Efficacy and Safety of Oral Bruton Tyrosine Kinase Inhibitor (BTKi) Rilzabrutinib in Adults with Previously Treated Immune Thrombocytopenia (ITP): A Phase 3, Placebo-Controlled, Parallel-Group, Multicenter Study (LUNA 3)

Introduction: Patients with primary ITP who are not sufficiently responsive or intolerant to available therapies experience higher rates of morbidity, mortality, and impaired quality of life (QoL). Phase 2 results with covalent, reversible BTKi rilzabrutinib in ITP showed rapid and durable platelet responses with favorable safety.

Methods: The phase 3 LUNA 3 study enrolled adults ≥18 y and pediatrics 10-<18 y with primary persistent/chronic ITP and platelet counts <30×10⁹/L within 2 wk of study initiation (NCT04562766; 2020-002063-60). Patients had response (platelet count ≥50×10⁹/L) to previous IVIg/anti-D or corticosteroids (CS) that was not sustained and documented as intolerance, insufficient response, or any contraindication to any standard-of-care ITP therapy. Patients were stratified by splenectomy status (yes/no) and thrombocytopenia severity (averaged platelet counts <15×10⁹/L or ≥15×10⁹/L) and randomized 2:1 to oral rilzabrutinib 400 mg bid or placebo for up to 24 wk (double-blind), followed by rilzabrutinib only in the 28-wk open-label period (+4-wk safety follow-up) or long-term extension, if eligible. After the initial 12 wk, non-responders could join the open-label part or discontinue. Stable baseline doses of concomitant CS and/or TPO-RA, and rescue medication use were permitted. The primary endpoint was durable platelet response: platelet counts ≥50×10⁹/L for ≥8 of the last 12 wk of the 24 wk blinded period without rescue therapy. This is the first report of efficacy and safety of the adult population.

Results: As of March 14, 2024, 202 randomized adults (n=133 rilzabrutinib, n=69 placebo) had a similar overall median baseline age of 47 y (range, 18-80), median baseline platelet count of 15×10⁹/L, and 46% received ≥5 prior ITP therapies (including 28% splenectomized in both arms). Median duration of ITP was longer for rilzabrutinib-treated patients at 8.1 y (range, 0.3-52.2) vs placebo at 6.2 y (range, 0.3-35.8).

Platelet response (ie, responders: ≥50×10⁹/L or ≥30-<50×10⁹/L and doubled from baseline) was achieved in 86 (65%) rilzabrutinib vs 23 (33%) placebo patients. The primary endpoint of durable response was met in 31 (23%) rilzabrutinib vs 0 placebo patients (P<0.0001). For double-blind and open-label periods combined, durable response was met in 38/133 (29%) rilzabrutinib-randomized patients. Significant improvements with rilzabrutinib over placebo were seen in all secondary efficacy endpoints. Median time to first platelet count ≥50×10⁹/L or ≥30-<50×10⁹/L and ≥doubled from baseline was 36 d (95% CI, 22-44) for rilzabrutinib vs not achieved for placebo (HR=3.1 [95%, 1.9-4.9]; P<0.0001). Among patients who randomized to rilzabrutinib and achieved response, median time to first platelet response was 15 d (range, 2-99). Rilzabrutinib significantly reduced the need for rescue therapy by 52% vs placebo (P=0.0007). Significant and clinically meaningful improvements were observed with rilzabrutinib vs placebo, respectively, in physical fatigue (ITP-PAQ item 10) with a mean change (SE) from baseline at week 13 of 7.95 (2.13) vs -0.13 (2.86; P=0.01), and bleeding (per IBLS) with a mean change (SE) from baseline at week 25 of -0.04 (0.02) vs 0.05 (0.02; P=0.0006).

During the double-blind part, rilzabrutinib and placebo patients received treatment for a median of 98 days (range, 22-182) and 84 days (range, 17-173), respectively, with a median compliance rate of ≥98% for both. A similar percentage of rilzabrutinib and placebo patients had all-cause, any-grade adverse events (AEs) and serious AEs (SAEs); grade ≥2 GI AEs were comparable at 6% vs 4%. The most common treatment-related AEs for rilzabrutinib vs placebo were diarrhea (23% vs 4%), nausea (17% vs 6%), headache (8% vs 1%), and abdominal pain (6% vs 1%), all grade 1 or 2. All other related AEs were ≤5%. In the rilzabrutinib arm, 1 patient with multiple risk-factors had a treatment-related grade 3 peripheral embolism (SAE) and 1 patient died due to pneumonia unrelated to treatment.

Conclusion: Pivotal LUNA 3 phase 3 study results in patients with ITP showed that first-in-class BTKi rilzabrutinib has a robust therapeutic effect as shown by rapid and durable platelet response, reduced bleeding and need for rescue therapy, improved physical fatigue and QoL, and favorable safety and tolerability.

