IBRUTINIB VERSUS PLACEBO IN PATIENTS WITH ASYMPTOMATIC, TREATMENT‐NAÏVE EARLY STAGE CLL: PRIMARY ENDPOINT RESULTS OF THE PHASE 3 DOUBLE‐BLIND RANDOMIZED CLL12 TRIAL

Introduction: So far, treatment of asymptomatic, early stage CLL patients has not been proven beneficial. Ibrutinib is a BTK inhibitor with impressive clinical efficacy in advanced or relapsed CLL. Therefore we wished to evaluate whether ibrutinib prolongs event-free survival (EFS) in early stage CLL patients with increased risk of progression. Methods: Asymptomatic Binet A patients were stratified according to a recently developed score (Pflug et al., Blood 2014). Patients with intermediate, high and very high risk were randomized 1:1 to receive ibrutinib 420 mg per day or placebo. EFS was defined as time from randomization until occurrence of active disease according to iwCLL guidelines, new CLL treatment or death. Secondary endpoints progression free survival (PFS) and time to next treatment (TTNT) were defined as time from randomization until progression/death (PFS) or until the date of initiation of subsequent treatment for CLL (TTNT). Survival will be analyzed later with 60% (N=28) of the required events being reported. Patients with low risk (N=152) were allocated to an observational arm and were not included in primary endpoint analysis. Results: A total of 182 or 181 patients were assigned to receive ibrutinib or placebo, respectively. At median observation time of 31 months EFS was not reached in the ibrutinib arm and was 47.8 months in the placebo arm (HR 0.25; 95%CI, 0.14 to 0.43; P<0.0001; Figure 1). Similarly PFS was not reached for ibrutinib and 14.8 months with placebo (HR 0.18; 95%CI, 0.12 to 0.27). TTNT was longer in the ibrutinib arm (HR 0.21; 095%CI, 0.11 to 0.39). EFS, PFS and TTNT improvement was consistent across all risk groups analyzed, except for very high risk patients due to small numbers (N=8). At cut-off, 6 and 5 deaths were documented in the ibrutinib and placebo arm, respectively. There was no significant difference in non-serious and serious adverse events (SAE) in ibrutinib and placebo treated patients respectively (82.7 vs. 84.3%). SAEs were reported in 34.6 and 34.8% of ibrutinib and placebo treated patients respectively; most common SAEs were infections (11.4 vs. 11.8%), neoplasms (5.9 vs. 10.7%) and cardiac disorders (8.6 vs. 6.7%). AEs of particular interest were mostly of CTC-grade 1-2 and significantly more frequent in ibrutinib treated patients (Table 1). Disclosures: Langerbeins, P: Consultant Advisory Role: Sunesis; Honoraria: Janssen, Abbvie; Research Funding: Janssen. Cramer, P: Consultant Advisory Role: Janssen, Novartis; Honoraria: Roche, Janssen; Research Funding: Roche, Gilead, GlaxoSmithKline/Novartis, Janssen. Al-Sawaf, O: Honoraria: Roche, Gilead, Abbvie, Janssen; Research Funding: Beigene. von Tresckow, J: Honoraria: Roche, AbbVie, Janssen; Research Funding: Roche, Janssen. Fink, A: Honoraria: Roche; Research Funding: Celgene. Wendtner, C: Consultant Advisory Role: AbbVie, Roche, Genentech, Gilead, Novartis, Janssen; Honoraria: AbbVie, Roche, Genentech, Gilead, Novartis, Janssen; Research Funding: AbbVie, Roche, Genentech, Gilead, Novartis, Janssen. Fischer, K: Other Remuneration: travel grants by Roche. Stilgenbauer, S: Consultant Advisory Role: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann La-Roche, Janssen, Novartis; Honoraria: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann La-Roche, Janssen, Novartis; Research Funding: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann La-Roche, Janssen, Novartis. Eichhorst, B: Consultant Advisory Role: Janssen, Gilead, Roche, Abbvie, Novartis, Celgene; Honoraria: Roche, Novartis, Gilead, Janssen, Abbvie, Celgene; Research Funding: Roche, Janssen, Abbvie, Gilead. Hallek, M: Consultant Advisory Role: Roche Gilead, Mundipharma, Janssen, Celgene, Pharmacyclics, Boehringer; Honoraria: Roche Gilead, Mundipharma, Janssen, Celgene, Pharmacyclics, Boehringer; Research Funding: Roche, Gilead, Mundipharma, Janssen, Celgene, Pharmacyclics, Abbvie.