AstraZeneca's Calquence (acalabrutinib), a next generation, selective Bruton's tyrosine kinase (BTK) inhibitor, has been conditionally approved in China for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. This is the first approved indication for Calquence in China.

The conditional approval by the National Medical Products Administration (NMPA) was based on positive results from two clinical trials, including the ACE-LY-004 global Phase II trial in adults with relapsed or refractory MCL and a Phase I/ II trial in Chinese patients with relapsed or refractory MCL and other B-cell malignancies.[1,2] Continued approval for this indication may be contingent upon verification of ongoing randomised controlled confirmatory trials.

MCL is typically an aggressive, rare form of non-Hodgkin lymphoma (NHL) that accounts for between 2-6% of all patients diagnosed with NHL in China. Patients are generally diagnosed around 60 years of age, often at later stages of the disease.[3]

Jun Zhu, Chief Physician, Department of Lymphatic Oncology, Peking University Cancer Hospital, Beijing, said: "Mantle cell lymphoma progresses rapidly and responds poorly to conventional treatment such as immunochemotherapy. Before the emergence of BTK inhibitors, there were few satisfactory treatment options for patients. The next-generation BTK inhibitor Calquence has higher target selectivity, fewer side effects, and a higher response rate compared to currently available treatments. This approval of Calquence in China can provide a new treatment option which can better benefit patients with this disease."

Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: "This approval for Calquence offers people living with mantle cell lymphoma in China an effective and tolerable new treatment option to help control their disease. As the first approval in China for Calquence, it is also an exciting step forward for AstraZeneca in blood cancers, enabling us to help more patients across the globe gain access to innovative treatments."

Results from the ACE-LY-004 Phase II trial showed at a median follow up of 15.2 months, investigator-assessed overall response rate (ORR) with Calquence was 80.6% (95% confidence interval [CI] 72.6-87.2), with a complete response (CR) achieved in 39.5% of patients with relapsed or refractory MCL (95% CI 30.9-48.7).[1] Longer-term follow-up data showed at 38.1 months, patients treated with Calquence remained progression-free for a median of 22 months, with median overall survival (OS) of 59.2 months (95% CI 36.5-NE).[4]

Additionally, results from a Phase I/II trial conducted in China showed Calquence achieved a 82.4% ORR, with a CR achieved in 35.3% of patients with MCL based on a blinded independent central-review (BICR) analysis (95% CI 65.5-93.2). Calquence reduced the risk of disease progression or death by 51.5% (95% CI 33.3-67.0) at 12 months, with an estimated duration of response (DOR) of 65.5% (95% CI 66.6-93.3). The median DOR was not reached.[2]

The safety and tolerability of Calquence in these trials was consistent with that observed in previous clinical trials.[1,2,4]

Calquence is approved (https://www.astrazeneca.com/media-centre/press-releases/2019/calquence-approved-in-the-us-for-adult-patients-with-chronic-lymphocytic-leukaemia-21112019.html) for the treatment of chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL) in the US and Japan and is approved (https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2020/calquence-approved-in-the-eu-for-cll.html) for the treatment of CLL in the EU and in several other countries worldwide in the treatment-naïve and relapsed or refractory settings. Calquence is also approved in the US and several other countries for the treatment of adult patients with MCL who have received at least one prior therapy. Calquence is not currently approved for the treatment of MCL in Japan or the EU.

Notes

Mantle cell lymphoma (MCL)
MCL is a rare B-cell malignancy subtype and is typically clinically aggressive with a poor prognosis.[3] The epidemiology of MCL in Asia is not well documented, with few published datasets describing the incidence and outcomes.[3] MCL accounts for between 2-6% of all patients diagnosed with NHL China.[3] Patients are generally diagnosed around 60 years of age and often at later stages of disease (Stage III or IV).[3]

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.[5] Patients in the trial were adults with MCL and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 or lower 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. Patients received oral Calquence 100mg twice-daily until progressive disease or toxicity. ORR (investigator-assessed partial response or better per Lugano classification), DOR, progression-free survival (PFS), OS and safety were assessed.[1]

Phase I/II trial in Chinese patients
The Phase I/II trial is an open-label, multicentre clinical trial evaluating pharmacokinetics, safety and efficacy of Calquence in adult Chinese patients with relapsed or refractory MCL and other advanced B-cell malignancies.[2] In Phase I, patients with relapsed or refractory B-cell malignancies received a single dose of Calquence 100mg orally followed by a two-day washout period and subsequent treatment with Calquence 100mg orally twice daily in 28-day cycles, until progressive disease (PD) or treatment discontinuation (TD) for any other reason. In Phase II, patients with relapsed or refractory MCL and ECOG status of 2 or lower received Calquence 100mg orally twice daily in 28-day cycles until PD or TD. The primary efficacy endpoint was ORR per Lugano classification for NHL assessed by BICR. Secondary endpoints were investigator-assessed ORR, BICR- and investigator-assessed time to response, DOR, PFS, OS and adverse events.[ 2]

Calquence
Calquence (acalabrutinib) is a next-generation, selective inhibitor of BTK. Calquence binds covalently to BTK, thereby inhibiting its activity.[6] In B cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis and adhesion.

Calquence is approved for the treatment of CLL and SLL in the US, approved for CLL in the EU and many other countries worldwide and approved in Japan for relapsed or refractory CLL and SLL.

As part of an extensive clinical development programme, AstraZeneca is currently evaluating Calquence in more than 20 company-sponsored clinical trials. Calquence is being evaluated for the treatment of multiple B-cell blood cancers, including CLL, MCL, diffuse large B-cell lymphoma, Waldenström's macroglobulinaemia, marginal zone lymphoma and other haematologic malignancies.

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References

1. Wang M, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2017;391(10121):659-667.

2. Zhu J, et al. Pharmacokinetics, safety, and efficacy of acalabrutinib in Chinese patients with relapsed/refractory mantle cell lymphoma and other b-cell malignancies: an open-label, multicenter phase 1/2 trial. Blood. 2022;(140): 6496-6497

3. Yoon DH, et al. Treatment of mantle cell lymphoma in Asia: a consensus paper from the Asian Lymphoma Study Group. JHematol Oncol. 2020;13(1):21.

4. Wang M, et al. Acalabrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma: final results from a phase 2 study. Hematol Oncol. 2021;(39):213-216.

5. 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. Accessed March 2023.

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