TKIs. Because of its site of activity, CARDINAL excluded patients with resistance mutations at that pocket.
The phase 1 trial followed a dose-escalation phase, then a dose-expansion phase. By September 13, 2025, 63 patients had been enrolled in the escalation portion, receiving 320 mg or 500 mg once daily in the higher-dose cohorts. In the expansion portion, initiated in April 2025, patients were randomized to receive either 320 mg or 500 mg with the goal of about 40 patients per arm; enrollment is ongoing.
Key efficacy signals across the heavily pretreated CP-CML population
- At RP2D (≥320 mg), MMR was 75% in patients without baseline MMR and 100% in those with baseline MMR; the deep molecular response rate (MR4/MR4.5) was 36% across 28 evaluable patients.
- Across all dose levels, MMR and deep molecular response rates were 64% and 29%, respectively.
- The median age across all patients was 57 years (range 29–86), and the median number of prior TKIs was 3 (range 1–6). A substantial portion had received 3 or more prior TKIs (60%), including prior asciminib (38%) and ponatinib (22%). A majority entered without prior MMR (82%). Common resistance mutations included T315I (10%), F317L (3%), and E255K (2%), with no compound mutations observed.
- Primary reasons for prior TKI discontinuation were lack of efficacy (64%), lack of tolerability (29%), and other reasons (8%). For asciminib, lack of efficacy and tolerability accounted for 75% and 25%, respectively; for ponatinib, 79% and 21% respectively.
Safety and tolerability remained a primary endpoint, followed by efficacy and pharmacokinetics. Among patients treated at the RP2D, 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%. Discontinuation reasons mirrored prior therapies, with lack of efficacy and tolerability as the most common causes.
Efficacy across additional analyses
- In a pharmacokinetic assessment, TERN-701 demonstrated linear, dose-proportional increases in plasma concentration across escalation doses, and target coverage exceeded efficacious thresholds in preclinical models. Food did not meaningfully alter exposure.
- Median duration of treatment among evaluable patients was 6.1 months, with improvements in response observed across the board and no observed worsening.
- In 38 efficacy-evaluable patients without atypical transcripts, the overall MMR rate was 74% with TERN-701. Those entering without MMR had an MMR rate of 64%, while those entering with MMR maintained it at 100% for at least 24 weeks. MR4/MR4.5 rates were 29% and 27%, respectively.
- Baseline BCR-ABL1 levels influenced response: among patients with >10% BCR-ABL1, MMR was 45%; for 1–10%, it was 83%; and for <0.1% to 1% (MR2), all achieved MMR.
- Among patients with prior efficacy failures (n = 19), MMR was 63%; among those with tolerability issues (n = 7), MMR was 71%. Prior exposure to asciminib or other TKIs showed varying MMR rates, with some decline in patients who had prior asciminib, ponatinib, or ELVN-001 exposure.
Safety snapshot
As of the data cut, 87% of patients remained on treatment. The main reason for stopping was treatment failure, with a few discontinued due to physician decision or adverse events. The most common all-grade TEAEs were diarrhea (21%), headache (19%), nausea (19%), thrombocytopenia (16%), fatigue (14%), neutropenia (13%), abdominal pain (13%), and myalgia (13%). Grade 3 or higher TEAEs included thrombocytopenia (8%), neutropenia (8%), with smaller shares of anemia, fatigue, abdominal pain, and rash. Importantly, no clinically meaningful blood pressure changes, pancreatitis, or symptomatic lipase elevations were observed.
Bottom line and what to watch
- The CARDINAL data hint at meaningful clinical activity of TERN-701 in a challenging patient population, with substantial MMR and a notable fraction achieving deep molecular responses at RP2D.
- Safety appears manageable so far, with mostly low-grade AEs and limited hematologic toxicity.
- Nevertheless, these are early-phase results. Confirmation in larger, randomized trials is essential to determine whether these responses translate into durable remissions and improved long-term outcomes.
Controversy and discussion prompts
- Do these early signals justify early adoption or off-label use in heavily pretreated CML, or should clinicians await randomized phase 2/3 data?
- How should we weigh deep molecular responses against potential safety concerns in patients with extensive prior therapies?
- If TERN-701 proves its value, will it complement or replace existing allosteric inhibitors for BCR-ABL1, or will it carve out a distinct niche in treatment sequencing?
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