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Venetoclax, a potent B-cell lymphoma-2 (BCL-2) inhibitor, has demonstrated clinical efficacy in chronic lymphocytic leukemia (CLL). VENICE II is an open-label, single-arm, phase 3b study (NCT02980731) evaluating the impact of venetoclax monotherapy (400 mg once daily) for ≤2 years on health-related quality of life (HRQoL) of patients with relapsed/refractory CLL. The primary endpoint was mean change in the global health status (GHS)/quality of life (QoL) subscale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) from baseline to Week 48. Overall, 210 patients received ≥1 dose of venetoclax; median treatment duration was 67.4 weeks. The primary endpoint was met with mean improvement of +9.3 points (n = 156, 95% confidence interval 6.1-12.5; p=.004) in GHS/QoL. At Week 48, clinically meaningful improvements were observed for role functioning, fatigue, and insomnia domains of EORTC QLQ-C30, suggesting venetoclax monotherapy has a positive impact on HRQoL. No new safety signals were reported.

Background: The combination of venetoclax (Ven), a selective oral B-cell lymphoma-2 inhibitor, and obinutuzumab (Obi), a type II anti-CD20 monoclonal antibody, is approved as a 12-cycle fixed duration treatment for adult patients (pts) with previously untreated chronic lymphocytic leukemia (CLL). In the CLL14 study, pts with CLL and coexisting conditions treated with Ven-Obi achieved high rates of undetectable minimal residual disease (uMRD), translating into a 4-year progression free survival (PFS) of 74%. Despite these favorable results, disease relapse may occur after cessation of the fixed duration therapy, particularly for those with higher risk genetics, such as TP53 aberrancy and unmutated IgHV. A key unanswered question in the field is, for pts who initially had a clinical response after first-line (1L) Ven-Obi treatment, how much clinical benefit would they receive from retreatment with Ven-Obi after developing progressive disease (PD)? Retreatment with Ven-Obi would provide a line of treatment in addition to other regimens such as BTK inhibitors. In patients with relapsed/refractory (R/R) CLL, one of the current standard therapies is the combination of Ven and rituximab (R). Updated results from the phase 3 MURANO trial of 24-cycle fixed duration Ven-R demonstrated that patients with disease progression after treatment completion and clinical response had a best overall response rate (ORR) of 72.2% upon Ven-R retreatment. The results of the MURANO study and the favorable safety profile of Ven-Obi suggest that retreatment with Ven-Obi after initial therapy with Ven-Obi may be effective in pts with relapsed CLL. The present study is the first prospective clinical trial to evaluate the efficacy and safety of retreatment with Ven-Obi at the time of PD in pts who had initially responded to 1L Ven-Obi for at least 12 months (mo) after completing therapy. Study Design and Methods: Pts are eligible for this multicenter, open-label, non-randomized, phase 2 study (NCT04895436) if they have a diagnosis of CLL according to iwCLL criteria, were treated with Ven-Obi fixed duration therapy, and achieved a best response of either complete remission (CR), CR with incomplete marrow recovery (CRi), nodular partial remission (nPR), or partial remission (PR). Pts must also have had at least 12 mo of remission between the last dose of Ven and PD. Pts will be divided into two cohorts: PD more than 2 years after completing 1L treatment (Co-1), and pts with PD between 1-2 years post 1L therapy (Co-2). Pts receive Obi (100 mg intravenously [IV] on Day [D] 1 and additional 900mg on either D1 or D2, then 1000mg on D8 and D15 of Cycle [C] 1 and subsequently on D1C2-6). Ven is administered orally once daily (QD) beginning on C1D22, including a 5-week ramp-up period (weekly dose increases from 20, 50, 100, 200, to 400mg QD), followed