Efficacy and Safety Results of TQB3909 in Patients (Pts) with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Background:

TQB3909 is a novel, highly potent, orally bioavailable, and selective BCL-2 inhibitor that has shown safety profiles and preliminary antitumor activity under daily dose ramp-up scheme in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Aims:

We present safety and efficacy results from ongoing TQB3909-Ib/II-02 (NCT05959694) after 8-month follow-up.

Methods

Eligible patients were ≥18 years of age and had a confirmed diagnosis of CLL/SLL (per 2018 iwCLL guidelines). CLL/SLL patients (pts) were relapsed or refractory to standard treatments such as BTK inhibitor or CD20 antibody-based immunochemotherapy or alkylator based regimes, and were required to have adequate function of major organs. TQB3909 (300 and 400 mg) was administered orally once daily to pts with R/R CLL/SLL in repeated 28-day cycles. A daily ramp-up schedule and close monitoring were used for prevention and early detection of tumor lysis syndrome (TLS). Pts received TQB3909 until disease progression, intolerable toxicity, death, or any other reasons for termination. Adverse events (AEs) were reported per NCI CTCAE v5.0, and response was evaluated per 2018 iwCLL criteria.

Results

As of July 1, 2024, 27 pts went through a daily ramp-up of TQB3909 treatment at an assigned dose (300 [n=15] and 400 [n=12]). The median (range) age was 60 (41-80) years (male, 66.6%). At enrollment, 80.0% of pts were in Rai stage III/IV, and 70.6% Binet stage C. ALL pts had intermediate, high, or very high-risk disease per the CLL-International Prognostic Index (IPI)(100%) and most pts had adverse prognostic features, including unmutated IGHV (65.0%) and Del(17p)/TP53 mutation(36%).A total of 44.4% of pts had received ≥ 2 prior systematic treatments, 59.3% Bruton tyrosine kinase (BTK) inhibitors, and 44.4% a CD20 antibody-based immunochemotherapy. Reasons for discontinuing BTK inhibitors were resistance(93.8%) and intolerance(6.3%).All pts experienced treatment-related adverse events(TRAEs),TRAEs of any grade occurred in ≥ 30% of patients were leukopenia (55.6%), thrombocytopenia (51.9%), neutropenia (48.1%), lymphocytopenia(33.3%) .Grade 3 or 4 TRAEs (≥ 10%) were hematological toxicities including neutropenia (29.6%), leukopenia (14.8%), anemia (14.8%), lymphocytopenia(11.1%),thrombocytopenia (11.1%) and which were manageable. Incidences of TRAEs were not dose related. 4 Serious TRAEs occurred in 4(14.81%) patients, including thrombocytopenia, lung infection and TLS.

23 patients were evaluable. With a median duration of treatment (DOT) of 3.2 months (range, 1.1-8.8), The overall response rate (ORR) was 82.6% (19/23), and the complete remission (CR) /CR with incomplete marrow recovery (CRi) rate was 26.1 % (6/23). The ORR was 83.3% (10/12) and CR/CRi 25.0% (3/12) in pts of CLL-IPI high, or very high-risk disease. The median (range) time to first response was 2.0 (2.0-2.6) months. Median progression-free survival (PFS) and Median progression-free survival (DOR) were NR (95% CI, NR-NR) months. Peripheral blood MRD negativity was observed in 3 of 8 (37.5%) pts. The rate of ORR and CRR seemed to be dose-dependent (78.6% and 7.1% at 300mg, 88.9% and 55.5% at 400 mg), supporting 400mg as recommended phase 2 dose (RP2D) of TQB3909 monotherapy in patients with R/R CLL/SLL.

Conclusions

TQB3909 demonstrated remarkable efficacy in pts with R/R CLL who were pretreated and had been exposed to BTK inhibitors. ORR and CR/CRi exhibited a trend of positive correlation with escalating dose levels. No significant new safety findings were observed. The phase II study is ongoing.