Four-Year Analysis of Murano Study Confirms Sustained Benefit of Time-Limited Venetoclax-Rituximab (VenR) in Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)
Authors: Seymour John F. , Kipps Thomas J. , Eichhorst Barbara F. , Hillmen Peter , D'Rozario James , Assouline Sarit , Owen Carolyn , Robak Tadeusz , de la Serna Javier , Jaeger Ulrich , Cartron Guillaume , Montillo Marco , Lamanna Nicole , Kim Su Young , Wu Jenny , Jiang Yanwen , Wang Jue , Lefebure Marcus , Boyer Michelle , Humphrey Kathryn , Kater Arnon P 
Published: February 2020

Introduction: Venetoclax (Ven) is a highly selective oral inhibitor of key apoptosis regulator BCL-2, which is overexpressed in CLL. MURANO (a randomized Phase III study) compared fixed-duration VenR with standard bendamustine-rituximab (BR) in R/R CLL. The superior progression-free survival (PFS) of VenR versus BR was established in the first pre-planned analysis (Seymour et al. N Engl J Med 2018); continued PFS benefit was seen with longer follow-up and after all patients (pts) had completed therapy (Kater et al. J Clin Oncol 2019). We now present data from a further analysis (median follow-up 48 months) when all pts had been off Ven treatment for median 22 months.
Methods: As previously published, pts were randomized to 6 cycles of VenR then Ven 400mg once daily for 2 years in total, or 6 cycles of BR. PFS status was based on investigator assessment. Central analysis of minimal residual disease (MRD) status in peripheral blood (PB) was performed at Cycle 4, end of combination treatment (EOCT) then every 3-6 months. Pts were categorized as undetectable MRD (uMRD; &lt;1 CLL cell/10,000 leukocytes [&lt;10-4]), low-MRD (≥10-4 - &lt;10-2), or high-MRD (≥10-2) status. All p-values are descriptive. Safety data collected for the current analysis period were pre-specified adverse events (AEs) of concern, serious AEs (SAEs) related to study drug, and development of a second primary malignancy.
Results: 389 pts were enrolled: VenR (n=194), BR (n=195). At data cutoff (May 8, 2019), all pts were off treatment and with a median follow-up from enrolment of 48 months.
With a median follow-up period of 22 months since Ven completion (1-35 months), the PFS benefit of VenR over BR was sustained (HR, 0.19 [95% CI 0.14, 0.25]; p&lt;0.0001; Figure 1). The 4-year PFS estimates were 57.3% (95% CI 49.4, 65.3) versus 4.6% (95% CI, 0.1, 9.2), respectively. For the pts who completed 2 years of Ven (n=130), the 18- and 24-month post-treatment cessation PFS estimates were 75.5% (95% CI 67.4, 83.7) and 68.0% (95% CI 57.6, 78.4), respectively. Thirty-five of 130 pts had developed progressive disease (PD, defined by International Workshop on Chronic Lymphocytic Leukemia criteria) after completion of Ven.
Sustained overall survival (OS) benefit was demonstrated with VenR over BR (HR, 0.41 [95% CI 0.26, 0.65]; p&lt;0.0001; 4-year rate: 85.3% vs 66.8%; Figure 2). This OS benefit was seen despite 103/142 (73%) BR pts receiving treatment after progression; 81/103 (79%) pts in the BR arm received novel targeted agents (Bruton tyrosine kinase inhibitors [BTKis; n=60], PI3K inhibitors [PI3Kis; n=9], BH3-only mimetics [n=10] or investigational medicinal products [IMPs; n=2]). The response rate to novel targeted agents in the BR arm was 47/81 (58%; Figure 3). Forty-two of 64 (66%) pts in the VenR arm received anti-CLL therapy after PD. Of these, 28 received novel targeted therapies (BTKis, n=12; PI3Kis, n=1; BH3-only mimetics, n=14; IMPs, n=1) and the response rate to these treatments was 9/28 (32%; Figure 3). Fourteen of the VenR arm pts with PD subsequently received Ven or were re-treated with VenR, producing an overall response rate of 2/14 (14%); 10/14 pts (71%) were without an evaluable or available response. Updated response data for these pts will be presented.
In both treatment arms, the previously reported association between uMRD in PB at the EOCT response visit with improved PFS was maintained with this extended follow-up (Figure 4A). In the VenR cohort, improved PFS was observed for pts who were uMRD at end of treatment (EOT; Figure 4B). Among VenR pts who had detectable PB MRD at the EOCT response visit and at EOT, low-MRD pts continued to show improved PFS versus high-MRD pts.
There were no new SAEs considered related to study drug. Excluding non-melanoma skin malignancies, 3 second primary malignancies were detected (1 who received BR [melanoma] and 2 who received VenR [melanoma and breast cancer]) since the previous update. There were no new reported events of Richter's transformation.
Conclusions: Four-year data from MURANO demonstrate sustained PFS and OS benefits with VenR versus BR. 24-month post-treatment cessation PFS was 68.0% in pts completing 2 years of Ven, and pts who attained PB uMRD showed particularly durable responses. These follow-up data provide further support for the application of time-limited VenR in R/R CLL.

Disclosures
Seymour: Celgene: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy; Acerta: Consultancy; Janssen: Consultancy, Research Funding. Kipps:Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, 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; 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; AstraZeneca, Inc.: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees. Eichhorst:ArQule: Membership on an entity's Board of Directors or advisory committees; BeiGene: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Hillmen:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; Apellis: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees. D'Rozario:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees. Assouline:Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau. Owen:AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Teva: Honoraria; Merck: Honoraria; Acerta: Research Funding. Robak:Takeda: Consultancy, Research Funding; UCB: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grant, Research Funding; Amgen: Consultancy, Other: Travel grant; Roche: Consultancy, Other: Travel grant, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel grant, Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Acerta: Research Funding; Morphosys AG: Research Funding. de la Serna:Roche, AbbVie, Janssen, Gilead: Speakers Bureau; Roche, AbbVie, Gilead, Janssen, Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jaeger:Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees. Cartron:Sanofi, Gilead, Janssen, Roche, Celgene: Honoraria; Roche, Celgene: Consultancy. Montillo:Versatem: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Acerta: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding. Lamanna:Celgene: Consultancy; Infinity/ Verastem: Research Funding; Ming: Research Funding; TG Therapeutics: Research Funding; Oncternal: Research Funding. Kim:AbbVie: Employment, Other: Stock or options. Wu:Genentech, Inc.: Employment, Equity Ownership, Other: Stock options. Jiang:F. Hoffman-La Roche: Equity Ownership; Genentech: Employment, Equity Ownership. Wang:Genentech, Inc.: Employment; Roche: Equity Ownership. Lefebure:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Boyer:F. Hoffmann-La Roche Ltd: Employment. Humphrey:F. Hoffmann-La Roche Ltd: Employment. Kater:Genentech: Research Funding; Roche: Other: Travel funding, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding.