Type: Oral
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: New Inhibitors and Cellular Therapies for Treatment of Relapsed CLL
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, clinical trials, Research, CLL, Clinical Research, Diseases, Therapies, Lymphoid Malignancies
Methods: Relapsed cBTKi pre-treated CLL pts in the phase 1/2 BRUIN trial (NCT03740529) who subsequently developed disease progression (PD) on pirtobrutinib monotherapy were included. Targeted next-generation sequencing (NGS) was centrally performed on peripheral blood mononuclear cells collected at baseline and within four months of PD .
Results: As of May 5, 2023, 86 cBTKi pre-treated CLL pts had paired NGS data available at baseline and pirtobrutinib progression. In this group, the median age was 69 years (range, 36-86), median number of prior lines of therapy was 4 (range, 1-10), 74 pts (86%) had discontinued prior cBTKi due to PD and 12 pts (14%) discontinued due to toxicity/other. Pts received one or more of the following prior cBTKi: ibrutinib (n=77, 90%), acalabrutinib (n=15, 17%), or zanubrutinib (n=2, 2%). Median time on pirtobrutinib treatment was 16 months (range, 1.2-39 months). Among these 86 pts who ultimately progressed on pirtobrutinib, the ORR (including partial response with lymphocytosis) was 83% (95%CI, 73-90). The most common baseline alterations were mutations in BTK (53%), TP53 (48%), SF3B1 (35%), ATM (23%), NOTCH1 (20%), XPO1 (16%), PLCG2 (14%), and BCL2 (9%). In 46 pts, 64 BTK mutations were detected at baseline and included C481S (n=45), C481F/R/Y (n=11), T474I/F/S (n=6), A428D (n=1), D149G (n=1). Among 42 pts with C481, BTK C481 VAF decrease or complete clearance was observed at PD in the majority of pts (86%, 36/42, complete clearance = 55%, 23/42). NGS of samples at PD showed 69% (59/86) of pts acquired ≥1 mutation. In 38 (44%) pts, 52 acquired BTK mutations were detected and most commonly included gatekeeper mutations (T474I/F/S/L/Y, n=25 in 22 pts), kinase-impaired (L528W, n=14 in 14 pts), C481S/R/Y (n=6 in 4 pts) and others proximal to the ATP-binding pocket (n=7 in 5 pts), including D539A/G/H (n=3 in 1 pt), V416L (n=2 in 2 pts), Y545N (n=1) and A428D ([n=1] Figure). A total of 83 non-BTK acquired mutations were observed at PD in 45 pts (52%), including 14 TP53 mutations in 12 pts (14%), 6 PLCG2 mutations in 6 pts (7%), 6 PIK3CA mutations in 6 pts (7%) and 3 BCL2 mutations in 3 pts (3%).
Conclusions: Despite this cohort representing the first relapsing CLL patients from BRUIN and presenting with frequent baseline BTK mutations, response to pirtobrutinib was high, with an ORR of 83%, and substantial clearance of BTK C481 clones. At progression, the majority of pts (56%) either acquired non-BTK mutations or did not acquire any resistance mutations in this targeted panel, suggesting alternative resistance mechanisms. A smaller group of patients (44%) displayed emergence of non-C481 clones, particularly gatekeeper T474 and kinase-impaired L528W mutations. Whether similar patterns of resistance would manifest if pirtobrutinib was utilized in earlier lines of therapy or prior to cBTKi treatment remains uncertain.
Disclosures: Brown: Grifols Worldwide Operations: Consultancy; Pfizer: Consultancy; Merck: Consultancy; Genentech/Roche: Consultancy; Kite: Consultancy; iOnctura: Consultancy, Research Funding; Gilead: Research Funding; Loxo/Lilly: Consultancy, Research Funding; Pharmacyclics: Consultancy; SecuraBio: Research Funding; BeiGene: Consultancy, Research Funding; Alloplex Biotherapeutics: Consultancy; Acerta/AstraZeneca: Consultancy; Numab Therapeutics: Consultancy; Hutchmed: Consultancy; Abbvie: Consultancy; TG Therapeutics: Research Funding; MEI Pharma: Research Funding. Nguyen: Loxo@Lilly: Current Employment. Won: Loxo@Lilly: Current Employment; Eli Lilly and Company: Current equity holder in publicly-traded company. McNeely: Loxo@Lilly: Current Employment; Eli Lilly and Company: Current equity holder in publicly-traded company. Marella: Loxo@Lilly: Current Employment; Eli Lilly and Company: Current equity holder in publicly-traded company. Ebata: Loxo@Lilly: Current Employment; Eli Lilly and Company: Current equity holder in publicly-traded company. Woyach: Newave: Consultancy; Loxo: Consultancy; Beigene: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy; Schrodinger: Research Funding; Morphosys: Research Funding; Karyopharm: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Patel: Xencor: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Fate Therapeutics: Research Funding; Epizyme: Consultancy, Research Funding; ADC Therapeutics: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy, Research Funding, Speakers Bureau; Loxo Oncology: Consultancy, Research Funding; Merck: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Morphosys: Consultancy; Nurix: