Phase 2 Study Results of the Novel TL-895 BTK Inhibitor in Treatment-Naïve and Relapsed/Refractory CLL/SLL

A multicenter phase 2 study (NCT02825836) is evaluating the safety and anti-leukemic activity of the second-generation, irreversible, oral covalent Bruton tyrosine kinase inhibitor (BTKi) TL-895 in patients with treatment-naïve (TN) and relapsed/refractory (R/R) cohorts of patients with chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL). Results of this study were presented at the 2023 American Society of Hematology annual meeting and summarized here

The study enrolled symptomatic, BTKi-naïve patients aged ≥18 years with CLL/SLL at 12 sites throughout the US and Europe. The R/R and TN arms enrolled sequentially and patients were randomized to receive TL-895 at 2 dose levels, 100 mg or 150 mg twice a day (BID) continuously until progression or unacceptable toxicity; R/R 100 mg BID (Arm 1), R/R 150 mg BID (Arm 2), TN 100 mg BID (Arm 4), TN 150 mg BID (Arm 3). The primary end point was objective response rate (ORR); key secondary end points were complete response (CR) rate, safety, and BTK occupancy. Date of data cut-off was July 11, 2023.

A total of 84 patients were enrolled in the study, with 21 patients each enrolled in R/R 100 mg, R/R 150 mg, TN 100 mg, and TN 150 mg. In the TN cohort, 57% of patients were IGHV-UNMUT, 14% had del17p/TP53MUT, and 29% had bulky (≥5 cm) adenopathy. In the R/R cohort, patients received a median of 2 prior therapies, 69% of patients were IGHV-UNMUT, 48% had del17p/TP53MUT, and 52% had bulky adenopathy.

In the TN cohort (median follow-up: 11.4months), the ORR was 86% in the 100 mg arm and 85% in the 150 mg arm. In the R/R cohort (median follow-up of 26.4 months), an ORR of 86% was achieved in the 100 mg cohort and 81% in R/R 150 mg cohort. At the 100 mg dose, there was 1 CR among R/R patients and 2 unconfirmed CR (uCR) in TN patients, pending bone marrow biopsy. At the 150 mg dose, one CR, one uCR pending BM biopsy, and 2 nodular partial responses (nPRs) were reported in R/R (n=2) and TN patients (n=2).

In the TN 150 mg dose cohort, a faster time to response was observed compared to TN 100 mg dose cohort (median ALC reduction of 50%: 3 months vs 6 months). At a median of 5 months, a higher proportion of patients in the TN 150 mg cohort had complete resolution of lymphocytosis in their blood (<4 x109/L) compared with those in TN 100 mg cohort (60% vs 30%). The median time to resolution of lymphocytosis was 5.1 months in the TN 150 mg arm versus 7.7 months in the 100 mg TN arm.

Median progression free survival (PFS; excluding COVID-related deaths) was not reached in any cohort; at data cutoff, the estimated PFS for TN arms (Arm 3 and Arm 4) were 95% and 90.5%, respectively, and 89.5% and 80% in R/R Arm 2 and Arm 1, respectively. In both R/R and TN arms, PFS rates were higher among 150 mg arms versus 100 mg arms.

In the TN arms, treatment-emergent adverse events (TEAEs) were reported in 88% of patients; of these, 38% were grade 3, none were grade 4. The most common TEAEs (>10%) were anemia (24%), neutropenia (14%), COVID-19 (12%), and upper respiratory tract infection (URTI; 14%). Most common grade 3/4 TEAEs (>10%) were anemia (12%) and neutropenia (12%). There were no reports of atrial fibrillation or major hemorrhage. Treatment discontinuations due to AE were reported in both TN dose cohorts (Richter’s transformations).

In the R/R arms, TEAEs were reported in 98% of patients; of these, 31% were grade 3 and 14% were grade 4. The most common TEAEs were neutropenia (31%), COVID-19 (36%), thrombocytopenia (24%), diarrhea (17%), anemia (14%), HTN (14%), URTI (14%), sinusitis (12%), and pneumonia (12%). The most common grade 3/4 TEAE (>10%) was neutropenia (26%). There were 6 patients that experience a grade 5 TEAE (3 at each dose, all not related to TL-895). Treatment discontinuations included 2 cases of disease progression (1 at each dose), withdrawal of consent (n=2), and 1 grade 4 hemorrhagic stroke.

Based on these results, it was concluded that the highly selective BTKi TL-895 therapy led to rapid bone marrow clearance of leukemic cells, with a favorable adverse event profile, in TN and R/R patients with CLL/CLL.


Byrd J, Woszczyk D, Illes A, et al. A phase (Ph) 2 study of TL-895, a highly selective, novel covalent BTK inhibitor (BTKi), in patients with treatment-naïve (TN) and relapsed/refractory (R/R) BTKi-naïve chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Presented at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition, December 9-12, 2023; San Diego, CA: Poster 4634.

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