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PURPOSE CAPTIVATE ( NCT02910583 ), a randomized phase II study, evaluates minimal residual disease (MRD)-guided treatment discontinuation following completion of first-line ibrutinib plus venetoclax treatment in patients with chronic lymphocytic leukemia (CLL). METHODS Previously untreated CLL patients age < 70 years received three cycles of ibrutinib and then 12 cycles of combined ibrutinib plus venetoclax. Patients in the MRD cohort who met the stringent random assignment criteria for confirmed undetectable MRD (Confirmed uMRD) were randomly assigned 1:1 to double-blind placebo or ibrutinib; patients without Confirmed uMRD (uMRD Not Confirmed) were randomly assigned 1:1 to open-label ibrutinib or ibrutinib plus venetoclax. Primary end point was 1-year disease-free survival (DFS) rate with placebo versus ibrutinib in the Confirmed uMRD population. Secondary end points included response rates, uMRD, and safety. RESULTS One hundred sixty-four patients initiated three cycles of ibrutinib lead-in. After 12 cycles of ibrutinib plus venetoclax, best uMRD response rates were 75% (peripheral blood) and 68% (bone marrow). Patients with Confirmed uMRD were randomly assigned to receive placebo (n = 43) or ibrutinib (n = 43); patients with uMRD Not Confirmed were randomly assigned to ibrutinib (n = 31) or ibrutinib plus venetoclax (n = 32). Median follow-up was 31.3 months. One-year DFS rate was not significantly different between placebo (95%) and ibrutinib (100%; arm difference: 4.7% [95% CI, –1.6 to 10.9]; P = .15) in the Confirmed uMRD population. After ibrutinib lead-in tumor debulking, 36 of 40 patients (90%) with high tumor lysis syndrome risk at baseline shifted to medium or low tumor lysis syndrome risk categories. Adverse events were most frequent during the first 6 months of ibrutinib plus venetoclax and generally decreased over time. CONCLUSION The 1-year DFS rate of 95% in placebo-randomly assigned patients with Confirmed uMRD suggests the potential for fixed-duration treatment with this all-oral, once-daily, chemotherapy-free regimen in first-line CLL.

Background : Ibr is the only once-daily inhibitor of Bruton tyrosine kinase with significant overall survival benefit demonstrated in 2 randomized phase 3 studies in first-line CLL (RESONATE-2; ECOG1912). Both Ibr and Ven, an oral inhibitor of BCL2, are approved in the US for treatment of CLL/SLL. The combination of Ibr + Ven may have synergistic anti-tumor activity given the capacity of Ibr to mobilize CLL cells from protected niches within lymphoid tissue to the blood where they may have greater dependence on BCL2 for survival. Recent clinical studies of Ibr + Ven in patients (pts) with CLL or mantle cell lymphoma show high rates of remission with undetectable minimal residual disease (uMRD) (Jain, NEJM 2018; Hillmen, JCO 2019; Tam, NEJM 2018). CAPTIVATE (PCYC-1142) is a multi-center phase 2 study (NCT02910583) evaluating the combination of Ibr + Ven to achieve deep response, including uMRD, in first-line treatment of CLL/SLL. We present results from the MRD cohort with 12 cycles of Ibr + Ven prior to MRD-guided randomized treatment discontinuation (data not yet available). Methods : Pts aged Results : We enrolled 164 pts (median age 58 y; del(17p) in 16%; del(17p) or TP53 mutation in 20%; del(11q) without del(17p) in 16%; complex karyotype in 19%; unmutated IGHV in 59%; lymph nodes ≥5 cm in 32%). In total, 151 pts (92%) completed Ibr lead-in and all 12 cycles of Ibr + Ven. uMRD was achieved at any time after baseline in 75% of pts (122/163) in PB and 72% (111/155) in BM (Figure). The proportion of pts who had uMRD in PB increased over time from 57% after 6 cycles of combined Ibr + Ven to 68% after 9 cycles and 73% after 12 cycles of Ibr + Ven. The high rates of BM uMRD were consistent across high-risk subgroups, including in pts with del(17p) (75%), del(17p) or TP53 mutation (70%), del(11q) (84%), complex karyotype (83%), and unmutated IGHV status (81%). In pts with uMRD in PB with matched BM samples, 93% had uMRD in both PB and BM. Response by iwCLL criteria was achieved in 97% of pts. With median follow-up of 14.7 mo (range, 0.5-19.9) only 3 pts (2%) had disease progression (1 Richter's transformation during single-agent Ibr lead-in; 1 after discontinuation of Ibr lead-in due to AE; and 1 during treatment with Ibr + Ven) and no pts died. At baseline, 24% of pts were high-risk for Ven-related TLS, which was reduced to 2% after 3 cycles of single-agent Ibr lead-in. One pt met laboratory TLS criteria. Laboratory TLS was reported as an AE in 3 other pts during the first 2 weeks of Ven ramp-up but none met Howard criteria. No pts developed clinical TLS. Mean plasma levels of Ven (area under the curve; AUC) (n=151) was higher when co-administered with ibrutinib compared with historical data for single-agent Ven but was within the AUC range observed in doses previously studied. No change in Ibr AUC (n=112) was observed with concurrent Ven. Median duration of treatment was 14.7 mo (range 0.5-19.9) with Ibr and 12.0 mo (range 0.8-12.7) with Ven. The most common AEs of any grade (in ≥20% of pts) were diarrhea (31%) and arthralgia (22%) during single-agent Ibr, and diarrhea (60%), neutropenia (40%), nausea (34%), upper respiratory tract infection (24%), and fatigue (20%) during Ibr + Ven. Overall, AEs leading to dose reductions occurred in 20% of pts (Ibr: 14%; Ven: 9%). AEs leading to discontinuation were infrequent, occurring in 7% of pts overall (Ibr: 5%; Ven: 4%). Conclusions : First-line treatment with Ibr + Ven represents an all oral, once-daily, chemotherapy-free regimen that provides high rates of uMRD in both PB and BM in pts with CLL. The safety profile of Ibr + Ven was consistent with AEs known