TERN-701 yielded a high response rate with deep molecular responses in patients with heavily pretreated chronic phase chronic myeloid leukemia.
The highly selective allosteric BCR-ABL1 inhibitor TERN-701 elicited a high response rate, including deep molecular responses, for a majority of heavily pretreated patients with chronic phase chronic myeloid leukemia (CP-CML), according to findings from the phase 1 CARDINAL study (NCT06163430) presented at the
At the recommended phase 2 dose (RP2D) of TERN-701, which is at least 320 mg once daily, the overall 24-week major molecular response (MMR) rate was 80% (95% CI, 61.4%-92.3%) among efficacy-evaluable patients with more than 24 weeks of follow-up (n = 30). For those who entered the study without an existing MMR (n = 24), the MMR rate with TERN-701 was 75% (95% CI, 53.3%-90.2%). For those who entered with an existing MMR (n = 6), the MMR was maintained in 100% with TERN-701 (95% CI, 54.1%-100.0%).
The deep molecular response rate (MR4 or MR4.5) with TERN-701 in 28 efficacy-evaluable patients was 36% (95% CI, 18.6%-55.9%). Of those who entered the study not in a cytogenetic complete response (CCyR; n = 13), 62% achieved an MR2 response (< 1% BCR-ABL1) or better with TERN-701.
"We see evidence of a dose-response relationship, with an increase in MMR achievement at the recommended phase 3 doses of 320 mg and above," lead investigator Elias Jabbour, MD, a professor in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston, said during a presentation of the results. "The majority of treatment-emergent adverse effects [TEAEs] were low grade, with no apparent dose relationship. Rates of cytopenias were generally low, with less than 10% grade 3 thrombocytopenia and neutropenia. The majority of nonhematologic AEs were grade 2 or less."
TERN-701 is active at the myristate pocket of BCR-ABL1, providing it with 10,000 times greater selectivity than active-site tyrosine kinase inhibitors (TKIs), Jabbour said. Given the site of activity, patients with resistance mutations at this location were excluded from the CARDINAL study.
The phase 1 trial consisted of up-front dose escalation followed by dose expansion. At the time of the presentation, which had a data cutoff of September 13, 2025, 63 patients had been enrolled in the initial dose escalation portion of the study. In this group, TERN-701 was administered at 4 once-daily doses, starting at 160 mg and increasing to 500 mg. Of these patients, 53 received the 320- or 500-mg once-daily doses of TERN-701.
A dose expansion arm of the study opened in April 2025 to explore the 2 larger doses from the escalation portion. In this portion of the study, patients are randomly assigned to receive either 500 mg or 320 mg of TERN-701, with a goal of enrolling 40 patients at each dose. The dose expansion portion of the study continues to enroll patients, Jabbour noted.
Across all patients, the median age was 57 years (range, 29-86). The median number of prior TKIs was 3 (range, 1-6), with most (60%) having received 3 or more prior TKIs, including prior asciminib (38%; Scemblix) and ponatinib (22%; Iclusig). Baseline BCR-ABL1 transcript levels were above 1% for 57% of patients, with 44% having a transcript level above 10%. Levels between 0.1% to 1% were reported for an additional 25%, indicating that 82% of patients entered the study without having experienced MMR prior to therapy, Jabbour noted. The most common BCR-ABL1 resistance mutations were T315I (10%), F317L (3%), and E255K (2%). "No patients had compound mutations," Jabbour noted.
The cause of prior TKI discontinuation was lack of efficacy by ELN 2020 criteria in 64% of patients, a lack of tolerability in 29%, and other reasons in 8%. "Those in the other category were patients with multiple prior TKI failures who elected to discontinue their last TKI early to come on study," Jabbour said. The primary causes of discontinuation for asciminib were lack of efficacy (75%) and tolerability (25%). For ponatinib, the causes were lack of efficacy (79%) and tolerability (21%).
