Clinical activity and safety of rilzabrutinib in patients with previously treated immune thrombocytopenia (LUNA3): results from the open-label period of a phase 3 trial.

Abstract

Rilzabrutinib showed robust efficacy and favourable safety profile in patients with persistent or chronic immune thrombocytopenia in the double-blind period of the phase 3 LUNA3 trial. We report long-term activity and safety of rilzabrutinib in the LUNA3 open-label period. LUNA3 was a multicentre, randomised, phase 3 trial that was done at 103 centres in 24 countries in adolescents and adults. In this study, adults aged 18 years or older with primary persistent or chronic immune thrombocytopenia with a previous response to intravenous or anti-D immunoglobulins or corticosteroids were enrolled during the double-blind period and were randomised 2:1 to receive either rilzabrutinib 400 mg twice daily orally or placebo. Patients entered the 28-week open-label period either after completing the 24-week double-blind period or after week 12 if they did not meet predefined response criteria, in which they received rilzabrutinib 400 mg twice daily orally. Endpoints of this open-label study were evaluated as secondary (stable platelet response over the double-blind and open-label periods [no two platelet counts, at least 4 weeks apart, <50 × 10⁹ platelets per L, without an intervening count of ≥50 × 10⁹ platelets per L, within 24 weeks of initial platelet response] and safety) and exploratory (proportion of patients who received either placebo or rilzabrutinib during the double-blind period and had a durable response during the open-label period [platelet counts ≥50 × 10⁹ platelets per L for at least two-thirds of at least ten non-missing weekly platelet counts during the last 16 of 28 weeks of the open-label period without rescue therapy]; complete response [platelet count ≥100 × 10⁹ platelets per L on two consecutive visits at least 5 days apart without bleeding or rescue immune thrombocytopenia therapy]; Immune Thrombocytopenic Purpura Patient Assessment Questionnaire physical fatigue score; and immune thrombocytopenic purpura bleeding scale score). Activity and safety analyses were done in patients exposed to rilzabrutinib during the double-blind and open-label periods according to the intention-to-treat principle. This trial is registered with ClinicalTrials.gov (NCT04562766) and the EU Clinical Trials Register (2023-509401-71); the adult part of the trial is complete. Between April 16, 2021, and Oct 15, 2024, 180 patients of the 202 patients randomly assigned during the double-blind period entered the open-label period (115 who were randomly assigned to rilzabrutinib and 65 to placebo during the double-blind period; median age 48 years [IQR 33-61], 112 [62%] females and 68 [38%] males, and 113 [63%] White). 46 (23%) of 198 patients exposed to rilzabrutinib in the double-blind and open-label periods had stable platelet responses by the data cutoff date of Oct 15, 2024 (31 [23%] of 133 in the double-blind rilzabrutinib group and 15 [23%] of 65 in the double-blind placebo group). Treatment-related adverse events occurred in 46 (26%) of 180 patients, of which the most frequent were grade 1 or 2 diarrhoea (17 [9%] patients) and nausea (17 [9%]). Treatment-related grade 3 adverse events occurred in four (2%) patients (one had hypertension, one had petechiae, one had interstitial lung disease, and one had bronchopulmonary aspergillosis and cytomegalovirus viraemia). Serious treatment-related adverse events occurred in two (1%) patients (interstitial lung disease and bronchopulmonary aspergillosis along with cytomegalovirus viremia). No deaths occurred during the open-label period. 14 (22%) of 65 patients in the double-blind placebo group had a durable platelet response). Median follow-up was 196 days (IQR 89-197). Complete response was attained by 42 (23%) of 180 patients. Physical fatigue (maximum mean change from baseline of 11·7 [SD 27·4] across all patients) and bleeding scores (mean change from baseline of -0·13 [SD 0·19]) were sustained or improved. Rilzabrutinib showed continued, stable, and sometimes improved platelet responses, including in patients who were initially non-responsive in the double-blind trial. Additionally, rilzabrutinib improved several disease aspects, including physical fatigue and bleeding, supporting its multi-immune modulation mechanism in immune thrombocytopenia, and had a favourable safety profile. The long-term extension period of LUNA3 will further characterise the long-term efficacy and safety of rilzabrutinib in patients with difficult-to-treat immune thrombocytopenia, and the ongoing LUNA4 trial (NCT07007962) will determine the efficacy of rilzabrutinib in earlier-line treatment and its potential to achieve sustained treatment-free response. Sanofi. For the German, French, Japanese, Spanish, Arabic and Italian translations of the abstract see Supplementary Materials section.