MRD-Directed Ibrutinib Plus Venetoclax Bests FCR in CLL

Treatment with ibrutinib (Imbruvica) in combination with venetoclax (Venclexta) guided by measurable residual disease (MRD) led to a survival benefit over fludarabine plus cyclophosphamide and rituximab (Rituxan; FCR) in patients with chronic lymphocytic leukemia (CLL), according to findings from the phase 3 FLAIR trial (ISRCTN01844152; EudraCT 2013-001944-76) published in The New England Journal of Medicine.

At a median follow-up of 43.7 months (IQR, 35.1-51.5), findings from a planned interim analysis demonstrated that the risk of disease progression or death was reduced by 87% in the ibrutinib plus venetoclax arm compared with the FCR arm (HR, 0.13; 95% CI, 0.07-0.24; P < .001); the median progression-free survival (PFS) was not estimable (NE) in either arm. Moreover, the risk of death was reduced by 69% in the ibrutinib plus venetoclax arm (HR, 0.31; 95% CI, 0.15-0.67); the median overall survival (OS) was NE in both arms as well.

“In this cohort of the FLAIR trial in which patients with previously untreated CLL were randomly assigned to receive ibrutinib [plus] venetoclax, ibrutinib monotherapy, or FCR, we found that MRD-guided ibrutinib/venetoclax was superior to FCR with respect to PFS; results for OS also favored ibrutinib/venetoclax over FCR. The results appear better than those in previous studies of ibrutinib monotherapy or venetoclax, as monotherapy or in combination with anti-CD20 [agents],” study authors wrote.

FLAIR was an open-label, adaptive platform trial that enrolled treatment-naive patients with CLL across 96 sites in the United Kingdom who were considered fit for treatment with FCR by their treating clinician. Those with Richter’s transformation, central nervous system involvement, symptomatic cardiac disease, and those who had disease where greater than 20% of CLL cells displayed del17p, were excluded from the study.

Patients were randomly assigned 1:1:1 to receive FCR, ibrutinib monotherapy, or ibrutinib plus venetoclax. FCR was given every 28 days for 6 cycles until disease progression or unacceptable toxicity. Ibrutinib was given orally daily at 420 mg for 8 weeks, then daily venetoclax up to 400 mg was initiated. Patients continued treatment with the ibrutinib/venetoclax combination for a total of 6 years, unless the algorithm-based MRD stopping rules were reached, or progressive disease or unacceptably toxicity occurred.

The primary end point was PFS and secondary end points included OS, undetectable MRD as well as response to therapy at 9 months after random assignment, pattern of MRD relapse and retreatment, safety, health-related quality of life, and cost-effectiveness.

The baseline patient characteristics were well-balanced between the 2 arms; the median age in the ibrutinib plus venetoclax arm (n = 260) was 62 years (IQR, 55-67) and was also 62 years (IQR, 57-67) in the FCR arm (n = 263). Most patients in both arms were male (71.5% vs 71.1%), White (89.6% vs 91.3%), had a WHO performance status of 0 (69.6% vs 68.8%), and had Binet stage progressive A or B disease (58.1% vs 57.8%), respectively.

Additional findings from FLAIR revealed that patients with unmutated IGHV (HR, 0.07; 95% CI, 0.02-0.19) as well as mutated IGHV (HR, 0.54; 95% CI, 0.21-1.38) experienced a PFS benefit with ibrutinib plus venetoclax vs FCR. Moreover, OS also favored ibrutinib plus venetoclax in both the unmutated IGHV (HR, 0.23; 95% CI, 0.06-0.81) and the mutated IGHV (HR, 0.61; 95% CI, 0.20-1.82) subgroups. The 3-year OS rates were 98.0% (95% Cl, 95.2%-99.2%) in the ibrutinib plus venetoclax arm vs 93.0% (95% Cl, 88.9%-95.6%) in the FCR arm.

The 2-year MRD-negativity rates in the bone marrow were 52.4% (95% CI, 45.9%-58.9%) in the ibrutinib plus venetoclax arm compared with 49.8% (95% CI, 43.2%-56.5%) in the FCR arm; the 5-year rates were 65.9% (95% CI, 59.5%-72.3%) vs 49.8% (95% CI, 43.2%-56.5%), respectively. The respective median times to undetectable MRD in the peripheral blood were 12.0 months (95% CI, 11.5-17.3) vs 8.9 months (95% CI, 8.5-9.1)—the 5-year rates of undetectable MRD in peripheral blood were 92.7% (95% CI, 88.1%-97.3%) in the ibrutinib plus venetoclax arm and 67.9% (95% CI, 61.9%-73.9%) in the FCR arm.

In terms of safety, any-grade adverse effects (AEs) occurred at a rate of 91.6% overall. The most common any-grade AEs in the combination and FCR arms included fatigue (15.5% vs 49.0%) and neutropenia (19.4% vs 58.6%). Common AEs of grade 3 to 5 severity included neutropenia (10.3% vs 47.3%), anemia (0.8% vs 15.5%), and thrombocytopenia (2.0% vs 10.0%), and serious cardiac AEs occurred at rates of 10.7% vs. 0.4%, respectively. Eight patients died in the ibrutinib plus venetoclax arm compared with 23 in the FCR arm, with investigators noting that 1 and 6 patients, respectively, likely died in each arm due to treatment.

“The CLL treatment landscape has been transformed by targeted drugs. Continuous BTK inhibitor therapy has improved outcomes in patients with CLL. Fixed-duration venetoclax in combination with obinutuzumab [Gazyva] or ibrutinib has also been shown to improve patient outcomes. However, only trends toward improvement in OS have been seen as compared with chlorambucil and obinutuzumab. These approaches are based on the principle that ‘one size fits all,’ and therapy is not individualized on the basis of response. Using MRD to define the duration of ibrutinib/venetoclax treatment, as in the FLAIR trial, may result in improved outcomes, allowing the individualization of therapy based on response in real-time.”

Reference

Munir T, Cairns DA, Bloor A, et al; National Cancer Research Institute Chronic Lymphocytic Leukemia Subgroup. Chronic lymphocytic leukemia therapy guided by measurable residual disease. N Engl J Med. 2024;390(4):326-337. doi:10.1056/NEJMoa2310063