AbbVie announces phase III data showing VENCLYXTO®▼(venetoclax) in combination with rituximab improves progression-free survival in previously treated chronic lymphocytic leukaemia

• Phase III MURANO results presented for the first time as one of six late breaking abstracts during the 59th American Society of Hematology (ASH) Annual Meeting in Atlanta 
• Prolonged progression-free survival (PFS) of 84.9 percent estimated at 24 months with venetoclax and rituximab, compared to 36.3 percent with bendamustine and rituximab1 
• Regulatory submissions to health authorities based on MURANO results are now underway for this chemotherapy-free combination 

Maidenhead, UK, Thursday 14 December 2017 – AbbVie has announced the first efficacy and safety results from MURANO, a pivotal phase III study of venetoclax in combination with rituximab compared with bendamustine in combination with rituximab, in patients with relapsed or refractory (R/R) CLL. The MURANO results were presented as one of only six late breaking abstracts during the 59th American Society of Hematology (ASH) Annual Meeting in Atlanta. Venetoclax is being developed by AbbVie and Roche. It is commercialised by AbbVie outside of the U.S. and jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. 

The data confirmed that the study had met its primary endpoint and that patients with R/R CLL achieved significantly prolonged median progression-free survival (PFS) with a fixed duration of treatment with venetoclax in combination with rituximab [median PFS, not reached], compared with bendamustine in combination with rituximab [median PFS, 17.0 months; hazard ratio, 0.17; 95% CI, 0.11–0.25; P<0.0001].1 Twenty-four month PFS estimates were 84.9 percent and 36.3 percent, respectively. 1

Additionally, consistent improvement in PFS was observed across the patient subgroups assessed in the trial, including patients with a specific gene mutation known as 17p deletion [hazard ratio 0.14; 95% CI, 0.06–0.33]. 1 At the time of the interim analysis, safety data were consistent with the known safety profiles of the medicines.1

Secondary endpoints included Independent Review Committee (IRC) assessed PFS, as well as PFS in patients with 17p deletion, best overall response (defined as complete response [CR], complete response with incomplete marrow recovery [CRi], nodular partial response [nPR], or partial response [PR]), overall survival (OS), event-free survival, duration of response, time to next anti-CLL treatment, and percentage of patients achieving minimal residual disease (MRD)-negativity.2 As of May 8 2017, median follow-up was 23.8 months (range, 0-37.4 months).1 

Dr Peter Hillmen, Professor of Experimental Haematology and Honorary Consultant Haematologist at Leeds Teaching Hospitals NHS Trust, commented: “The MURANO study clearly demonstrates that the combination of venetoclax with rituximab shows greater efficacy than our best chemotherapy based treatment in relapsed CLL. These data are a critical step forward in our development of new combinations, such as venetoclax with rituximab, which have the potential to extend the survival of patients with CLL compared to conventional treatment. Notably, patients in the venetoclax andrituximab group showed significantly higher rates of MRD negativity, meaning that the leukaemic cells are undetectable with very sensitive tests in the blood or bone marrow following treatment. In relapsed patients MRD negativity is currently rarely achieved with chemotherapy-containing regimens, which have considerable toxicity, and is not seen in patients treated with B-cell receptor inhibitors. More research is needed but we are encouraged by the early findings as our goal is to drive disease to such low levels that patients’ have the potential to remain symptom and cancer-free as long as possible, and ultimately indefinitely.” 

Dr Adrian Bloor, Consultant Haematologist, The Christie NHS Foundation Trust, Manchester, said: “While advances in CLL treatments over the past few years have improved outcomes for patients, those who experience progression or a relapse can still be very challenging to treat. Venetoclax has already been shown to be an effective single line therapy option, but these early data from the MURANO study suggest that in combination with rituximab it offers significant improvements in survival time in relapsed or refractory patients compared to the current combination regime. A number of patients also achieved MRD negativity in the peripheral blood and bone marrow. This is an important prognostic marker associated with superior, ongoing progression-free survival and overall survival in CLL patients.” 

David Innes, Chairman of CLL Support Association UK commented on the research: “The MURANO data is welcome news for patients with progressive or relapsing forms of CLL, who have limited treatment options available. The new combination was shown to offer patients an improved chance of survival compared to current combination therapy as well as reducing the debilitating effects of the disease, such as fatigue and infection, which can severely affect patients’ quality of life. We look forward to further findings from this promising research.” 

Alice Butler, Medical Director at AbbVie, added: “We are delighted to share the first interim results from the MURANO study which was one of only six late breaking abstracts to be featured at this year’s ASH meeting. In patients with relapsed and refractory CLL we found a significant improvement in patients living with the disease but without their disease worsening in the venetoclax plus rituximab group versus the bendamustine plus rituximab group. These early results are encouraging and we remain committed to gathering more clinical data.” 