Kuter:PER: Consultancy; Peerview: Consultancy; New York Blood Center: Consultancy; Merck Sharp Dohme: Consultancy; Medscape: Consultancy; Ligand: Consultancy; Inmagenebio: Consultancy; Immunovant: Consultancy; Hengrui: Consultancy; Chugai: Consultancy; Cellphire: Consultancy; Cellularity: Consultancy; Caremark: Consultancy; Bristol Myers Squibb: Consultancy; Argenx: Consultancy; Apellis: Consultancy; Amgen: Consultancy; Alnylam: Consultancy, Research Funding; Alpine: Consultancy; Alexion: Consultancy; Sanofi: Consultancy, Research Funding; Rigel: Consultancy, Research Funding; Principia: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Hutchmed: Consultancy, Research Funding; Biocryst: Consultancy, Research Funding; Pfizer: Consultancy; Platelet Disorder Support Association: Consultancy; Regeneron: Consultancy; Seismic: Consultancy; Sobi: Consultancy; Takeda: Consultancy, Research Funding; UCB: Consultancy, Research Funding; Up-To-Date: Consultancy; Verve: Consultancy; AIRx: Consultancy; CRICO: Consultancy; Daiichi Sankyo: Consultancy; Dianthus: Consultancy; Electra Therapeutics: Consultancy; Fuji: Consultancy; Hemopure: Consultancy; Incyte: Consultancy; Kezar: Consultancy; Kyowa-Kirin: Consultancy; Momenta: Consultancy; Nuvig: Consultancy; Platelet Biogenesis: Consultancy; Protagonist: Consultancy; Zafgen: Consultancy. Ghanima:Grifols: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; SOBI: Consultancy, Honoraria, Research Funding, Speakers Bureau; UCB: Consultancy; Argenx: Consultancy; Cellphire: Consultancy; Alpine: Consultancy; Kedrion: Consultancy; HiBio: Consultancy; HUTCHMED: Consultancy; Takeda: Consultancy; Bristol Myers Squibb: Honoraria; Bayer: Honoraria; Amgen: Consultancy, Honoraria; Hutchmed: Consultancy, Honoraria; Argenx: Consultancy, Honoraria; Alpine: Consultancy; Kedrion: Consultancy; Pfizer: Consultancy; Principia Biopharma Inc- a Sanofi Company: Consultancy. Cooper:Griffols: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Argenx: Consultancy, Honoraria; Rigel: Honoraria, Research Funding; Sobi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Liebman:University Southern California- Keck School of Medicine: Current Employment; Novartis: Consultancy; Sanofi: Consultancy, Research Funding; Alpine: Consultancy; Momenta: Research Funding. Miyakawa:Alexion: Research Funding; BioMarin: Research Funding; Chugai: Research Funding; CSL Behring: Research Funding; Janssen: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisc: Research Funding; Pfizer: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Asahi Kasei: Honoraria; Zenyaku: Consultancy; UCB: Consultancy, Research Funding; argenx: Consultancy, Honoraria. Basquiera:Amgen: Honoraria; Bristol: Honoraria; Servier: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Saydam:MSD: Research Funding. Hütter-Krönke:University Hospital Charité- Universitätsmedizin Berlin: Current Employment; Amgen: Honoraria; Sanofi: Honoraria; Jazz Pharmaceuticals: Honoraria; SOBI: Honoraria. Gomez-Almaguer:Astex Pharmaceuticals: Research Funding; Incyte: Research Funding; Seattle Genetics: Research Funding; AbbVie: Research Funding, Speakers Bureau; Gilead/Forty Seven: Research Funding; Kartos Therapeutics: Research Funding; Roche: Speakers Bureau; Sanofi: Speakers Bureau; Blueprint Medicines: Research Funding; Tevas: Speakers Bureau; ConstellationPharmaceuticals: Research Funding; BMS: Consultancy, Other: Advisory board, Speakers Bureau; Takeda: Consultancy, Other: Advisory board, Research Funding, Speakers Bureau; Novartis: Consultancy, Other: Advisory board, Speakers Bureau; Janssen: Consultancy, Other: Advisory board, Speakers Bureau; Amgen: Consultancy, Other: Advisory board, Research Funding, Speakers Bureau. Lucchini:Azienda Sanitaria Universitaria Giuliano-Isontina: Current Employment. Audia:Sanofi: Honoraria; Argenx: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Cordoba:Sanofi: Current Employment, Current holder of stock options in a privately-held company. Diab:Sanofi: Current Employment, Other: Stocks. Lee:NCI: Other: This work was supported by the Hawaii Tumor Registry of the Univ of Hawaii Cancer Center through NCI SEER Contract Award HHSN261201300009I. The content is solely the responsibility of the authors. Does not necessarily represent the official views of NCI.. Daak:Sanofi: Current Employment, Current equity holder in publicly-traded company.

Yes, it is off label. Rilzabrutinib is an investigational therapy being evaluated in a clinical study for the treatment of patients with immune thrombocytopenia.