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ACE-CL-001 trial showed an overall response rate of 97% with a sustained safety profile for previously untreated patients after more than four years

In pivotal ASCEND trial, 82% of patients with relapsed or refractory disease treated with Calquence remained progression free at 18 months vs. 48% for comparators

LONDON, UK I June 12, 2020 I Detailed results from both the Phase II ACE-CL-001 trial and the pivotal Phase III ASCEND trial showed the long-term efficacy and tolerability of Calquence (acalabrutinib) in chronic lymphocytic leukaemia (CLL), one of the most common types of adult leukaemia.1,2,3

The results will be presented during the Virtual Edition of the 25th European Hematology Association (EHA) Annual Congress, 11 to 14 June 2020.

In the single-arm ACE-CL-001 trial, 86% of CLL patients treated with Calquence as a 1st-line monotherapy remained on treatment at a median follow up of more than four years. The trial showed an overall response rate of 97% (7% complete response; 90% partial response) and a 100% overall response rate in subgroups of patients with high-risk disease characteristics, including genomic aberrations (17p deletion and TP53 mutation), immunoglobulin mutation status (unmutated IGHV), and complex karyotype. Safety findings showed no new long-term issues.1,4

In the final analysis of ASCEND, an estimated 82% of patients with relapsed or refractory CLL treated with Calquence remained alive and free from disease progression at 18 months compared with 48% of patients on rituximab combined with idelalisib or bendamustine.2 The trial previously met the primary endpoint of Independent Review Committee-assessed progression-free survival at the interim analysis.5

Richard R. Furman, Director of the CLL Research Center, Weill Cornell Medicine said: These data demonstrate no new safety concerns for acalabrutinib, confirming its ability to safely provide meaningful, long-term clinical benefit for patients with treatment-naive and relapsed or refractory disease. The safety profile of acalabrutinib makes treatment to progression an important and plausible option for patients.

Jos Baselga, Executive Vice President, Oncology R&D said: These long-term data reaffirm that Calquence delivers a durable response with a favourable safety profile for chronic lymphocytic leukaemia patients. Patients with chronic lymphocytic leukaemia are typically 70 years or older with comorbidities and often require treatment over a long time, making the sustained safety and efficacy profile highly relevant to their quality of life.

Results from the Phase II ACE-CL-001 trial informed the development of the pivotal Phase III ELEVATE TN trial, which, along with findings from the Phase III ASCEND trial, formed the basis for the US approval of Calquence for the treatment of patients with CLL or small lymphocytic lymphoma (SLL).

Calquence in previously untreated CLL: 4.4-year follow-up from Phase II trial (abstract #S163)

The Phase II ACE-CL-001 trial investigated safety and efficacy of Calquence (100mg twice-daily [n=62] or 200mg once-daily [n=37]) in previously untreated patients with CLL.1 On 1 May 2015, patients receiving the 200mg dosing regimen were switched to the 100mg regimen.1

Key data from the Calquence Phase II ACE-CL-001 trial1

CI, confidence interval; CR, complete response; DoR, duration of response; EFS, event free survival; TTR, time to response; NR, not reached; ORR, overall response rate; PR, partial response

Response rates were 100% in each subgroup of patients with high-risk disease characteristics (unmutated IGHV [n=57], 17p deletion [n=9], TP53 mutation [n=9], and complex karyotype [n=12]), and reduction in lymph node disease was noted in all patients tested (n=97).1

At the time of data cut-off, 85 (86%) patients receiving Calquence remained on treatment. Six patients discontinued treatment due to adverse events (AEs) and three patients discontinued for progressive disease (PD). No patient discontinued Calquence due to bleeding events, hypertension, or atrial fibrillation. Incidence of AEs generally diminished with time on the trial. The most common AEs (40%) of any grade in the trial were diarrhoea (52%), headache (45%), upper respiratory tract infection (44%), arthralgia (42%), and contusion (42%). All-grade and Grade 3 events of clinical interest included infection (84% and 15%, respectively), bleeding events (66%, 3%), hypertension (22%, 11%), leukopenia (9%, 9%), and thrombocytopenia (3%, 1%). Atrial fibrillation (all grades) occurred in 5% of patients with Grade 3 occurring in 2%. Second primary malignancies (SPM) excluding non-melanoma skin (all grades) occurred in 11% of patients.1 Serious adverse events (SAEs) were reported in 38% of patients. SAEs occurring in more than two patients included pneumonia (n=4) and sepsis (n=3).1

Final results of Calquence Phase III ASCEND trial in relapsed or refractory CLL (abstract #S159)

ASCEND was a global, randomised, multicentre, open-label, Phase III trial that investigated the efficacy and safety of Calquence (100mg twice-daily) versus investigators choice of rituximab combined with idelalisib (IdR) or bendamustine (BR) in patients with relapsed or refractory CLL.2