Research Funding; Pharmacyclics/Janssen: Consultancy, Research Funding; Trillium Therapeutics/Pfizer: Consultancy, Research Funding; TG Therapeutics: Consultancy, Speakers Bureau; Sunesis Pharmaceuticals: Research Funding; CRISPR Therapeutics: Research Funding; Caribou Biosciences: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding, Speakers Bureau; BeiGene: Consultancy; Curis, Inc: Research Funding; Adaptive Biotechnologies: Research Funding; Abbvie: Consultancy. Tam: Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; LOXO: Honoraria; Novartis: Honoraria; Roche: Honoraria. Eyre: Loxo Oncology: Consultancy, Honoraria, Other, Speakers Bureau; KITE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Autolus: Consultancy; Beigene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Eli Lilly and Company: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Loxo Lilly: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PeerView: Speakers Bureau; Medscape: Speakers Bureau; Secura Bio: Membership on an entity's Board of Directors or advisory committees. Cheah: Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZenecca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Ascentage Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Menarini: Consultancy, Honoraria; Genmab: Consultancy, Honoraria; Dizal: Consultancy, Honoraria. Shah: Tundra Therapeutics: Current holder of stock options in a privately-held company; BMS/Juno: Consultancy; Epizyme: Consultancy; TG therapeutic: Consultancy; Novartis: Consultancy; Janssen: Consultancy; LOXO-Lilly: Consultancy, Other: Travel support; Umoja: Consultancy; Seattle Genetics: Consultancy; Gilead/Kite: Consultancy; Incyte: Consultancy; Abbvie: Consultancy; Lilly Oncology: Consultancy, Research Funding; Miltenyi Biotec: Consultancy, Other: Travel support, Research Funding. Ghia: BeiGene: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Lilly/Loxo Oncology: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Jurczak: AstraZeneca: Consultancy; BeiGene: Consultancy; AbbVie: Consultancy; Eli Lilly: Consultancy; Pfizer: Consultancy; Roche: Consultancy; SOBI: Consultancy; Takeda: Consultancy; AbbVie: Research Funding; AstraZeneca: Research Funding; Bayer: Research Funding; BeiGene: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Eli Lilly: Research Funding; Merck: Research Funding; Pfizer: Research Funding; Roche: Research Funding; SOBI: Research Funding; Takeda: Research Funding. Balbas: Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Nair: Loxo@Lilly: Current Employment. Abada: Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Wang: Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Wang: Loxo@Lilly: Current Employment. Roeker: Curio: Other: CME speaker; Pharmacyclics: Consultancy; Pfizer: Consultancy, Research Funding; DAVA: Other: CME speaker; Genentech: Research Funding; TG Therapeutics: Consultancy; AbbVie: Consultancy, Research Funding; Adaptive Biotechnologies: Research Funding; Abbott Laboratories: Current equity holder in publicly-traded company; Ascentage: Consultancy; PeerView: Other: CME speaker; Janssen: Consultancy; AstraZeneca: Consultancy, Research Funding; Medscape: Other: CME speaker; Loxo Oncology: Consultancy, Other: travel support, Research Funding; Beigene: Consultancy; Aptose Biosciences: Research Funding; Dren Bio: Research Funding; Qilu Puget Sound Biotherapeutics: Research Funding. Gandhi: Sunesis: Honoraria, Research Funding; AbbVie: Research Funding; Clear Creek Bio: Consultancy, Research Funding; LOXO: Research Funding; Dava Oncology: Honoraria; Pharmacyclics: Research Funding. Wierda: Miragen: Research Funding; Sunesis: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Bristol Myers Squibb (Juno & Celgene): Consultancy, Research Funding; Numab THerapeutics: Research Funding; Pharmacyclics LLC: Research Funding; Gilead Sciences: Research Funding; Loxo Oncology, Inc./Lilly: Research Funding; Accutar Biotechnology: Research Funding; National Comprehensive Cancer Network: Other: Nonrelevant Financial Relationship/Chair, CLL). Supported by the NIH/NCI under award number P30 CA016672 and used MDACC Cancer Center Support Grant (CCSG) shared resources; NIH P30 CA016672/MDACC Cancer Center Support Grant: Research Funding; AstraZeneca/Acerta Pharma: Consultancy, Research Funding; KITE Pharma: Research Funding; GlaxoSmithKline: Research Funding; Genentech: Research Funding; Janssens Biotech: Research Funding; Cyclacel: Consultancy, Research Funding; Janssens Biotech Inc: Research Funding; AbbVie: Consultancy, Research Funding; Juno Therapeutics: Research Funding; Nurix THerapeutics: Research Funding; GSK/Novartis: Research Funding.
OffLabel Disclosure: Pirtobrutinib is approved in the USA to treat R/R mantle cell lymphoma after at least two lines of systemic therapy including prior BTKi treatment.