Calquence shows long-term efficacy and tolerability at three years for patients with relapsed or refractory mantle cell lymphoma

ACE-LY-004 Phase II trial results substantiate established efficacy and safety profile of Calquence in mantle cell lymphoma

Long-term follow-up results from the positive ACE-LY-004 Phase II trial showed patients with relapsed or refractory mantle cell lymphoma (MCL) treated with Calquence (acalabrutinib) remained progression free for a median of 22 months, with median overall survival not yet reached at three years of follow-up. The safety and tolerability profile remained consistent.¹ These results were presented at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition on 6 December 2020.

MCL is typically an aggressive, rare form of non-Hodgkin lymphoma (NHL) that accounts for nearly 6% of all NHL cases and is mostly found in males during their early sixties.^2,3

At a median follow up of 38.1 months (range: 0.3-59.5), 55 patients (44%) either remained on treatment (24 patients) or continued to be followed for survival (31 patients). The safety profile remained largely unchanged from the last analysis at 26 months, with only 14 patients (11%) having discontinued treatment due to adverse events (AE).¹

Michael L. Wang, MD, Professor, Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, and principal investigator of the ACE-LY-004 Phase II trial, said: “Mantle cell lymphoma is an aggressive, difficult-to-treat blood cancer that is typically diagnosed at an advanced stage and often becomes resistant to treatment. This data shows that patients treated with acalabrutinib experienced deep responses over time, while the safety profile remained largely the same, including low rates of Grade 3/4 events, cardiac events and bleeding events, which are important in this patient population.”

José Baselga, Executive Vice President, Oncology R&D, said: “These results add to the mounting evidence that Calquence can provide sustained responses in patients over more than three years. Calquence is an important chemo-free treatment option for relapsed or refractory mantle cell lymphoma and is rapidly being embraced across the clinical and patient community.”

Summary of efficacy results¹

Median follow up of 38.1 months (range: 0.3-59.5)

 PR, partial response; CR, complete response; DOR, duration of response; PFS, progression-free survival; DOR was measured in the 101 subjects who achieved a CR or PR

Additionally, an exploratory analysis of 30 patients meeting the criteria for minimal residual disease (MRD) evaluation showed six patients (20%) achieved a complete response and undetectable MRD (uMRD) and maintained uMRD at last assessment.¹

AEs in the trial remained largely unchanged with an additional year of follow up. The most frequent AEs of any grade (greater than or equal to 20% of patients) included headache (39%), diarrhoea (37%), fatigue (30%), cough (23%), myalgia (22%) and nausea (22%), and were primarily Grade 1/2. Grade 3/4 AEs included neutropenia (11%), anaemia (10%) and pneumonia (6%).¹

Overall, 16 patients (13%) had cardiac AEs (11 with prior cardiac risk factors), with three of the 16 cardiac AEs occurring in the last year of follow up (two were Grade 3/4). Overall, six patients (5%) had Grade 3/4 cardiac AEs. One patient had Grade 3/4 hypertension in the last year (total any grade, n=5 [4%]; total Grade 3/4, n=2 [2%]), and five patients had bleeding AEs in the last year (total any grade, n=46 [37%]). Three patients had Grade 3/4 infections in the last year.¹

Initial results from the ACE-LY-004 Phase II trial were presented on 9 December 2017 at the 59th ASH Annual Meeting and Exposition and served as the basis for the first FDA approval of Calquence in adult patients with MCL who have received at least one prior therapy.⁴ Calquence is approved for this indication in many other 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.

Mantle cell lymphoma

Mantle cell lymphoma (MCL) is an uncommon type of B-cell non-Hodgkin lymphoma.⁵ MCL comprises 3% to 6% of non-Hodgkin lymphomas, with an annual incidence of 0.5 per 100,000 population in Western countries; in the US, it was estimated that approximately 3,300 new cases of MCL were diagnosed in 2016.^5,6 The median age at diagnosis is 68 years, with MCL occurring more often in men than women. While MCL patients initially respond to treatment, there is a high relapse rate.⁵

ACE-LY-004

ACE-LY-004 is an open-label, single-arm Phase II clinical trial evaluating Calquence in adult patients with relapsed or refractory MCL.⁷ Adults with MCL and ECOG PS ≤2 who had relapsed or were refractory to 1-5 prior therapies, had no prior BTK/BCL-2 inhibitor exposure, and did not require warfarin/vitamin K antagonists, received oral Calquence 100mg twice-daily until progressive disease or toxicity. Overall response rate (investigator-assessed partial response or better per Lugano classification), duration of response, progression-free survival, overall survival, and safety were assessed. Minimal residual disease was analysed in formalin-fixed, paraffin-embedded samples and peripheral blood by next-generation sequencing (5x10^-6) in patients with available paired samples.¹

Calquence

Calquence (acalabrutinib) is a next-generation, selective inhibitor of Bruton’s tyrosine kinase (BTK). Calquence binds covalently to BTK, thereby inhibiting its activity.^4,8 In B-cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.⁴

Calquence is approved for the treatment of chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma in the US and is approved for CLL in the EU and several other countries worldwide. Calquence is also approved for the treatment of adult patients with MCL who have received at least one prior therapy in the US and several other countries. Calquence is not currently approved for the treatment of MCL in Europe.

As part of an extensive clinical development programme, AstraZeneca and Acerta Pharma are currently evaluating Calquence in more than 20 company-sponsored clinical trials. Calquence is being developed for the treatment of multiple B-cell blood cancers including CLL, MCL, diffuse large B-cell lymphoma, Waldenström’s 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 Company’s haematology franchise includes two medicines approved by the US Food and Drug Administration and a robust global development programme for a broad portfolio of potential blood cancer treatments. Acerta Pharma serves as AstraZeneca’s 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 seven 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.

By harnessing the power of six scientific platforms - Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response, Antibody Drug Conjugates, Epigenetics, and Cell Therapies - 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/Nasdaq: 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 & 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 visit astrazeneca.com and follow the Company on Twitter @AstraZeneca.

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References

1. Wang M, et al. Acalabrutinib Monotherapy in Patients With Relapsed/Refractory Mantle Cell Lymphoma: Long-Term Efficacy and Safety Results From a Phase 2 Study. Abstract #2040 at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition.

2. O’Connor OA and Vose JM. Mantle Cell Lymphoma: Getting the Facts. Lymphoma Research Foundation. Available at: https://lymphoma.org/aboutlymphoma/nhl/mcl/.

3. American Cancer Society. Non Hodgkin Lymphoma. Available at: https://www.cancer.org/cancer/non-hodgkin-lymphoma.html.

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

5. Cheah CY, et al. Mantle cell lymphoma. J Clin Oncol. 10 Apr 2016;34(11):1256-1269. Published online ahead of print on 11 Jan 2016.

6. Teras LR, et al. 2016 US Lymphoid Malignancy Statistics by World Health Organization Subtypes. Ca Cancer J Clin. 2016;66(6):443-459.

7. ClinicalTrials.gov. An Open-label, Phase 2 Study of ACP-196 (Acalabrutinib) in Subjects With Mantle Cell Lymphoma. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02213926.

8. Wu J, et al. Acalabrutinib (ACP-196): a selective second generation BTK inhibitor. J Hematol Oncol. 2016;9(21).