Randomized phase 3 trial of ibrutinib/rituximab vs placebo/rituximab in Waldenström's macroglobulinemia.

8003 Background: Single-agent ibrutinib (ibr) is highly active in relapsed Waldenström’s Macroglobulinemia (WM) and is approved in the US and EU for WM. We report the results of a multinational, prospective, randomized trial of ibr/rituximab (IR) vs placebo/rituximab (R) in WM at a preplanned interim analysis. Methods: Pts with confirmed symptomatic WM were randomized to daily ibr (420 mg) or placebo, both with R (375 mg/m2/wk IV for infusions at wks 1-4 and 17-20). Pts treated with a prior R-based regimen required a response (≥MR) to the last R therapy. The primary endpoint was PFS by IRC. We also report response rates, Hb improvement, TTnT, OS, and safety. Results: For 150 randomized pts, median age was 69 y; 38% had a high IPSSWM; 45% were treatment-naïve. MYD88L265P and CXCR4WHIM mutations were found in 85% and 36% of 136 pts with available data. At median follow-up of 26.5 mo, IR prolonged PFS compared with R (median PFS, not reached [NR] vs 20 mo; HR, 0.20; CI: 0.11-0.38, P < 0.0001); 30-mo PFS rates were 82% vs 28%. PFS improved in all relevant subgroups, including treatment-naïve (HR, 0.34; CI: 0.12-0.95), relapsed (HR, 0.17; CI: 0.08-0.36), MYD88L265P/CXCR4WT (HR, 0.17; CI: 0.06-0.49), MYD88L265P/CXCR4WHIM (HR, 0.24; CI: 0.09-0.66), and MYD88WT/CXCR4WT (HR, 0.21; CI: 0.04-1.1). Overall (≥MR) and major (≥PR) response rates by IRC were higher for IR vs R, 92% vs 47% and 72% vs 32% (both P < 0.0001). Improvements in Hb were seen in 73% vs 41% of IR and R patients (P < 0.0001). 75% of IR pts continued on treatment. Median TTnT was NR for IR and 18 mo for R (HR, 0.096; P < 0.0001). The 30-mo OS rates were 94% vs 92% in the 2 arms. With median time on treatment of 25.8 mo for IR, grade ≥3 treatment-emergent AEs occurred in 60% vs 61% of pts on each arm. Serious AEs occurred in 43% vs 33% of pts on IR vs R, whereas no fatal AEs occurred with IR and 3 with R. Meaningful reductions in any grade IgM flare (8% vs 47%) and grade ≥3 infusion reactions were observed (1% vs 16%) with IR. Conclusions: The IR combination demonstrated superior efficacy to R, producing significant improvements in PFS for all WM patients regardless of prognostic or genotypic factors with a predictable toxicity profile. IR should be considered a standard therapeutic option for patients with WM. Clinical trial information: NCT02165397.