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

Abstract

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. Disclosures Moreno: Janssen: Consultancy; AbbVie: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy. Greil:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Honoraria, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Demirkan:Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Janssen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding. Tedeschi:Gilead: Consultancy; AbbVie: Consultancy; Janssen: Consultancy, Speakers Bureau. Larratt:Alexion Pharmaceuticals, Inc.: Honoraria, Research Funding. Simkovic:Roche/Genentech: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Novak:Amgen: Consultancy; Takeda: Consultancy; Roche: Consultancy; Celgene: Consultancy; Pfizer: Consultancy. Strugov:Beigene Ltd: Equity Ownership; Kite Pharma: Equity Ownership; Portola Pharmaceuticals Inc: Equity Ownership; Juno Therapeutics: Equity Ownership; TG Therapeutics Inc: Equity Ownership; Loxo Oncology Inc: Equity Ownership; Crispr Therapeutics AG: Equity Ownership; Intellia Therapeutics Inc: Equity Ownership; Editas Medicine Inc.: Equity Ownership; Ignyta Inc.: Equity Ownership; Astellas: Honoraria; AbbVie: Equity Ownership, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES; Janssen: Honoraria; ECO-SAFETY Medical Center: Employment; Aptose Biosciences Inc: Equity Ownership; Esperion Therapeutics Inc: Equity Ownership; Merck & Company: Other: TRAVEL, ACCOMODATIONS, EXPENSES. Gill:Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau. Gribben:Roche: Honoraria; Abbvie: Honoraria; Kite: Honoraria; NIH: Research Funding; Wellcome Trust: Research Funding; Unum: Equity Ownership; Pharmacyclics: Honoraria; Acerta Pharma: Honoraria, Research Funding; Novartis: Honoraria; TG Therapeutics: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Cancer Research UK: Research Funding; Medical Research Council: Research Funding. Hsu:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Zhou:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Clow:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment, Other: LEADERSHIP; TRAVEL, ACCOMODATIONS, EXPENSES. James:AbbVie: Equity Ownership, Other: Spouse's employment and stocks, Patents & Royalties: AbbVie Patent Applications; Pharmacyclics LLC, an AbbVie Company: Employment. Styles:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Flinn:Genentech: Research Funding; Pharmacyclics: Research Funding; Trillium: Research Funding; Curis: Research Funding; Agios: Research Funding; Forty Seven: Research Funding; Kite: Research Funding; Janssen: Research Funding; ArQule: Research Funding; Gilead: Research Funding; Calithera: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Research Funding; Verastem: Research Funding; Celgene: Research Funding; Infinity: Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Forma: Research Funding; BeiGene: Research Funding; Merck: Research Funding; Portola: Research Funding.

Single-agent ibrutinib in RESONATE-2™ and RESONATE™ versus treatments in the real-world PHEDRA databases for patients with chronic lymphocytic leukemia

“…In the E1912 trial of young (≤ 70 years of age), fit patients with TN CLL, ibrutinib combined with rituximab led to superior PFS and OS compared with FCR [20], whereas in the ALLIANCE A014202 trial of fit, older patients (≥ 65 years of age), first-line treatment with single-agent ibrutinib or ibrutinib + rituximab significantly prolonged PFS compared with BR [21]. Further, in the iLLUMINATE study of patients with CLL and ≥ 65 years of age (or younger but with comorbidities), a chemotherapy-free regimen of ibrutinib + obinutuzumab improved PFS, response rates, and depth of remission compared with chlorambucil + obinutuzumab chemoimmunotherapy, irrespective of the presence of high-risk genomic features [22]. These RCT findings are likely to be practice changing in the TN setting.…”

“…In randomized registration trials of patients with CLL, ibrutinib significantly improved progression-free survival (PFS) and overall survival (OS) versus chlorambucil in TN patients (RESONATE-2™; NCT01722487) [13] and versus ofatumumab in R/R patients (RESONATE™; NCT01578707) [14]. Additional head-to-head clinical trial comparisons of ibrutinib-based regimens versus other widely used treatments (including current standard-of-care chemoimmunotherapy regimens and other novel regimens incorporated into CLL guidelines [15–17]) are ongoing [18, 19], and recent results from multiple phase 3 trials have been positive [data available as abstracts] [20–22].…”

Geriatric Hematology Research presented at the 2018 American Society of Hematology Annual Meeting: Young International Society of Geriatric Oncology Perspective Paper

“…There were no difference between arms; the mean score for Activities of Daily Living (ADL) was 13.7 (possible range 0-14; higher is better), mean score for Instrumental ADL was 79.7 (possible range 0-100; higher is better), 9.7% had ≥1 falls in the last 6 months, 5.4% screened positive for cognitive impairment (using the Blessed Orientation Memory Concentration Test), and 23.9% had N5% weight loss in the last 6 months. In another phase 3 trial, iLLUMINATE, presented by Moreno et al, the combination of ibrutinibobinutuzumab was superior to chlorambucil-obinutuzumab in patients aged ≥65 years, or b 65 years with pre-existing conditions (median age 71 years) [11]. PFS with ibrutinibobinutuzumab was not reached compared to 19 months with chlorambucil-obinutuzumab [HR 0.23, p < .0001), with similar toxicity profiles.…”

Ibrutinib in the treatment of chronic lymphocytic leukemia: 5 years on

“…In contrast, the rate of grade 3, 4, or 5 nonhematological AEs was lower in the BR arm (63%) than with the ibrutinib-containing regimens (74% for IR or ibrutinib alone). An industry-sponsored study, the phase 3 iLLUMINATE trial, indicated that the combination of ibrutinib and obinutuzumab provided a 77% reduction in the risk of progression or death compared to chlorambucil and obinutuzumab 10,11 (Table 1).…”