Ibrutinib plus rituximab leads to superior progression-free and overall survival to FCR in previously untreated CLL: Results of the Phase III NCRI FLAIR trial

Abstract Introduction: The most effective chemoimmunotherapy (CIT) in previously untreated CLL is the combination of fludarabine, cyclophosphamide and rituximab (FCR). Ibrutinib (I), the first irreversible inhibitor of Bruton's tyrosine kinase approved for CLL, has improved outcomes in numerous clinical trials compared to different CIT regimens. Methods: FLAIR (ISRCTN01844152) is an ongoing, phase III, multicentre, randomised, controlled, open, parallel group trial for previously untreated CLL requiring therapy according to the IWCLL 2008 guidelines. Patients over 75 years or with >20% 17p-deleted cells were excluded. Participants were randomised on a 1:1 basis to receive 6 cycles of FCR (oral fludarabine 24mg/m 2/day for 5 days, oral cyclophosphamide 150mg/m 2/day for 5 days with IV rituximab [375 mg/m 2 on day 1/2 of cycle 1; 500 mg/m 2 on day 1 of cycles 2-6]) every 28-days, or IR (Ibrutinib [420mg/day] plus rituximab [6 doses as for FCR]) given for up to 6 years, with stratification by disease stage, age, gender and centre. The primary endpoint was to assess whether IR was superior to FCR in terms of investigator-assessed PFS. Secondary endpoints included overall survival (OS); attainment of undetectable MRD; response to therapy; safety and toxicity; health-related quality of life and cost-effectiveness. A formal interim analysis of this part of FLAIR was presented at ASH 2021 and published in Lancet Oncology. Here we report the final updated results of IR vs FCR. Results: A total of 771 patients were randomised (385 to FCR and 386 to IR) from 113 UK centres between 9/19/2014 and 7/19/2018. The data was locked on 06/23/2025; 73.3% were male, median age was 63 years (33.3% >65yo) and 43.6% were Binet Stage C. IGHV data was available for 725 (94.0%) patients with 50.2% IGHV unmutated (uIGHV), 38.0% IGHV mutated (mIGHV) and 5.8% Subset 2. Hierarchical FISH testing revealed 0.4% 17p del, 15.4% ATM deletion, 12.3% trisomy 12, 29.7% normal and 35.0% 13q del. The arms were well-balanced for disease variables. With a median follow-up of 97 (IQR: 86,108) months, IR had a superior PFS compared to FCR (median PFS is 112 months for IR versus 80 months for FCR; HR: 0.53; p<0.001). The PFS was significantly better for IR in patients with uIGHV CLL (HR: 0.45; p<0.001), but not for patients with mIGHV CLL at this follow-up (HR: 0.74; p=0.130). There was a significant difference in OS between the two arms with IR proving superior (HR: 0.66; p=0.014) with a total of 86 deaths in FCR arm (including 7 from CLL, 9 Richter transformation [RT], 8 AML/MDS, 8 COVID-19 and 5 cardiac/sudden) and 60 in the IR arm (including 7 CLL, 4 RT, 1 AML/MDS, 7 COVID-19 and 11 cardiac/sudden). The OS was significantly better for IR in patients with uIGHV CLL (HR: 0.58; p=0.0132), but not for patients with mIGHV CLL at this follow-up (HR: 0.78; p=0.4102). 7-year OS estimates are FCR: 81.1% and IR: 87.5%, uIGHV: FCR 76.1% - IR 85.2%, mIGHV: FCR 87.3% - IR 89.5%. Second line treatment was initiated for 149 patients after FCR (including 87 BTKi, 41 venetoclax+R [Ven-R], 3 Bendamustine -R [BR] and 5 CHOP-R []) and 99 after IR (including 8 FCR, 68 Ven-R, 3 BR, 3 CHOP-R [RT], 1 ABVD [Hodgkin's]). 243 patients completed 6 years of treatment of IR. 70/243 patients have finished six years of I on FLAIR and have been enrolled on STATIC (ISRCTN51675454) where patients are randomised to continuous vs intermittent therapy with ibrutinib. Overall, 80.1% of patients have received targeted therapies for CLL progression after . SAEs were reported in 54% of patients on FCR and 60.7% on IR. Notable differences for SAEs by organ class for FCR vs IR: infections in 33.6% of patients vs 33.1%; blood and lymphatic in 20.4% vs 12%; and cardiac in 1.1% vs 10.7%. With current follow-up, there were 16 sudden or cardiac deaths: 11 IR and 5 FCR. A history of hypertension or cardiac disease was observed in 7 of the 11 cardiac/sudden deaths in the IR arm. There were 24 cases of secondary MDS/AML: 22 in the FCR arm and 2 in the IR arm. Conclusion:Ibrutinib plus rituximab resulted in a superior PFS and OS compared to FCR, despite use of modern targeted agents as salvage therapy for patients progressing on FCR. With longer follow-up, continuous IR leads to improved outcomes especially in uIGHV patients whilst no new safety signals emerge with longer follow-up on ibrutinib. This data re-affirms the use of targeted agents in treatment-naive CLL.