Preliminary efficacy and safety of TT-01488, a novel, non-covalent, reversible BTK inhibitor, in patients with relapsed/refractory mantle cell lymphoma

Abstract Background: Mantle cell lymphoma (MCL) is a rare and aggressive B-cell malignancy, accounting for 6% of non-Hodgkin lymphomas (NHL). It presents with heterogenous clinical behavior, ranging from indolent to highly aggressive disease. Bruton's tyrosine kinase (BTK) inhibitors have significantly improved outcomes in relapsed/refractory (r/r) MCL. However, the prognosis remains poor for patients who develop resistance to covalent BTK inhibitors, with limited treatment options, response rates of 25-40%, and a median overall survival of 6 to 10 months. TT-01488, a novel, non-covalent, reversible BTK inhibitor designed to target both wide-type and C481S-mutant BTK, a key resistance mechanism to covalent BTK inhibitors. TT01488CN02 is a phase 1, open-label, multi-center study evaluating TT-01488 monotherapy in patients (pts) with r/r B-cell NHL. Here, we report updated efficacy and safety results from patients with r/r MCL enrolled in the phase 1 study. Methods: Pts with r/r or treatment-intolerant MCL, who received ≥1 line of prior therapies, had an ECOG performance status of 0-2, and adequate organ function were enrolled.Adverse events (AE) are evaluated per CTCAE v5.0 criteria. Tumor responses are evaluated per 2014 Lugano criteria. Pts receive single or twice daily oral administration of TT-01488 continuously for 28-day cycles. Results: As of the data cut-off date on July 8, 2025, a total of 16 pts with r/r MCL were enrolled and received at least one dose of TT-01488 in 6 dose levels: 100 mg qd (n=2),150mg qd (n=5), 200mg qd (n=1), 100mg bid (n=8). Thirteen pts were non-blastoid subtypes. The median age was 63.5 (range: 44~78), 15 (93.8%) were males, and 14 (87.5%) had ECOG PS≤1.The median number of prior therapies was 3 (range: 1~7), 15 (93.8%) had prior chemotherapy, 15 (93.8%) had prior anti-CD20 antibody therapy, 13 (81.3%) had prior covalent BTK inhibitor therapy. Treatment-related AEs (TRAEs) were reported in 14 (87.5%) pts, grade 3 in 5 (31.3%), grade 4 in 2 (12.5%), and no grade 5. The most common TRAE (≥20%) were hypertriglyceridemia, anemia, nausea, decreased appetite, increased blood creatinine, hyperuricemia, and decreased platelet count. In 10 efficacy evaluable pts with non-blastoid MCL treated across all dose levels, the ORR was 70% (7/10), including 4 complete responses (CR, 40%) and 3 partial responses (PR, 30%). In the subgroup of non-blastoid MCL pts who previously received covalent BTK inhibitors, the ORR was 62.5% (5/8). One pt who previously received Orelabrutinib and had a BTK C481S mutation achieved CR lasting for over 22 months. Pharmacokinetics (PK) data among MCL pts showed that TT-01488 was rapidly absorbed in plasma with a median Tmax of 1 h post-dose. TT-01488 had an estimated mean terminal elimination half-life (t1/2)of 15.6 h and the steady state appeared to have been achieved by Cycle 1 Day 3~4 days with median accumulation factor (AUC) of approximately 4.8. PK and pharmacodynamics (PD) analysis indicated that after multiple dosing of 150 mg qd and 100 mg bid dose levels, sustained pBTK C481S-mutant inhibition (approximately 90%) could be observed at steady state. Conclusion: TT-01488, a novel, non-covalent, reversible BTK inhibitor, demonstrated promising antitumor activity and a manageable safety profile in heavily pretreated patients with r/r MCL, including those previously treated with covalent BTK inhibitors and those harboring BTK C481S mutations. The observed overall response rate of 70% supports its potential clinical benefit in this difficult-to-treat population. PK analyses showed rapid absorption and sustained BTK inhibition at steady state, indicating favorable exposure and targe engagement. These findings support continued clinical development of TT-01488 in BTKi resistant MCL. Clinical trial information: NCT05683717