Background:

Covalent BTKi have become the backbone of CLL/SLL therapy. Through improved target kinase selectivity, second generation BTKi offer improved safety with potentially better efficacy, yet compartmental clearance leading to complete remission (CR) remains elusive.

TL-895 is a potent, second generation, irreversible, oral BTKi with best-in-class selectivity (Gulrajani 2023) over other second generation BTKi; which may lead to improved safety and clearance of leukemic disease to induce deeper and more durable responses.

Methods:

This multicenter Ph 2 study (NCT02825836) enrolled symptomatic, BTKi-naïve CLL/SLL pts ≥18 years with ECOG PS 0-2. The R/R and TN arms enrolled sequentially and pts were randomly assigned to receive TL-895 at 100 mg (Arm 1 [R/R] and Arm 4 [TN]) or 150 mg (Arm 2 [R/R] and Arm 3 [TN]) twice a day continuously until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR: partial remission [PR], nodular PR [nPR], or CR) per iwCLL 2018 criteria and key secondary were CR rate, safety and BTK occupancy.

Results:

As of 11 July 2023, 84 pts were enrolled at 12 sites throughout the US and Europe. In TN Arms 3 and 4 (n=21 each), 57% of pts were IGHVUNMUT, 14% had del17p/ TP53MUT and 29% bulky (≥5 cm) adenopathy. Median baseline ALC was 77x10 9/L (range 2-444) in Arm 3 and 46x10 9/L (range 3-215) in Arm 4. In R/R Arms 1 and 2 (n=21 each), pts received a median of 2 prior therapies (range 1-5), 69% of pts were IGHVUNMUT, 48% had del17p/ TP53MUT and 52% bulky adenopathy. Median baseline ALC was 21x10 9/L (range 1-235) in Arm 1 and 34x10 9/L (range 2-178) in Arm 2.

In TN Arms 3 and 4, at a median follow-up of 8 months ([mo] range 1-10), the ORR was 86%. In the R/R Arms 1 and 2, at a median follow-up of 23 mo (range 1-26), the ORR was 86% and 81%, respectively. At the 100 mg dose, two unconfirmed CRs (uCR) pending bone marrow (BM) biopsy were reported in R/R Arm 1. At the 150 mg dose, one CR, one uCR pending BM biopsy and two nPRs were reported, two each in R/R Arm 2 and TN Arm 3. All CRs/uCRs and nPRs occurred by week 48.

In TN Arm 3 150 mg dose, a faster time to response was observed compared to TN Arm 4 100 mg dose ( Figure 1), with a median ALC reduction of 50% by 3 mo compared to 6 mo, respectively (Figure 2). Additionally, at a median of only 5 mo (range 0.3-8.3), 62% (13/21) of pts in Arm 3 compared with 20% (4/21) of pts in Arm 4 had complete resolution of lymphocytosis in their blood (<4 x10 9/L). Full trough target occupancy (median ≥95%) was achieved in both TN and R/R pts, with low intrapatient variability and near complete inhibition of signaling proteins downstream of BTK by FACS analysis.

In the TN arms, treatment-emergent adverse events (TEAEs) regardless of causality were reported in 88% of pts (36% grade [Gr] 3, 0% Gr 4). Most common TEAEs (>10%), were anemia (21%), neutropenia (14%), COVID-19 and upper respiratory tract infection (URTI; 12% each). Most common Gr 3/4 TEAEs (>10%) were anemia and neutropenia (12% each). In the R/R arms, TEAEs were reported in 98% of pts (31% Gr 3, 14% Gr 4). Most common TEAEs were neutropenia (31%) and COVID-19 (21%), thrombocytopenia (19%), diarrhea (17%), anemia, hypertension (HTN) and URTI (14% each), sinusitis and pneumonia (12% each). Most common Gr 3/4 TEAE was neutropenia (26%).

In the TN arms, incidence of TEAEs of interest (any Gr; Gr 3/4) were rash (2%; 0%), HTN (5%; 2%), and headache (2%; 0%) with no events of atrial fibrillation (AFib) or major hemorrhage. In the R/R arms, incidence of TEAEs of interest (any Gr; Gr 3/4) were rash (5%; 0%), HTN (14%; 5%), headache (5%; 0%), AFib (5%; 5%) and major hemorrhage (2%, 2%). Gr 5 TEAEs occurred in six R/R pts (three in each arm) and one TN Arm 4 pt, including three COVID-related deaths; none were considered related to TL-895. Excluding COVID-related deaths, median progression free survival (PFS) was not reached with an estimated 8 mos PFS rate of 93% (95% CI, 79-95) in TN pts and 84% (95% CI, 69-93) at 22 mos in R/R pts. Treatment discontinuations included 2 Richter's transformations, one each in TN Arms 3 and 4.

Conclusion:

Treatment with TL-895 resulted in rapid clearance of leukemic compartments, particularly in TN pts, leading to earlier and deeper responses than expected with monotherapy BTKi. In R/R pts with a very high frequency of del17p/ TP53MUT, remissions have been durable. With a very low incidence of AEs typical of less selective BTKi (e.g., AFib, major hemorrhage, rash and headache), TL-895 has the potential to be a best-in-class backbone BTKi.

Byrd:Kurome: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Vincerx: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; OSU Drug Devel. Inst.: Consultancy; Orbimed: Consultancy, Research Funding; Eilean Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Research Funding; Orange Grove Bio: Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees, Research Funding; American Cancer: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Illes:AbbVie: Consultancy; Janssen: Consultancy, Other: travel and conference support; Celgene: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Other: travel and conference support; Pfizer: Consultancy, Other: travel and conference support; Roche: Consultancy, Other: travel and conference support. Jurczak:SOBI: Consultancy, Research Funding; Maria Sklodowska-Curie National Research Institute of Oncology: Current Employment; Roche: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Lilly: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bayer: Research Funding; BMS: Research Funding; BeiGene: Consultancy, Research Funding; Celgene: Research Funding; Astra Zeneca: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Janssen: Research Funding; Merck: Research Funding; MSD: Research Funding. Giannopoulos:Janssen Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Research Funding. Mikhailova:ROCHE: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Bhat:Aptitude Health: Honoraria; Abbvie: Consultancy; AstraZeneca: Consultancy, Research Funding. Usenko:Abbvie: Honoraria; Acerta: Honoraria; Ascentage: Honoraria; AstraZeneca: Honoraria; Celgene: Honoraria; IL-Yang: Honoraria; janssen: Honoraria; Rigel: Honoraria; Takeda: Honoraria; UCB: Honoraria. Kuchkova:MSD: Research Funding. Chandler:BeiGene: Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Amgen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Abbvie: Research Funding; ADC Therapeutics: Research Funding; MorphoSys: Research Funding; Mi-Care Path: Current equity holder in private company; Seagen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; BMS: Consultancy, Research Funding. Bilotti:Independent contractor - Telios Pharma: Current Employment; Independent contractor - Kartos Therapeutics: Current Employment. Shen:Kartos Therapeutics: Current Employment. Cheung:Kartos Therapeutics: Current Employment, Current holder of stock options in a privately-held company; Telios Pharma Inc: Current holder of stock options in a privately-held company. Verstovsek:Kartos Therapeutics, Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. McGreivy:Kartos Therapeutics,Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Rothbaum:Kartos Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Patents & Royalties; Telios Pharma: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Patents & Royalties; Iovance Biotherapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Quogue IP Holdings: Patents & Royalties; Quogue Capital: Current Employment.

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