for both agents. Results from the MRD-guided randomized treatment discontinuation cohort and Fixed duration cohort of CAPTIVATE await further follow-up, and are expected to provide the evidence to support a time-limited treatment option with a fixed-duration regimen of 12 cycles of Ibr + Ven in pts with CLL. Disclosures Tam: Novartis: Honoraria; Pharmacyclics LLC, an AbbVie company: Honoraria; AbbVie: Honoraria, Research Funding; BeiGene: Honoraria; Janssen: Honoraria, Research Funding; Roche: Honoraria. Siddiqi:Astra Zeneca: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Kite: Research Funding; TG Therapeutics: Research Funding; Celgene: Research Funding; BeiGene: Research Funding; Seattle Genetics: Speakers Bureau; Janssen: Speakers Bureau; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding, Speakers Bureau; Juno: Consultancy, Research Funding. Allan:Bayer: Consultancy; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Consultancy; Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie company: Consultancy; Janssen: Consultancy, Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kipps:Verastem: Membership on an entity's Board of Directors or advisory committees; AstraZeneca, Inc.: Membership on an entity's Board of Directors or advisory committees; Velos-Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen Pharmaceutical Companies of Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Flinn:TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding. Opat:Celgene: Consultancy, Honoraria, Research Funding; Epizyme: Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; Novartis: Consultancy; BMS: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Research Funding; Janssen: 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; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Barr:Astra Zeneca: Consultancy, Research Funding; Verastem: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; AbbVie: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy; Merck: Consultancy; TG Therapeutics: Consultancy, Research Funding; Celgene: Consultancy. Tedeschi:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; BeiGene: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen spa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; SUNESIS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jacobs:AbbVie: Consultancy, Speakers Bureau; JUNO: Consultancy; Gilead: Consultancy; AstraZeneca: Speakers Bureau; TG Therapeutics: Honoraria, Research Funding; Genentech: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Research Funding, Speakers Bureau. Badoux:AbbVie: Honoraria, Other: Travel, Accommodations, Expenses. Ghia:ArQule: Consultancy, Honoraria; Dynamo: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Juno/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Sukbuntherng:Pharmacyclics LLC, an AbbVie Company (self),: Employment; Theras, Inc. (spouse): Employment; AbbVie: Equity Ownership; Global Blood Therapeutics: Equity Ownership; Portola: Equity Ownership. Salem:AbbVie: Employment, Other: Stock/stock options. Russell:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment. Eckert:Pharmacyclics LLC, an AbbVie Company: Employment, Other: Travel, Accommodations, Expenses; AbbVie: Equity Ownership. Zhou:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Ninomoto:Amgen: Equity Ownership; AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment; Celgene: Equity Ownership. James:Pharmacyclics LLC, an AbbVie Company: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; AbbVie: Equity Ownership. Wierda:Cyclcel: Research Funding; KITE pharma: Research Funding; Gilead Sciences: Research Funding; Genentech: Research Funding; Juno Therapeutics: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; Pharmacyclics LLC: Research Funding; Sunesis: Research Funding; Loxo Oncology Inc.: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding; Xencor: Research Funding; Janssen: Research Funding; Acerta Pharma Inc: Research Funding. OffLabel Disclosure: Ibrutinib in combination with venetoclax is not approved in any indication.

The efficacy of ibrutinib has been demonstrated in patients with chronic lymphocytic leukemia (CLL), including as first‐line therapy. However, outcomes after ibrutinib discontinuation have previously been limited to higher‐risk populations with relapsed/refractory (R/R) disease. The objective of this study was to evaluate outcomes of ibrutinib‐treated patients based on prior lines of therapy, including after ibrutinib discontinuation. Data were analyzed from two multicenter phase 3 studies of single‐agent ibrutinib: RESONATE (PCYC‐1112) in patients with R/R CLL and RESONATE‐2 (PCYC‐1115) in patients with treatment‐naive (TN) CLL without del(17p). This integrated analysis included 271 ibrutinib‐treated non‐del(17p) patients with CLL (136 TN and 135 R/R). Median progression‐free survival (PFS) was not reached for subgroups with 0 and 1/2 prior therapies but was 40.6 months for patients with ≥3 therapies (median follow‐up: TN, 36 months; R/R, 44 months). Median overall survival (OS) was not reached in any subgroup. Overall response rate (ORR) was 92% in TN and 92% in R/R, with depth of response increasing over time. Adverse events (AEs) and ibrutinib discontinuation due to AEs were similar between patient groups. Most patients (64%) remain on treatment. OS following discontinuation was 9.3 months in R/R patients (median follow‐up 18 months, n = 51) and was not reached in TN patients (median follow‐up 10 months, n = 30). In this integrated analysis, ibrutinib was associated with favorable PFS and OS, and high ORR regardless of prior therapies in patients with CLL. The best outcomes following ibrutinib discontinuation were for patients receiving ibrutinib in earlier lines of therapy.