TERN-701 Decreases BCR-ABL Levels, Generates Molecular Responses in R/R CML

Treatment with the small molecule, allosteric BCR-ABL inhibitor TERN-701 led to decreases in BCR-ABL transcript levels and produced major molecular responses (MMRs) in heavily pretreated patients with relapsed/refractory chronic myeloid leukemia (CML), according to preliminary data from the phase 1 CARDINAL trial (NCT06163430).¹

Findings showed that 88% of efficacy-evaluable patients with a baseline BCR-ABL transcript level of more than 1% (n = 8) achieved a decrease in BCR-ABL levels during treatment. Evaluable patients who did not harbor a BCR-ABL1 T315I mutation and completed 3 or more months of treatment (n = 10) experienced a cumulative MMR rate of 50%. All 4 patients who had a MMR at baseline maintained their response and remained on treatment at data cutoff.

Regarding safety, no dose limiting toxicities (DLTs) were reported at daily doses ranging from 160 mg to 400 mg. Additionally, adverse effects (AEs) did not lead to any treatment discontinuations or dose reductions. No grade 3 or higher treatment-related AEs (TRAEs) or serious TRAEs were reported.

“These exciting early data from our phase 1 dose-escalation cohorts clearly show TERN-701 has compelling clinical activity with a highly encouraging cumulative MMR rate of 50% at 3 months. At the first 2 dose levels, we see clinically meaningful molecular and hematologic responses in patients with high baseline BCR-ABL transcript levels who had poor responses on prior second-generation TKIs [or] third-generation TKIs, including ponatinib [Iclusig], as well as asciminib [Scemblix],” Emil Kuriakose MD, chief medical officer of Terns Pharmaceuticals, stated in a news release.

The open-label, nonrandomized, dose-escalation and -expansion CARDINAL trial is enrolling patients at least 18 years of age with cytopathologically confirmed BCR-ABL1–positive CML in chronic phase, irrespective of T315I mutation status.² Prior treatment with active site–targeting TKIs is required; notably, patients without resistant/relapsing disease who were intolerant to asciminib are allowed to enroll. Other key inclusion criteria consist of an ECOG performance status of 0 to 2 and adequate organ function.

Patients are being excluded if they have CML in accelerated or blast phase; received systemic antineoplastic therapy or other experimental therapy within 7 days of the first dose of TERN-701; or completed previous anticancer therapy without resolution of all associated clinically significant toxicities to grade 2 or lower or baseline.

As of the October 28, 2024, data cutoff, 15 patients had been enrolled and treated with TERN-701 once per day at 160 mg (n = 7), 320 mg (n = 5), and 400 mg (n = 3).¹ The full efficacy-evaluable population (n = 12) included patients with baseline BCR-ABL transcripts and 2 or more post-baseline BCR-ABL transcripts who were treated at dose levels of 160 mg or 320 mg. The 500-mg dose level is also under ongoing evaluation.

The primary end points of the dose-escalation portion of the study include the incidence of DLTs, AEs, and serious AEs.² In dose expansion, the primary end points will be complete hematologic response rate, MMR rate, and best shift in BCR-ABL1 transcript levels from baseline.

Among the 15 patients treated thus far, the median treatment duration was 3 months (range, 0.79-7.5).¹ The patient population received a median of 4 prior TKIs (range, 1-6); 80% of patients received 3 or more prior TKIs, included ponatinib (47%) and asciminib (40%). Additionally, 73% of patients were not in MMR at baseline, and 60% had a baseline BCR-ABL transcript of more than 1%. Fourteen patients remained on treatment at data cutoff.

Additional safety data showed that the rate of hematologic treatment-emergent AEs was low. No grade 3 or higher treatment-related cytopenias were reported, and no non-hematologic TRAEs higher than grade 2 occurred. There were no clinically meaningful changes in liver and pancreatic enzymes; blood pressure and other vitals; or electrocardiograms.

As of December 3, 2024, 19 patients had been enrolled in the 500-mg cohort and all dose-escalation cohorts have enrolled at least 3 patients. The dose-expansion portion of CARDINAL is expected to start in the first half of 2025, and additional efficacy data are anticipated in the fourth quarter of 2025.

“We are thrilled to share these impactful early data from the phase 1 CARDINAL study of TERN-701, which support its potential to be a best-in-class allosteric inhibitor for the treatment of CML,” Amy Burroughs, chief executive officer of Terns Pharmaceuticals, added in the news release. “In addition to the meaningful clinical data, the CARDINAL study highlights yet another example of excellent clinical and operational execution at Terns, with patients enrolled in all 4 dose-escalation cohorts in less than a year. We are well-positioned to initiate dose expansion cohorts in the first half of 2025 and look forward to sharing additional safety and efficacy data, including longer-term MMR data in late 2025.”

References

1. Terns Pharmaceuticals announces positive early data from phase 1 CARDINAL trial of TERN-701 for chronic myeloid leukemia. News release. December 3, 2024. Accessed December 4, 2024. https://ir.ternspharma.com/news-releases/news-release-details/terns-pharmaceuticals-announces-positive-early-data-phase-1
2. CARDINAL- a clinical study to evaluate the safety, tolerability, pharmacokinetics, and efficacy of TERN-701 in participants with chronic myeloid leukemia. ClinicalTrials.gov. Updated December 8, 2023. Accessed December 4, 2024. https://clinicaltrials.gov/study/NCT06163430