Key data from the final analysis of the Calquence Phase III ASCEND trial2

BR, rituximab in combination with bendamustine; CI, confidence interval, DoR, duration of response; HR, hazard ratio; IdR, rituximab in combination with idelalisib; INV, investigator; NR, not reached; ORR, overall response rate; OS, overall survival; PFS, progression-free survival

Sixteen per cent of patients on Calquence, 56% of patients on IdR, and 17% of patients on BR discontinued treatment because of AEs. Common AEs occurring in greater than 15% of patients of any grade in the Calquence arm of the trial included headache (22%), neutropenia (21%), diarrhoea (20%), upper respiratory tract infection (20%), cough (16%), and anaemia (16%). Events of clinical interest for Calquence versus controls included atrial fibrillation (all grade, 6% and 3%, respectively), major haemorrhage (all grade, 3% in both arms), infections (Grade 3, 20% and 25%, respectively), and SPM excluding non-melanoma skin cancer (all grade, 5% and 2%, respectively). SAEs (any grade) occurred in 33% of patients receiving Calquence, 56% of IdR patients, and 26% of BR patients.2

Chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) is one of the most common types of leukaemia in adults, with an estimated 105,000 new cases globally in 2016 and 21,040 new cases in the US in 2020, and the number of people living with CLL is expected to grow with improved treatment as patients live longer with the disease.3,6,7,8 In CLL, too many blood stem cells in the bone marrow become abnormal lymphocytes and these abnormal cells have difficulty fighting infections.3 As the number of abnormal cells grows there is less room for healthy white blood cells, red blood cells, and platelets.3 This could result in anaemia, infection, and bleeding.3 B-cell receptor signalling through Brutons tyrosine kinase is one of the essential growth pathways for CLL.

Calquence

Calquence(acalabrutinib) is a next-generation, selective inhibitor of Brutons tyrosine kinase (BTK).Calquencebinds covalently to BTK, thereby inhibiting its activity.4,9 In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.4

Calquenceis approved for the treatment of adult patients with chronic lymphocytic leukaemia (CLL) in nine countries and for adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy in 14 countries. The US MCL indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. As part of an extensive clinical development programme, AstraZeneca and Acerta Pharma are currently evaluatingCalquencein 23 company-sponsored clinical trials.Calquenceis being developed for the treatment of multiple B-cell blood cancers including CLL, MCL, diffuse large B-cell lymphoma, Waldenstrm macroglobulinaemia, follicular lymphoma, and other haematologic malignancies.

AstraZeneca in haematology

Leveraging its strength in oncology, AstraZeneca has established haematology as one of four key oncology disease areas of focus. The Companys haematology franchise includes two US FDA-approved medicines and a robust global development programme for a broad portfolio of potential blood cancer treatments. Acerta Pharma serves as AstraZenecas haematology research and development arm. AstraZeneca partners with like-minded science-led companies to advance the discovery and development of therapies to address unmet need.

AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients' lives and the Company's future. With six new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca's main capabilities, the Company is actively pursuing innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms - Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates - and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

AstraZeneca

AstraZeneca (LSE/STO/NYSE: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal and Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visitastrazeneca.comand follow the Company on Twitter@AstraZeneca.

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References

1. Byrd JC, et al. Acalabrutinib in Treatment-Nave Chronic Lymphocytic Leukemia: Mature Results From Phase 2 Study Demonstrating Durable Remissions and Long-Term Tolerability. Abstract S163 presented at the Virtual Edition of the 15th European Hematology Association (EHA) Annual Meeting. Available online. Accessed June 2020.

2. Ghia P, et al. Acalabrutinib (Acala) vs Idelalisib plus Rituximab (IdR) or Bendamustine plus Rituximab (BR) in Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL): ASCEND Final Results. Abstract S159 presented at the Virtual Edition of the 15th European Hematology Association (EHA) Annual Meeting. Available online. Accessed June 2020.

3. National Cancer Institute. Chronic Lymphocytic Leukemia Treatment (PDQ)Patient Version. Available online. Accessed June 2020.

4.Calquence(acalabrutinib) [prescribing information]. Wilmington, DE; AstraZeneca Pharmaceuticals LP; 2019.

5. Ghia P, et al. ASCEND Phase 3 Study of Acalabrutinib vs Investigators Choice of Rituximab Plus Idelalisib (IdR) or Bendamustine (BR) in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL). Abstract LB2606 at the 2019 European Hematology Association (EHA) Annual Meeting. Available online. Accessed June 2020.

6. Global Burden of Disease Cancer Collaboration. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2016. JAMA Oncol. 2018;4(11):1553-1568.

7. American Cancer Society. Key Statistics for Chronic Lymphocytic Leukemia. Available online. Accessed June 2020.

8. Jain N, et al. Prevalence and Economic Burden of Chronic Lymphocytic Leukemia (CLL) in the Era of Oral Targeted Therapies. Blood. 2015;126:871.

9. Wu J, Zhang M & Liu D. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor.J Hematol Oncol. 2016;9(21).

SOURCE: AstraZeneca

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