Type: Oral
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Treating Refractory Disease-Novel Agents and Quality-of-Life
Hematology Disease Topics & Pathways:
Lymphomas, Diseases, Lymphoid Malignancies
Methods: Eligible patients must have confirmed R/R CLL/SLL (≥2 prior therapies), an ECOG performance status of 0-2, and adequate organ function. In the US, EU, and Australia, patients must have previously received a covalent BTK inhibitor (cBTKi). BGB-16673 was dosed once daily orally in 28-day cycles. Dose escalation used a Bayesian optimal interval design (6 planned dose levels, 50-600 mg once daily). Primary objectives were to assess safety/tolerability (CTCAE v5.0 and iwCLL hematologic toxicity criteria), and to establish the maximum tolerated dose (MTD) and the recommended phase 2 dose. Dose-limiting toxicities (DLTs) were assessed in the first 4 weeks (cycle 1). A secondary objective was to evaluate the overall response rate (ORR, iwCLL 2018 criteria or 2014 Lugano criteria for SLL), with the first assessment occurring after 12 weeks of treatment.
Results: As of May 24, 2024, 49 patients with CLL were enrolled and treated (50 mg, n=1; 100 mg, n=5; 200 mg, n=16; 350 mg, n=15; 500 mg, n=12). The median age was 70 years (range, 50-91 years), and the median number of prior therapies was 4 (range, 2-10), including prior cBTKis (n=45 [92%]), BCL2 inhibitors (n=42 [86%]), and noncovalent BTK inhibitors (ncBTKis; n=12 [24%]). Of tested patients, 63% (31/49) had del(17p) and/or TP53 mutation and 82% (32/39) had unmutated IGHV. The median follow-up was 7.9 months (range, 0.3-23.1 months).
Ninety-six percent of patients reported any-grade treatment-emergent adverse events (TEAEs; grade ≥3, 57%), of which the most common (≥25%) were fatigue (35%; grade ≥3, 2%), contusion (29%; no grade ≥3), and diarrhea (27%; grade ≥3, 2%). The most common grade ≥3 TEAEs (≥10%) were neutropenia/neutrophil count decreased (20%) and pneumonia (10%). One patient (2%) each experienced hypertension (grade 1), febrile neutropenia (in the context of COVID-19 pneumonia and norovirus diarrhea), and major hemorrhage. No atrial fibrillation was observed. Three patients (6%) experienced a TEAE that led to dose reduction. One DLT occurred in 1 patient at 200 mg (grade 3 maculopapular rash on day 27; decreased to grade 1 after 5-day hold; patient continues on treatment). The MTD was not reached. Three patients had TEAEs that led to death (septic shock, bronchopulmonary aspergillosis/cerebral aspergillosis, and pneumonia in the context of disease progression; n=1 each); none of the deaths were considered related to treatment.
In 49 response-evaluable patients, the ORR (partial response with lymphocytosis or better) was 78% (38/49), and the CR/CR with incomplete hematologic recovery rate was 4% (n=2). At 200 mg, the ORR was 94% (15/16) including the 2 CRs. Median time to first response was 2.8 months (range, 2.6-8.3 months). Seventeen patients remained on treatment for ≥9 months and all 17 have ongoing responses. Responses were seen at the lowest dose, as well as in patients previously treated with a cBTKi, ncBTKi, double- (cBTKi and BCL2i) and triple- (cBTKi, BCL2i, ncBTKi) exposed patients, and in patients with and without BTK mutations.
Conclusions: Emerging data from this ongoing, first-in-human study demonstrate that the novel BTK degrader BGB-16673 has a tolerable safety profile and shows promising and deep overall responses in heavily pretreated patients with R/R CLL/SLL, including those with prior BTK inhibitor treatment and BTK resistance mutations.
Disclosures: Thompson: Nurix Therapeutics: Other: Reimbursed travel, Research Funding; Genentech: Research Funding; BeiGene: Consultancy, Research Funding; Genmab: Other: Reimbursed travel, Research Funding; Pharmacyclics/Janssen Pharmaceuticals: Consultancy; Loxo Oncology at Lilly: Consultancy; AbbVie: Consultancy, Research Funding; Dava Oncology: Honoraria, Other: Reimbursed travel; Peerview Institute for Medical Education: Honoraria; Mashup Media LLC: Honoraria, Other: Reimbursed Travel; Clinical Care Options: Honoraria; AstraZeneca: Consultancy, Research Funding; eScientiq: Honoraria; Adaptive Biotechnologies: Research Funding. Parrondo: Sanofi Aventis: Honoraria; AstraZeneca: Honoraria; Bristol Myers Squibb, GSK: Research Funding. Frustaci: AbbVie, BeiGene: Other: Travel, accommodations, expenses; AbbVie, BeiGene, AstraZeneca, Janssen: Consultancy. Allan: Pharmacyclics LLC, an AbbVie Company: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding; Epizyme: Consultancy; ADC Therapeutics: Consultancy; Genentech: Consultancy, Research Funding; Janssen: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; BeiGene: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; AstraZeneca: Consultancy. Ghia: Galapagos: Consultancy; Johnson&Johnson: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; BeiGen: Consultancy; AstraZeneca: Consultancy, Research Funding; AbbvVie: Consultancy, Research Funding; Loxo@Lilly: Consultancy; MSD: Consultancy; Galapagos: Consultancy; Roche: Consultancy. Tam: Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Lilly: Honoraria; BeiGene: Honoraria, Research Funding. Trotman: BMS: Research Funding; Beigene: Research Funding; Cellectar: Research Funding; Janssen: Research Funding; Roche: Research Funding. Ahn: Eli Lilly: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; AstraZeneca: Consultancy. Stilgenbauer: Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Galapagos: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Lilly: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Sunesis: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau. Scarfo: Janssen: Honoraria; Lilly: Honoraria; BeiGene: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Octapharma: Honoraria. By: BeiGene: Current Employment. Fabre: BMS: Current Employment, Current equity holder in publicly-traded company; BeiGene: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Persky: BeiGene: Current Employment. Agarwal: BeiGene: Current Employment, Current equity holder in publicly-traded company. Seymour: Roche: Honoraria, Research Funding, Speakers Bureau; Beigene: Honoraria; Gilead: Honoraria; TG Therapeutics: Consultancy; AbbVie: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Genor Bio: Consultancy; AstraZeneca: Honoraria, Speakers Bureau; Janssen: Honoraria.