Ibrutinib Plus Venetoclax with MRD-Directed Duration of Treatment Is Superior to FCR and Is a New Standard of Care for Previously Untreated CLL: Report of the Phase III UK NCRI FLAIR Study

Hillmen, Peter; Cairns, David Allan; Bloor, Adrian John Clifton; Allsup, David; Cwynarski, Kate; Pettitt, Andrew; Paneesha, Shankaranarayana; Fox, Christopher P.; Eyre, Toby A.; Forconi, Francesco; Elmusharaf, Nagah; Kennedy, Ben; Gribben, John G.; Pemberton, Nicholas; Sheehy, Oonagh; Preston, Gavin; Schuh, Anna; Howard, Dena; Hockaday, Anna; Jackson, Sharon; Greatorex, Natasha; Girvan, Sean; Bell, Sue; Brown, Julia; Webster, Nichola; Dalal, Surita; de Tute, Ruth M; Rawstron, Andrew; Patten, Piers EM; Munir, Talha

Abstract

Introduction: Ibrutinib (I), an irreversible Btk inhibitor, and venetoclax (V), a Bcl-2 inhibitor, improve CLL outcomes in trials compared to chemoimmunotherapy. I and V target two key pathophysiological pathways in CLL and should be synergistic. This is supported both by in vitro studies and Phase II trials in which I+V results in high proportions of measurable residual disease (MRD) negativity. A Phase III trial comparing I+V (15 months [mo]) with chlorambucil-obinutuzumab led to the approval of I+V. However, mathematical disease modelling and Phase II studies favor defining duration of I+V according to individual patient sensitivity. We hypothesized that I+V is more effective than FCR in CLL and that treatment duration personalised using MRD response would optimize outcome.

Methods: FLAIR (ISRCTN01844152) is a phase III, multicentre, randomised, controlled, open, parallel group trial for untreated CLL. Patients (pts) with >20% 17p deleted cells were excluded. FLAIR was adapted in 2017 to add 2 arms, I alone and I+V compared to FCR. Here we report the planned analysis of I+V vs FCR. In I+V after 2 mo I, V was added with a 4-week dose escalation to 400mg/day and then I+V for up to 6 years with duration of I+V defined by MRD (<1 CLL cell in 10,000 [flow cytometry]). PB MRD was assessed at 12 mo and then 6 monthly and if negative, was repeated at 3 mo and 6 mo in PB and BM. If all were MRD neg, then the duration of I+V was double the time between start of I+V and the initial MRD neg PB (I+V duration: 2 to 6 years). The primary endpoint for I+V vs FCR was investigator-assessed PFS. Key secondary endpoints presented were OS, IWCLL response, MRD and safety. Appropriate endpoints were analysed by CLL prognostic sub-groups.