CLL is a cancer of the blood and bone marrow and is the most common form of adult leukaemia with almost 3,500 people affected in the UK each year.3,4 For those patients living with CLL requiring treatment, the majority will eventually have their disease recur.5 One in two patients failing current treatments can face survival as short as three months.6,7 For people with CLL who develop or harbour gene mutations, such as 17p deletion and/or TP53 mutation, treatment is particularly challenging and these are associated with poorer quality of life and a median life expectancy of less than two to three years with current standard-of-care regimens.8,9 

– Ends –

▼Adverse events should be reported. This medicinal product is subject to additional monitoring and it is therefore important to report any suspected adverse events related to this medicinal product. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to AbbVie UK Ltd. Please contact ukadverseevents@abbvie.com.

Editors’ Notes 

Additional information about the MURANO study

A total of 389 patients with R/R CLL who had received one to three prior therapies were enrolled in this international, multicentre, open-label, randomised Phase III MURANO study. 1 The study was designed to evaluate the efficacy and safety of venetoclax in combination with rituximab (194 patients; median age, 64.5 years) compared with bendamustine in combination with rituximab (195 patients; median age, 66.0 years).1 

For patients receiving venetoclax in combination with rituximab, a 4-week or 5-week dose ramp-up of venetoclax from 20 to 400 mg daily was used. Beginning at week 6, intravenous (IV) rituximab was given monthly for six 28-day cycles (375 mg/m2 first dose, then 500 mg/m2 ).1 

Patients continued with venetoclax 400 mg for a maximum of two years or until disease progression.1 For patients receiving bendamustine in combination with rituximab, patients were given bendamustine (70 mg/m2 IV) on days 1 and 2 of each of six 28-day cycles in combination with rituximab using the same dosing schedule.1 

Study results1 - see attached PDF

About VENCLYXTO® 

(venetoclax) Venetoclax is an oral B-cell lymphoma-2 (BCL-2) inhibitor that targets a specific protein in the body called BCL-2.11 When you have CLL, BCL-2 may build up and prevent cancer cells from self-destructing naturally.11 Venetoclax, which is given once daily, targets BCL-2 in order to help restore the process of apoptosis (or programmed cell death). 8 Through apoptosis, your body allows cancer cells and normal cells to self-destruct.12 Venetoclax is being developed by AbbVie and Roche. It is jointly commercialised by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research with venetoclax, which is currently being evaluated in clinical trials in several haematologic cancers.1,2,13,14,15,16

Venetoclax is currently approved in 49 countries, including the US, and across the EU. Venetoclax is indicated in the UK as a monotherapy for the treatment of CLL in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor; and for the treatment of CLL in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.8 For venetoclax’s Summary of Product Characteristics, please visit. https://www.medicines.org.uk/emc/medicine/32650.

REFERENCES 

1 American Society of Hematology 59th Annual Meeting and Exposition; December 9-12, 2017; Atlanta, GA. (2017). LBA-2 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. https://ash.confex.com/ash/2017/webprogram/Paper109076.html. Accessed December 2017. 

2 Clinicaltrials.gov. NCT02005471: A Study of Venetoclax in Combination With Rituximab Compared With Bendamustine in Combination With Rituximab in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia 

3 Macmillan. What is Chronic Lymphocytic Leukaemia. Available at: http://www.macmillan.org.uk/informationand-support/leukaemia/chronic-lymphocytic/understanding-cancer/about-cll.html. Last accessed December 2017. 

4 Cancer Research UK. Chronic lymphocytic leukaemia (CLL) statistics. Available at: http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/leukaemiacll/incidence#heading-Zero. Last accessed December 2017. 

5 American Cancer Society. (2013) Leukemia – Chronic Lymphocytic. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003111-pdf.pdf. Last accessed July 2017.

6 Jain PW et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood. 2015; 125: 2062-2067. 

7 Follows G. Outcomes for UK CLL patients post ibrutinib therapy. UK CLL Forum poster presented at BSH. 2017. 

8 Schnaiter A, et al. 17p deletion in chronic lymphocytic leukemia: risk stratification and therapeutic approach. Hematol Oncol Clin N Am. 2013; 27:289-301 

9 Stilgenbauer S, et al. Understanding and managing ultra high-risk chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2010; 1:481-488. 

10 American Society of Hematology 2017 Annual Meeting and Exposition. MURANO Study Interim Analysis Results. Presentation. December 12, 2017. 

11 Venclyxto (venetoclax) Summary of Product Characteristics. https://www.medicines.org.uk/emc/medicine/32650. Last accessed: December 2017 

12 Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 5th edition. New York: Garland Science; 2002. Programmed Cell Death (Apoptosis) Available from: http://www.ncbi.nlm.nih.gov/books/NBK26873/ 

13 Clinicaltrials.gov. NCT01994837: A Phase 2 Study of ABT-199 in subjects with Acute Myelogenous Leukemia (AML). Accessed December 2017 

14 Clinicaltrials.gov. NCT01794520: Study evaluating ABT-199 in subjects with relapsed or refractory Multiple Myeloma. Accessed December 2017 

15 Clinicaltrials.gov. NCT01328626: A Phase 1 study evaluating the safety and pharmacokinetics of ABT-199 in subjects with relapsed or refractory Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma. Accessed December 2017 

16 Clinicaltrials.gov. NCT01889186: A study of the efficacy of ABT-199 in subjects with relapsed or refractory chronic lymphocytic leukemia with the 17p deletion. Accessed December 2017

AXONC171790 Date of prep: December 2017