Single-Agent Ibrutinib Versus Chlorambucil-Obinutuzumab As First-Line Treatment in Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL): Results of a Cross-Trial Comparison
Authors: Tedeschi Alessandra , Greil Richard , Demirkan Fatih , Robak Tadeusz , Moreno Carol , Barr Paul , Anz Bertrand , Simpson David , Gaidano Gianluca , Bairey Osnat , Stevens Don , Gill Devinder , Flinn Ian W. , Kipps Thomas J. , Burger Jan A. , Lin Jennifer , Webb Thomas , Fedorov Viktor , Styles Lori , Gribben John G. 
Published: October 2019

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 or chemoimmunotherapy (CIT) with chlorambucil (clb) plus anti-CD20 therapy. As no data were available from phase 3 studies directly comparing single-agent ibr with CIT, we performed a cross-trial analysis using data from two phase 3 studies to assess single-agent ibr vs clb plus obinutuzumab (G) in first-line CLL.
Methods : In the ongoing PCYC-1115/1116 (RESONATE-2), pts with previously untreated CLL/SLL aged ≥65 years without del(17p) were randomized to receive ibr (420 mg once daily continuously) or clb. In PCYC-1130 (iLLUMINATE), pts with untreated CLL/SLL aged ≥65 years or <65 years with coexisting conditions or del17p/TP53 mutation were randomized to receive ibr plus 6 cycles of G or 6 cycles of clb-G. As pts with del(17p) were ineligible for RESONATE-2, pts with del(17p) in iLLUMINATE were excluded from cross-trial analyses. Primary analysis was investigator (INV)-assessed progression-free survival (PFS) with single-agent ibr in RESONATE-2 vs clb-G in iLLUMINATE; secondary analyses were PFS in the high-risk population (del(11)q, TP53 mutation, or unmutated IGHV), medical resource utilization in the first 6 mo, and safety (including time-matched analysis at 6 mo to account for different treatment durations). Additional exploratory analyses compared single-agent ibr in RESONATE-2 vs ibr-G in iLLUMINATE to evaluate lymphocytosis (≥50% increase in absolute lymphocyte count from baseline and ≥5 × 109/L), and overall response rate (ORR).
Results : Primary analysis included 136 pts treated with single-agent ibr and 98 pts treated with clb-G. Median age was 73 years in both groups. High-risk genomic features were generally well balanced (54% and 58% of pts, respectively), including del(11q) (21% and 22%), TP53 mutations (9% and 5%), and unmutated IGHV (43% and 46%). Bulky disease (≥5 cm) was present in 40% and 37% of pts, respectively. Median follow-up was 48.8 mo for ibr and 31.3 mo for clb-G. Single-agent ibr significantly prolonged PFS compared with clb-G (median not reached [NR] vs 22.2 mo), with an 82% reduction in risk of progression or death (HR 0.184; P<0.0001; Figure 1). PFS rates at 30 mo were 85% vs 40% for ibr vs clb-G. Superior PFS with ibr vs clb-G was also seen in the high-risk population (median NR vs 18.3 mo; HR 0.072; P<0.0001), with a 93% reduction in risk of progression or death. PFS consistently favored ibr over clb-G across all subgroups examined. Median treatment duration was 46.9 mo for ibr and 5.1 mo for clb-G, resulting in an AE collection period that was 9 times longer for ibr. Hospitalizations were similar for ibr vs clb-G (26% vs 28% of pts), while use of blood supportive products (16% vs 20%) or growth factors (6% vs 41%) was lower for ibr. Most common grade ≥3 adverse events (AEs) are in Table 1. During the first 6 mo, AEs led to discontinuation (DC) of ibr in 7% and DC of clb-G in 18% of pts; over the entire AE reporting period, AEs led to DC of ibr in 26%, and DC of clb-G in 18% of pts; (Table 1). With ibr, AEs leading to ibr DC in ≥2 pts were atrial fibrillation (n = 4), palpitations, pneumonia, death, and CLL (n = 2 each). With clb-G, AEs leading to DC of either clb or G in ≥2 pts were infusion-related reaction (n = 6) and neutropenia (n = 4). Exploratory analyses included 136 pts treated with single-agent ibr and 99 pts treated with ibr-G. Median follow-up was 31.3 mo for ibr-G. ORR by INV was similar with ibr vs ibr-G (91% vs 92%), but complete response (CR/CRi) was higher for ibr-G (44% vs 27%; P=0.006). Lymphocytosis occurred in 57% vs 8% of pts with ibr vs ibr-G and resolved in 95% vs 100%; median duration of lymphocytosis was 12.4 vs 3.1 weeks, respectively.
Conclusions : Despite limitations of this cross-trial analysis, results suggest that PFS with single-agent ibr was superior to clb-G, including, importantly, in patients with high-risk genomic characteristics or bulky disease. In a time-matched analysis, AE profile with single-agent ibr appeared favorable to clb-G. In comparing ibr and ibr-G, lymphocytosis was more common with ibr than ibr-G but resolved in almost all pts, and ORR was similar for ibr and ibr-G. While CR rate was higher for ibr-G vs ibr, CR was not needed to achieve long-term PFS benefit with single-agent ibr.

Disclosures
Tedeschi: AbbVie: Consultancy; Gilead: Consultancy; Janssen: Consultancy, Speakers Bureau. Greil:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Honoraria, Research Funding; Roche: 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; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Research Funding. Demirkan:AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding. Robak:Janssen: Consultancy, Honoraria; AbbVie, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria; Gilead: Consultancy. Moreno:AbbVie: Consultancy; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy. Barr:AbbVie, Gilead: Consultancy. Simpson:Acerta: Research Funding; Merck: Honoraria, Research Funding; BeiGene: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Novartis: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; MSD: Honoraria; Pharmacyclics LLC, an AbbVie Company: Research Funding; Roche: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding, TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria, Research Funding. Gaidano:Morphosys: Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Bairey:Jansen: Research Funding; AbbVie: Consultancy; ROCHE: Research Funding. Stevens:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gill:Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau. Flinn:Takeda: Research Funding; Calithera: Research Funding; Agios: Research Funding; Forma: Research Funding; Trillium: Research Funding; Infinity: Research Funding; ArQule: Research Funding; Gilead: Research Funding; TG Therapeutics: Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Verastem: Research Funding; Genentech: Research Funding; Kite: Research Funding; Curis: Research Funding; Portola: Research Funding; Novartis: Research Funding; Verastem: Consultancy, Research Funding; Merck: Research Funding; BeiGene: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Forty Seven: Research Funding; Constellation: Research Funding; Seattle Genetics: Research Funding. Kipps:Verastem: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech Inc: Consultancy, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lin:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Webb:Janssen: Employment; Johnson & Johnson: Equity Ownership. Fedorov:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Styles:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Gribben:TG Therapeutics: Honoraria; Pharmacyclics: Honoraria; NIH: Research Funding; Novartis: Honoraria; Acerta Pharma: Honoraria, Research Funding; Abbvie: Honoraria; Kite: Honoraria; Roche: Honoraria; Unum: Equity Ownership; Wellcome Trust: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Cancer Research UK: Research Funding; Medical Research Council: Research Funding.