Results: 523 pts were randomised to FCR (n=263) and I+V (n=260) at 96 UK Centers from 07/20/2017 to 03/24/2021. Data-lock on 05/23/2023. 71.3% male, median age 62 yrs (31.2% >65yo) and 40.9 % Binet Stage C. IGHV unmutated (≥98% homology to germline) in 56.9%, 37.6% IGHV mutated and 5.5% Subset 2. Hierarchical FISH: 20.6% 11q del, 20.1% trisomy 12, 27.8% normal and 31.4% 13q del. At 2 yrs 111/260 (42.7%) and 3 yrs 135/232 (58.1%) pts stopped I+V according to the MRD stopping rules. At a median 43.7 months there were 87 progressions - 75 FCR and 12 I+V. The hazard ratio (HR) for PFS for I+V vs FCR is 0.13 (95% CI: [0.07, 0.24]; p<0.0001; Fig). This result was consistent for gender, age or stage. At 3 yrs 2.8% had progressed on I+V compared to 23.2% on FCR. There have been 34 deaths (25 FCR and 9 I+V) resulting in improved overall survival for I+V vs FCR: HR 0.31 (95% CI: [0.15, 0.67]; p=0.0029; Fig). At 3 years 2.0% of I+V pts had died compared to 7.0% for FCR. At 9 months (3 mo post-FCR) 48.3% FCR pts became MRD neg in BM compared to 41.5% for I+V. However, with continued I+V more pts became MRD neg: the odds of MRD negativity at any time for I+V vs FCR were 2.03 (95% CI: [1.43, 2.89]; P<0.001) in BM and 3.91 (95% CI: [2.55, 6.00]; P<0.001) in PB. 90.6% pts achieved PB MRD negativity at up to 5 yrs I+V and 88% of these were BM MRD negative 6 mo after their first PB MRD neg result. At 9 months a higher proportion achieved CR and overall response for I+V; CR - FCR 49.0% (95% CI: [42.9%, 55.3%]), I+V 59.2% (53%, 65.3%); ORR - FCR 76.4% (70.8%, 81.4%); I+V 86.5% (81.8%, 90.4%). This difference was greater for best response at any time: ORR 83.7% (78.6%, 87.9%) for FCR vs 95.4% (92.1%, 97.6%) for I+V; CR 71.5% (65.6%, 76.9%) for FCR vs 92.3% (88.4%, 95.2%) for I+V. The odds ratios estimate to achieve CR with I+V vs FCR is 1.51 (95% CI: [1.07, 2.14]; p<0.05). Responses and outcomes by FISH and IGHV will be presented. SAEs were reported in 252 (51.3%) pts (129 FCR vs 123 I+V). Notable SAEs by organ class for FCR vs I+V were: infections 18.8% of FCR pts vs 22.2% for I+V; blood and lymphatic 31% vs 5%; and cardiac in 0.4% vs 10.7%. 4 pts had sudden or cardiac deaths - 2 FCR and 2 I+V. 69 other cancers were diagnosed (45 in FCR, 24 in I+V) in 51 pts (34 FCR, 17 I+V). The incidence of other cancers per 100 pt-years was greater for FCR than I+V; 5.4 (95% CI: [5.11, 5.68]) vs. 2.6 (2.40, 2.79). There were 7 cases of MDS/AML with FCR and 1 with I+V.

Conclusion: Ibrutinib plus venetoclax significantly improved progression-free and overall survival compared to FCR in untreated CLL. Using MRD to direct the duration of I+V maximizes outcome with 97.2% progression free survival at 3 years The efficacy seen in FLAIR is superior to previous Phase III CLL trials indicating that I+V with duration guided by MRD is a new gold standard for CLL treatment.

Citation

Hillmen, P., Cairns, D. A., Bloor, A. J. C., Allsup, D., Cwynarski, K., Pettitt, A., Paneesha, S., Fox, C. P., Eyre, T. A., Forconi, F., Elmusharaf, N., Kennedy, B., Gribben, J. G., Pemberton, N., Sheehy, O., Preston, G., Schuh, A., Howard, D., Hockaday, A., Jackson, S., …Munir, T. Ibrutinib Plus Venetoclax with MRD-Directed Duration of Treatment Is Superior to FCR and Is a New Standard of Care for Previously Untreated CLL: Report of the Phase III UK NCRI FLAIR Study. Presented at 65th ASH Annual Meeting and Exposition, San Diego, CA

• Presentation Conference Type: Conference Paper (published)
• Conference Name: 65th ASH Annual Meeting and Exposition
• Acceptance Date: Oct 2, 2023
• Online Publication Date: Nov 2, 2023
• Publication Date: Nov 28, 2023
• Deposit Date: Jan 17, 2024
• Publicly Available Date: Nov 3, 2024
• Print ISSN: 0006-4971
• Publisher: American Society of Hematology
• Peer Reviewed: Peer Reviewed
• Volume: 142
• Issue: Supplement 1
• Pages: 631
• DOI: https://doi.org/10.1182/blood-2023-178298
• Keywords: Cell Biology; Hematology; Immunology; Biochemistry
• Public URL: https://hull-repository.worktribe.com/output/4519241