by 400mg QD thereafter on 28-day cycles, for a total of 12 or 24 cycles in Co-1 and Co-2, respectively. Pts in Co-2 with detectable MRD (≥10 -4) after 15 months of therapy may continue Ven monotherapy beyond mo 24 at the investigator's discretion. The primary objective is to assess the efficacy of Ven-Obi in Co-1 as measured by ORR, defined as a proportion of pts achieving a best response of PR/nPR or CR/CRi at the end of combination therapy (EOCT) assessment (EOCT + 3 mo). Key secondary objectives are CR/CRi at EOCT, CR/CRi rate at end of therapy (EOT), ORR at EOT, time to response (TTR), duration of response (DOR), PFS, overall survival (OS), time to next treatment (TTNT), and uMRD (10 -4)rate at EOCT and EOT. Safety endpoints include the type, frequency, and severity of treatment-emergent adverse events (AEs), and serious AEs. Prespecified exploratory biomarker endpoints include MRD kinetics up to 12 mo post-treatment, and correlations of baseline characteristics of IgHV, TP53 mutation, and del (17p) status with outcomes. Point and interval estimates will be used to characterize the efficacy of Ven-Obi retreatment; exact binomial (Clopper-Pearson) 95% confidence intervals will be provided alongside the corresponding point estimates for the response rates of interest (ORR, CR rate, and uMRD rate), while Kaplan-Meier methodology will be used to summarize the time-to-event endpoints (DOR, PFS, OS, and TTNT). Finally, descriptive statistical summaries will be reported for several patient-reported outcome (PRO) measures, including the EORTC QLQ-CLL-17, EQ-5D-5L, and FACIT-F. Figure 1 Figure 1. Disclosures Davids: Takeda: Consultancy; Novartis: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Consultancy; Merck: Consultancy; MEI Pharma: Consultancy; Adaptive Biotechnologies: Consultancy; Pharmacyclics: Consultancy, Research Funding; Research to Practice: Consultancy; Ascentage Pharma: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Surface Oncology: Research Funding; Astra-Zeneca: Consultancy, Research Funding; Eli Lilly and Company: Consultancy; Genentech: Consultancy, Research Funding; Celgene: Consultancy; MEI Pharma: Consultancy, Research Funding; BeiGene: Consultancy; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding. Fischer: Abbvie: Honoraria; Roche: Honoraria, Other: Travel Grants. Porro Lurà: F. Hoffmann - La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Sinai: AbbVie Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Chyla: AbbVie: Current Employment, Current equity holder in publicly-traded company. Sail: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Pesko: AbbVie: Current Employment, Current equity holder in publicly-traded company. Pai: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Komlosi: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Hallek: Roche: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Mundipharma: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Speakers Bureau. Brown: Beigene: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Eli Lilly and Company: Consultancy; Nextcea: Consultancy; Genentech/Roche: Consultancy; Bristol-Myers Squib/Juno/Celegene: Consultancy; Novartis: Consultancy; Morphosys AG: Consultancy; MEI Pharma: Consultancy; Acerta/Astra-Zeneca: Consultancy; Abbvie: Consultancy; Invectys: Other: Data Safety Monitoring Committee Service; TG Therapeutics: Research Funding; Sun: Research Funding; SecuraBio: Research Funding; Loxo/Lilly: Research Funding; Gilead: Research Funding; Rigel: Consultancy; Catapult: Consultancy. Al-Sawaf: AbbVie: Honoraria, Research Funding; Adaptive: Honoraria; AstraZeneca: Honoraria; Beigene: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding. OffLabel Disclosure: Venetoclax is a B-cell lymphoma 2 inhibitor approved in combination with Obinutuzumab, a type II anti-CD20 monoclonal antibody, for first-line therapy for chronic lymphocytic leukemia.

