US FDA Grants Priority Review Status To AstraZeneca’s sNDA for Calquence

US FDA accepts and grants priority review status to AstraZeneca’s sNDA for Calquence to treat patients with untreated MCL

Overview

AstraZeneca’s supplemental New Drug Application (sNDA) for Calquence (acalabrutinib) has been accepted and granted Priority Review in the US for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL).

FDA Priority Review

• The Food and Drug Administration (FDA) grants Priority Review to applications for medicines that, if approved, would offer significant improvements over available options by demonstrating safety or efficacy improvements, preventing serious conditions or enhancing patient compliance. 
• The Prescription Drug User Fee Act date, the FDA action date for their regulatory decision, is anticipated during the first quarter of 2025.

About mantle cell lymphoma

• MCL is a rare and typically aggressive form of non-Hodgkin lymphoma (NHL), resulting when B-lymphocytes mutate into malignant cells within a region of the lymph node known as the mantle zone. 
• The disease is often diagnosed at advanced stages and remains largely incurable. 
• It is estimated that there are more than 27,500 people living with MCL worldwide.

Statement from the AstraZeneca

Susan Galbraith, executive vice president, oncology R&D, AstraZeneca, said: “Today’s Priority Review acceptance reinforces the potential of Calquence to transform outcomes in untreated mantle cell lymphoma. Data from the ECHO trial showed Calquence plus chemoimmunotherapy significantly delayed disease progression and showed a trend to improved survival in patients with this currently incurable blood cancer. We are working closely with the FDA to provide patients this potential new treatment as soon as possible.”

sNDA Review

The sNDA is being reviewed under Project Orbis, an initiative of the FDA which provides a framework for concurrent submission and review of oncology medicines among participating international partners to bring cancer treatments to patients around the world as early as possible.

Result Presentation

• Results from the ECHO phase III trial recently were presented during the late-breaking oral session at the European Haematology Association (EHA) 2024 Hybrid Congress.
• In the trial, Calquence plus bendamustine and rituximab reduced the risk of disease progression or death by 27% compared to standard-of-care (SoC) chemoimmunotherapy (hazard ratio [HR] 0.73; 95% confidence interval [CI] 0.57-0.94; p=0.016). 
• The addition of Calquence to SoC provided almost 1.5 years of additional median progression free survival (mPFS) with mPFS of 66.4 months for patients treated with the Calquence combination versus 49.6 months with SoC.

Overall Survival

• Overall survival (OS) showed a favourable trend for the Calquence combination compared to SoC chemoimmunotherapy (HR 0.86; 95% CI 0.65-1.13; p=0.2743). 
• The OS trend was sustained over time, although most patients in the SoC arm who needed subsequent therapy received a BTK inhibitor, mainly Calquence. 
• The OS data were not mature at the time of this analysis, and the trial will continue to assess OS as a key secondary endpoint.

About ECHO trial: For impact of Covid-19

• The ECHO trial was conducted during the Covid-19 pandemic, and prespecified PFS and OS analyses censoring for Covid-19 deaths were conducted to assess the impact of Covid-19 on the study outcome in alignment with FDA. 
• After censoring for Covid-19 deaths, the PFS was further improved in both arms, with the Calquence combination reducing the risk of disease progression or death by 36% (HR 0.64; 95% CI; 0.48-0.84; p=0.0017). 
• A favourable trend was seen for OS in this analysis for the Calquence combination, but OS data were not mature at the time of this analysis (HR 0.75; 95% CI 0.53-1.04; p=0.0797).
• The safety and tolerability of Calquence was consistent with its known safety profile, and no new safety signals were identified.

Relapse

•  While MCL patients initially respond to treatment, patients do tend to relapse. 
• MCL comprises about 3-6% of non-Hodgkin lymphomas, with an annual incidence of 0.5 per 100,000 population in Western countries; in the US, it is estimated that approximately 4,000 new patients are diagnosed with MCL each year.

ECHO Phase III Trial

• ECHO is a randomised, double-blind, placebo-controlled, multi-centre phase III trial evaluating the efficacy and safety of Calquence plus bendamustine and rituximab compared to SoC chemoimmunotherapy (bendamustine and rituximab) in adult patients at or over 65 years of age (n=635) with previously untreated MCL. 
• Patients were randomised 1:1 to receive either Calquence or placebo administered orally twice per day, continuously, until disease progression or unacceptable toxicity. 
• Additionally, all patients received six 28-day cycles of bendamustine on days 1 and 2 and rituximab on day 1 of each cycle, followed by rituximab maintenance for two years if patients achieved a response after induction therapy.
• Primary endpoint - The primary endpoint is PFS assessed by an Independent Review Committee; other efficacy endpoints include OS, overall response rate (ORR), duration of response (DoR) and time to response (TTR). The trial was conducted in 27 countries across North and South America, Europe, Asia and Oceania.

Trial Enrollment 

• The ECHO trial enrolled patients from May 2017 to March 2023, continuing through the Covid-19 pandemic. 
• Patients with blood cancer remain at a disproportionately high risk of severe outcomes from Covid-19, including hospitalisation and death compared to the general population.

About the Drug: Calquence

• Calquence (acalabrutinib) is a second-generation, selective inhibitor of Bruton’s tyrosine kinase (BTK). 
• Calquence binds covalently to BTK, thereby inhibiting its activity. In B-cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis and adhesion.
• Calquence has been used to treat more than 85,000 patients worldwide and is approved for the treatment of CLL and small lymphocytic lymphoma (SLL) in the US and Japan, approved for CLL in the EU and many other countries worldwide and approved in China for relapsed or refractory CLL and SLL. 
• Calquence is also approved in the US, China 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.

Calquence Study on Multiple B-cell Blood Cancers

As part of an extensive clinical development programme, Calquence is currently being evaluated as a single treatment and in combination with standard-of-care chemoimmunotherapy for patients with multiple B-cell blood cancers, including CLL, MCL, and diffuse large B-cell lymphoma.

AstraZeneca for Haematology

• AstraZeneca is pushing the boundaries of science to redefine care in haematology. 
• Our goal is to help transform the lives of patients living with malignant, rare and other related haematologic diseases through innovative medicines and approaches that are shaped by insights from patients, caregivers and physicians.

Other Works

• In addition to our marketed products, we are spearheading the development of novel therapies designed to target underlying drivers of disease across multiple scientific platforms. 
• Our acquisitions of Alexion, with expertise in rare, non-malignant blood disorders, and Gracell Biotechnologies Inc., pioneers of autologous cell therapies, expand our haematology pipeline and enable us to reach more patients with high unmet needs through the end-to-end discovery, development and delivery of novel therapies.

AstraZeneca: For Oncology

• AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.
• The company's focus is on some of the most challenging cancers. 
• It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.
•  AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

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