Ibrutinib + Obinutuzumab Versus Chlorambucil + Obinutuzumab As First-Line Treatment in Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL): Results from Phase 3 iLLUMINATE

Background: Ibrutinib (ibr), a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the US and EU for patients (pts) with CLL and allows for treatment without chemotherapy. Standard of care for first-line CLL in older pts or those with comorbidities includes single-agent ibr and chemoimmunotherapy (CIT) with chlorambucil (clb) plus anti-CD20 therapy. As the addition of obinutuzumab (G) to clb provides superior efficacy over clb alone or rituximab-G, we investigated the potential for improved efficacy with addition of G to single-agent ibr vs clb-G in an international, open-label, randomized phase 3 study (PCYC-1130; iLLUMINATE) in first-line CLL/SLL.

Methods: Eligible pts had previously untreated CLL/SLL requiring treatment per iwCLL criteria and were ≥65 years of age or were <65 years old with coexisting conditions (Cumulative Illness Rating Scale score >6, creatinine clearance <70 mL/min, and/or del(17p) or TP53 mutation). Pts were randomized 1:1 to receive ibr (420 mg once daily continuously) combined with G (1000 mg on days 1/2, 8, and 15 of cycle 1, and day 1 of subsequent 28-day cycles, for a total of 6 cycles), or clb (0.5 mg/kg on days 1 and 15 of each 28-day cycle for 6 cycles) combined with G (as above). Primary endpoint was progression-free survival (PFS) assessed by independent review committee (IRC). Secondary endpoints included PFS in high-risk population (del(17p)/TP53 mutation, del(11q), and/or unmutated IGHV), rate of undetectable minimal residual disease (MRD), overall response rate (ORR), overall survival (OS), and safety. Pts with IRC-confirmed progression on clb-G could cross over to next-line therapy with single-agent ibr.

Results: A total of 229 pts were randomized to ibr-G (n=113) or clb-G (n=116). Median age was 71 years (range, 40-87) and 65% of pts had high-risk genomic features. At a median follow-up of 31.3 mo, ibr-G significantly prolonged IRC-assessed PFS compared with clb-G (median not reached [NR] vs 19.0 mo; HR 0.231; 95% CI, 0.145-0.367; P<0.0001), with a 77% reduction in risk of progression or death (Figure 1). PFS rates at 30 mo were 79% and 31% with ibr-G and clb-G, respectively. Investigator (INV)-assessed PFS was also significantly improved with ibr-G vs clb-G (median NR vs 21.9 mo; HR 0.260; 95% CI, 0.163 to 0.415; P<0.0001). PFS benefit with ibr-G was consistent across subgroups examined. Superior PFS with ibr-G vs clb-G was also seen in the high-risk population (median NR vs 14.7 mo; HR 0.154; 95% CI, 0.087-0.270; P<0.0001), with an 85% reduction in risk of progression or death in this population (Figure 2). IRC-assessed ORR was 88% with ibr-G vs 73% with clb-G; complete response (CR/CRi) rate was also higher with ibr-G (19% vs 8%). INV-assessed ORR was 91% with ibr-G vs 81% with clb-G; CR/CRi rates were 41% and 16%, respectively. MRD was undetectable in blood and/or bone marrow (<10^-4 by flow cytometry) for 35% of pts with ibr-G and 25% with clb-G. 30-mo OS rates were 86% and 85% in the ibr-G and clb-G arms, respectively, with 40% of pts randomized to clb-G receiving single-agent ibr as second-line therapy. Over a median follow-up of 31.3 mo, 4% in the ibr-G arm and 44% in the clb-G arm initiated subsequent therapy. Median treatment duration was 29.3 mo with ibr-G and 5.1 mo with clb-G. Most common (≥3%) serious adverse events (AEs) were pneumonia (5%), atrial fibrillation (4%), febrile neutropenia (4%), and pyrexia (4%) with ibr-G, and infusion-related reactions (IRRs; 7%), febrile neutropenia (6%), pneumonia (4%), tumor lysis syndrome (4%), and pyrexia (3%) with clb-G. IRRs were less frequent with ibr-G vs clb-G for both any grade (25% vs 58%) or grade ≥3 or serious IRRs (3% vs 9%). No pt discontinued G due to IRRs with ibr-G vs 7 pts (6%) with clb-G. AEs leading to discontinuation of ibr or clb occurred in 18 (16%) and 11 pts (9%), respectively; AEs leading to discontinuation of G occurred in 10 pts (9%) in ibr-G arm and 15 (13%) in clb-G arm. With ~3 yrs of follow-up, 70% of pts in the ibr-G arm remain on single-agent ibr.

Conclusions: Ibr-G resulted in superior PFS regardless of high-risk genomic features, compared with clb-G, a standard CIT regimen. Response rates and depth of remission (CR and undetectable MRD) were also higher with ibr-G. Combination therapy with ibr-G was tolerable with no new safety signals identified and represents an effective chemotherapy-free treatment option for first-line CLL/SLL including the high-risk population.

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