For those treated with the RP2D, the median age was 57 years (range, 30-82). Baseline BCR-ABL1 levels were above 0.1% for 86% of patients, with 47% having a level above 10%. The primary causes of prior discontinuation were lack of efficacy (68%), lack of tolerability (23%), and other (9%). The median number of prior therapies was 3 (range, 1-6), with 60% having received 3 or more prior treatments. Twenty-one percent had received prior ponatinib, and 38% had received prior asciminib. Fifteen percent of patients had a BCR-ABL1 resistance mutation.
Safety and tolerability were the primary end points, followed by efficacy and pharmacokinetics. A similar measure for MMR was used to assess efficacy, as in other studies, Jabbour noted. If MMR was present at baseline, TERN-701 had to maintain the MMR level for 24 weeks or longer. If an MMR was not present, it had to induce an MMR or better for 24 weeks.
In a pharmacokinetic examination of TERN-701, linear dose-proportional increases in plasma concentration were observed across all dose levels examined in the dose escalation portion of the study. Additionally, target coverage exceeded the efficacy bar across all doses in the KCL22 xenograft mouse model. The C-average exceeded the efficacious dose, Jabbour noted, which "supports robust pharmacokinetic effect," he said. No clinical differences were noted in exposure when the TKI was administered with or without food.
At follow-up, the median duration of treatment was 6.1 months (range, 0.2-19). All patients had improvement in their response from baseline, with no patients experiencing a worsening of response, Jabbour noted.
In 38 efficacy-evaluable patients without atypical transcripts across all dose levels, the overall MMR rate was 74% (95% CI, 56.9%-86.6%) with TERN-701. The MMR rate with TERN-701 was 64% (95% CI, 44.1%-81.4%) for those who entered the study without an existing MMR (n = 28). For those who entered with an existing MMR before therapy (n = 10), the MMR was maintained for 100% (95% CI, 69.2%-100.0%). The deep molecular response rate was 29% (95% CI, 15.1%-47.5%) by MR4 criteria and 27% (95% CI, 13.8%-44.1%) by MR4.5 criteria with TERN-701.
Across all dose levels for patients with BCR-ABL1 levels of more than 10% at baseline (n = 11), the MMR rate was 45%, with the remaining patients listed as stable. For those with a level between 1% and 10% (MR1; n = 6), the MMR rate was 83%. All patients with a BCR-ABL1 level greater than 0.1% but less than 1% (MR2; n = 11) had an MMR. For those who entered the study without a CCyR (n = 17), an MR2 response was experienced by 59% (95% CI, 32.9%-81.6%).
In those with a lack of efficacy to prior TKIs (n = 19), the MMR was 63% (95% CI, 38.4%-83.7%). For those with a lack of tolerability to prior TKIs (n = 7), the MMR rate was 71% (95% CI, 29.0%-96.3%). By prior TKI, those who received prior asciminib (n = 7) had an MMR rate of 43% with TERN-701 (95% CI, 9.9%-81.6%). In those who received prior asciminib, ponatinib, or an investigational TKI (ELVN-001; n = 8), the MMR rate was 50% (95% CI, 15.7%-84.3%).
At the cutoff, treatment was ongoing for 87% of patients. The primary cause for treatment discontinuation was treatment failure (n = 4), other (n = 2), physician decision (n = 1), and AEs (n = 1). "The AEs of grade 2 diarrhea, fatigue, and joint pain had also occurred on their prior TKIs," Jabbour said.
Across all dose levels (n = 63), TEAEs of any grade were experienced by 81% of patients. A grade 3 or higher TEAE was seen in 32% of patients, regardless of causality. No dose-limiting toxicities were observed in the dose-escalation phase, and the maximum tolerated dose had not been reached.
The most reported all-grade AEs, regardless of causes, were diarrhea (21%), headache (19%), nausea (19%), thrombocytopenia (16%), fatigue (14%), neutropenia (13%), abdominal pain (13%), and myalgia (13%). The most reported grade 3 or higher AEs, regardless of cause, were thrombocytopenia (8%), neutropenia (8%), anemia (2%), fatigue (2%), abdominal pain (2%), and rash (2%). Jabbour noted that no clinical changes were seen in blood pressure, and there were no clinical cases of pancreatitis or symptomatic lipase elevations.