INTRODUCTION: Patients with chronic lymphocytic leukemia (CLL) have significantly decreased health related quality of life (HRQoL), particularly related to severe and progressive fatigue. Side effects of chemotherapies and the emotional burden of living with an often poor prognosis disease also negatively impact patient HRQoL. Venetoclax, an oral agent that targets the anti-apoptotic protein BCL2, has demonstrated high rates of deep and durable response in patients with relapsed/refractory (R/R) CLL, including those with 17p deletions, and has been shown to facilitate clinically relevant improvement in several key aspects of functioning and HRQoL. We evaluated the impact of venetoclax monotherapy on the quality of life of patients with R/R CLL. METHODS: VENICE II is an ongoing open-label, phase 3b, multicenter study (NCT02980731) that assessed patient-reported HRQoL in patients who were ≥18 years old with R/R CLL, including those with 17p deletion, TP53 mutations, and/or prior experience with B-cell receptor pathway inhibitor-containing (BCRi) therapy, treated with venetoclax monotherapy (5-week dose-titration, starting at 20mg once daily, then increased weekly to 50 mg, 100 mg, 200 mg, and 400 mg, followed by 400mg once daily). The primary endpoint was the mean change from baseline to Week 48 in the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) subscale. HRQoL subscales analyzed included: Global Health Status, Role Functioning, Emotional Functioning, Cognitive Functioning, Social Functioning, and Fatigue. The impact on QoL was also assessed on the CLL Module (EORTC QLQ-CLL16). Relevance of mean changes in HRQoL measures from baseline were analyzed based on minimum important difference (MID); a 5-10 point change was defined as MID, and >10 points was considered clinically meaningful.(Osoba, D., et al. J Clin Oncol. 1998;16:139-44. Osoba, D., et al. Qual Life Res. 1994;3:353-64.) Safety and adverse events (AEs) were also monitored. RESULTS: As of the data cutoff, April 30, 2018, the median time on study was 28 weeks (range: 1 - 73) and the median time on therapy was 23 weeks (range: 0.1 - 69) in this ongoing study. Of the 169 treated patients, 70% were male; the median age was 65 years (range: 24 - 86). Among those with available data, 17p deletions and TP53 mutations were confirmed in 34% (41/122) and 38% (19/50) of patients, respectively. Overall, 38%, 20%, and 42% of patients had one, two, and three (or more) prior lines of therapy respectively; 21% of patients had prior BCRi therapy. Clinically meaningful improvements from baseline were observed by week 12 and were sustained through week 48 in the EORTC-QLQ-C30 global health status and the role function, social function, and fatigue subscales (Table and Figure 1A) and EORTC-QLQ-CLL16 future health and disease effect subscales (Table and Figure 1B). Eighty-two percent of patients had at least 1 AE; most commonly observed AEs (≥10% of patients) were neutropenia (35%), diarrhea (17%), thrombocytopenia (15%), anemia (12%), nausea (12%), and upper respiratory infection (11%). Twenty-eight percent of patients had a serious AE, of which the most common were pneumonia (5%), febrile neutropenia (4%) and pyrexia (3%). Five percent of patients discontinued the study due to an AE. CONCLUSIONS: Preliminary data from this ongoing study suggest that patients with R/R CLL experienced improvement in several key aspects of functioning and quality of life with venetoclax monotherapy within the first 12 weeks which is sustained over time. Venetoclax monotherapy was well tolerated in R/R CLL patients. These findings are consistent with previous studies of R/R CLL patients who received venetoclax monotherapy. Disclosures Cochrane: Janssen: Membership on an entity's Board of Directors or advisory committees; Cilag: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Calgene: Honoraria; Amgen: Honoraria; Novartis: Honoraria; MSD: Honoraria. Robak:AbbVie, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy. Yeh:GNT Biotech & Medicals Crop.: Research Funding. Nikitin:AbbVie, Inc: Speakers Bureau. Breuleux:Roche: Employment, Equity Ownership; Gilead: Equity Ownership; Basilea: Patents & Royalties; Novartis: Patents & Royalties. Masud:AbbVie, Inc: Employment, Equity Ownership. Sail:AbbVie, Inc: Employment, Equity Ownership. Komlosi:AbbVie, Inc: Employment, Equity Ownership. Anderson:Walter and Eliza Hall: Employment, Patents & Royalties; AbbVie, Inc: Research Funding; Genentech: Research Funding.