LBA-4 A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy Vs. Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL): A Trial of the ECOG-ACRIN Cancer Research Group (E1912) Tait D. Shanafelt, MD1, Victoria Wang2*, Neil E. Kay, MD3, Curtis A. Hanson, MD4, Susan M. O'Brien, MD5, Jacqueline C Barrientos, MD6, Harry P. Erba, MD, PhD7, Richard M. Stone, MD8, Mark R. Litzow, MD3 and Martin S. Tallman, MD9

BACKGROUND Chronic lymphocytic leukemia (CLL) is one of the most common lymphoid malignancies, accounting for ~11% of all hematologic neoplasms. Over the last 15 years, a series of phase 3 trials have established that chemoimmunotherapy (CIT) with fludarabine, cyclophosphamide, and rituximab (FCR) improves both progression free survival (PFS) and overall survival (OS) compared with chemotherapy alone. FCR is the gold standard for young fit patients with treatment naïve CLL

IBRUTINIB Ibrutinib (an irreversible inhibitor of Bruton’s Tyrosine Kinase) - game changer Initial trials demonstrated robust and durable efficacy in patients with relapsed/refractory disease. Phase 3 trials showed improved PFS and OS with ibrutinib relative to chlorambucil in previously untreated, older CLL patients. Efficacy of ibrutinib as a first-line treatment for younger CLL patients (i.e. <70) relative to the most efficacious CIT regimens, such as FCR, is unknown.

MATERIALS AND METHODS Eligiblity criteria Inclusion criteria Treatment-naive individuals with CLL Age ≤70 Requiring therapy. Exclusion criteria: Patients with deletion 17p-

Hematologic toxicity was graded according to the 2008 IWCLL Working Group scale. All other adverse events were graded according to the NCI Common Toxicity Criteria (version 4). The study was approved by the Central Institutional Review Board for the National Cancer Institute, conducted in accordance with the principles of the Declaration of Helsinki, and registered with ClinicalTrials.gov (NCT02048813)

Randomly assigned in a 2:1 ratio Ibrutinib (420 mg/day until disease progression) and rituximab (50 mg/m2 on day 1 of cycle 2; 325 mg/m2 on day 2 of cycle 2; 500 mg/m2 on day 1 of cycles 3-7) Versus Six cycles of fludarabine (25 mg/m2 ) and cyclophosphamide (250 mg/m2) days 1-3 with rituximab (50 mg/m2 on day 1 of cycle 1; 325 mg/m2 on day 2 of cycle 1; 500 mg/m2 on day 1 of cycles 2-6) every 28-days.

A total of 529 patients were accrued between January 31, 2014 and June 9, 2016. 354 patients were assigned to ibrutinib and rituximab (IR) and 175 to FCR. Nineteen patients did not start protocol therapy. The first interim analysis was performed September 2018.

OBJECTIVES The primary endpoint Progression free survival (PFS) Secondary endpoint Overall survival (OS). Analysis was by intention to treat. The first planed interim analysis for PFS was scheduled to occur 24-27 months after full accrual with the first interim analysis for OS scheduled to occur if the boundary for PFS was crossed. The primary analysis was a stratified logrank test applied to all patients as randomized. Treatment effect p-values are one-sided.

RESULTS With median follow-up of 33.4 months, 77 PFS events and 14 deaths were observed . The hazard ratio (HR) for PFS favored IR over FCR (HR=0.352; 95% CI 0.223-0.558; p<0.0001). The HR for OS also favored the IR arm (HR=0.168, 95% CI 0.053-0.538; p=0.0003, pre-specified boundary for superiority p=0.0005). In subgroup analysis for PFS, IR was superior to FCR independent of age, sex, performance status, disease stage or the presence/absence of del11q23

With current follow-up, IR was also superior to FCR for IGHV unmutated patients (HR=0.262; 95% CI 0.137-0.498; p<0.0001) but not IGHV mutated patients (HR=0.435; 95% CI 0.140-0.1350; p=0.07).

SURVIVAL CURVES

Adverse Events Grade 3 and 4 treatment-related adverse events were observed in 58% of IR and 72% of FCR treated patients (p=0.0042). FCR was more frequently associated with grade 3 and 4 neutropenia (FCR: 69 [44%] of 158 vs. IR: 80 [23%] of 352; p<0·0001) and infectious complications (FCR: 28/158 [17.7%] vs. IR: 25/352 [7.1%]; p<0.0001).

CONCLUSION  The combination of ibrutinib and rituximab provides superior PFS and OS relative to FCR for patients with previously untreated CLL age ≤70. These findings have immediate practice changing implications and establish ibrutinib-based therapy as the most efficacious first-line therapy for patients with CLL.