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Venetoclax Plus Rituximab Is Superior to Bendamustine Plus Rituximab in Patients with Relapsed/ Refractory Chronic Lymphocytic Leukemia - Results from Pre-Planned Interim Analysis of the Randomized Phase 3 Murano Study

John F Seymour, Thomas J. Kipps, Barbara F. Eichhorst, Peter Hillmen, James M. D'Rozario, Sarit Assouline, Carolyn Jane Owen, John Gerecitano, Tadeusz Robak, Javier De la Serna, Ulrich Jaeger, Guillaume Cartron, Marco Montillo, Rod Humerickhouse, Elizabeth Punnoose, Yan Li, Michelle Boyer, Kathryn Humphrey, Mehrdad Mobasher and Arnon P. Kater

Abstract

Introduction

Venetoclax (V), an orally administered, highly selective, potent BCL-2 inhibitor, induces high ORR when given as monotherapy to pts with relapsed/refractory (R/R) CLL, including high-risk populations, e.g. del(17p). V is also well tolerated when combined with rituximab (R) and achieves improved CR rates and minimal residual disease negativity (MRD-). Here, we provide first released data from the primary analysis of MURANO (NCT02005471), the first Phase 3 study of V in pts with R/R CLL, which assessed efficacy/safety of VR vs standard chemoimmunotherapy, bendamustine (B) + rituximab (BR).

Methods

Eligibility for this open-label, randomized, Phase 3 study included R/R CLL requiring treatment (iwCLL guidelines), 1-3 prior lines of therapy (including ≥1 chemo-containing) and ECOG PS ≤1. Prior B was allowed provided response duration was ≥24 mo. Pts were randomized (1:1) to VR or BR. Stratification factors were del(17p), responsiveness to prior therapy and geographic region.

In the VR arm, a 4- or 5-wk graduated dose ramp-up of V from 20-400 mg daily was used to mitigate potential tumor lysis syndrome (TLS) risk. Beginning at Wk 6, R was then given monthly for six 28-day cycles (IV 375 mg/m2 first dose, then 500 mg/m2) in combination with V daily. Pts continued with V 400 mg for a maximum of 2 yr or until disease progression (whichever first). In the BR arm, pts were given B (IV 70 mg/m2) on Days 1 and 2 of each of six 28-day cycles in combination with R using same R dosing schedule. MRD was centrally assessed by ASO-PCR and/or flow cytometry in peripheral blood at screening, Mo. 4 and 9, and 3-monthly follow-up visits.

The primary endpoint was investigator (INV)-assessed PFS. An interim analysis was preplanned at ~140 INV-assessed PFS events. On data review, an Independent Data Monitoring Committee recommended study arms to be unblinded to the sponsor as pre-specified statistical boundaries for early stopping were crossed for PFS in favor of VR.

Results

389 pts were enrolled in VR (n=194) and BR (n=195) arms, which were well balanced: median (range) age, 64.5 (28-83) vs 66.0 (22-85) yr; 1 prior therapy, 57.2% vs 60.0%; fludarabine refractory, 14.1% vs 15.5%; del(17p), 26.6% vs 27.2%. At data cut-off (8 May 2017; median follow-up, 23.8 mo. [range 0.0-37.4]), INV-assessed PFS was superior for VR vs BR with HR 0.17, 95% CI 0.11-0.25, P<0.0001; median not reached vs 17.0 mo. (Fig 1). 24-mo. PFS estimates were 84.9% vs 36.3%, respectively. Consistent treatment effects on PFS were observed in all subgroups assessed (Fig 2). With HR 0.19, 95% CI 0.13-0.28, P<0.0001, Independent Review Committee-assessed PFS showed a similar magnitude of benefit. Key secondary efficacy endpoints showed consistent improvements for VR vs BR including a notable improvement in OS (HR 0.48, 95% CI 0.25-0.90). INV-assessed ORR was 93.3% with VR vs 67.7% with BR (Δ=25.6%, 95% CI 17.9-33.3%); CR/CRi was achieved in 26.8% vs 8.2% of pts, respectively (Table 1). Higher peripheral blood MRD- rates attained at any time were seen with VR vs BR (83.5% vs 23.1%; Δ=60.4%, 95% CI 52.3-68.6%) by ITT analysis. MRD negativity was more durable in the VR arm.

Consistent with known safety profiles of the regimens, Grade 3-4 neutropenia was higher in VR arm but there was no increase in febrile neutropenia or Grade 3-4 infection (Table 2). There were 6 (3.1 %) and 2 (1.1%) Grade ≥3 AEs of TLS reported for VR and BR, respectively; one clinical TLS event in each arm (a Grade 4 acute renal failure in BR, transient increase in creatinine in VR; VR event occurred on an earlier 4-week ramp-up schedule). Richter transformation was confirmed in 6 pts and 5 pts for VR vs BR, respectively. AEs leading to death were seen in 5.2% vs 5.9% of pts. Median relative V dose intensity was 97% of protocol-specified drug exposure.

Conclusion

The primary analysis of MURANO, the first Phase 3 study of V in R/R CLL, shows a profound improvement in PFS vs standard BR chemoimmunotherapy, with consistent effects in all-risk subsets. Key secondary endpoints, including OS, ORR and CR rate, also showed consistent improvements with remarkable rates of peripheral blood MRD- that exceed those previously attained in treatment of R/R CLL. This enhanced disease control was achieved in a multinational setting with an acceptable safety profile, without significant TLS, demonstrating that treatment with VR resulted in outcomes superior to that of BR for pts with R/R CLL.

Disclosures Seymour: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kipps: Celgene: Consultancy; Oncternal: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Eichhorst: Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Hillmen: Celgene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. D'Rozario: Roche: Consultancy. Assouline: Lundbeck: Other: Advisory Board; Paladin: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myer Squibb: Speakers Bureau; Roche Canada: Consultancy. Owen: AstraZeneca: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Lundbeck: Honoraria; Roche: Honoraria; Merck: Honoraria. Gerecitano: Merck: Consultancy; Mass Medical International: Consultancy; Incyte: Consultancy; Arcus Medica: Consultancy; Aratana: Consultancy; Bayer: Consultancy; Genentech: Consultancy; Samus Therapeutics: Consultancy; Abbvie: Consultancy; Gilead: Consultancy; Orexo: Consultancy. Robak: AbbVie: Honoraria, Research Funding; Akari Therapeutics Plc: Honoraria, Research Funding; Roche: Honoraria, Research Funding. De la Serna: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jaeger: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; Amgen: Honoraria; AOP Orphan: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; GSK: Honoraria; Infinity: Honoraria; Millennium: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Bioverativ: Honoraria, Research Funding. Cartron: Gilead: Honoraria; Janssen: Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria. Montillo: Novartis: Honoraria; Roche: Research Funding; Abbvie: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Humerickhouse: AbbVie: Employment, Equity Ownership. Punnoose: Genentech: Employment. Li: Genentech: Employment. Boyer: Roche: Employment. Humphrey: F-Hoffmann-La Roche: Employment, Equity Ownership. Mobasher: Roche: Equity Ownership; Genentech: Employment. Kater: Roche: Consultancy; Acerta/Astra Zeneca: Consultancy, Research Funding; Roche/Genentech: Research Funding; Abbvie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Research Funding; Sandoz: Consultancy.

  • * Asterisk with author names denotes non-ASH members.