Fixed-duration Calquence plus venetoclax demonstrated superior PFS vs. standard of care in previously untreated CLL, with 77% of patients progression free at three years in AMPLIFY Phase III trial

Calquence plus venetoclax with obinutuzumab reduced the risk of disease progression or death by 58% versus standard of care in this setting. Calquence plus venetoclax poised to become first all-oral fixed-duration regimen of a second-generation BTK inhibitor plus venetoclax in 1st-line CLL.

Positive results from the AMPLIFY Phase III trial showed AstraZeneca’s Calquence (acalabrutinib) in combination with venetoclax demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to standard-of-care chemoimmunotherapy in previously untreated adult patients with chronic lymphocytic leukaemia (CLL).

These results will be presented at the American Society of Hematology (ASH) 2024 Annual Meeting in San Diego, CA.

At a median follow up of 41 months, results showed Calquence plus venetoclax reduced the risk of disease progression or death by 35% compared to standard-of-care chemoimmunotherapy (hazard ratio [HR] 0.65; 95% confidence interval [CI] 0.49-0.87; p=0.0038). Calquence plus venetoclax with obinutuzumab demonstrated a 58% reduction in the risk of disease progression or death compared to standard-of-care chemoimmunotherapy (HR 0.42; 95% CI 0.30-0.59; p<0.0001). Median PFS was not reached for either experimental arm versus median PFS of 47.6 months for chemoimmunotherapy.

Interim overall survival (OS) data demonstrated a favourable trend which was nominally statistically significant for Calquence plus venetoclax (HR 0.33; 95% CI 0.18-0.56; p<0.0001), however the OS data were immature at the time of this analysis and the trial will continue to assess OS as a key secondary endpoint.

Jennifer R. Brown, MD, PhD, Director of the CLL Center of the Division of Hematologic Malignancies, Dana-Farber Cancer Institute, and the Worthington and Margaret Collette Professor of Medicine at Harvard Medical School, and principal investigator of the trial, said: “Chronic lymphocytic leukaemia is considered an incurable cancer and patients live with the disease and the long-term effects of their treatments for many years. The AMPLIFY results show the promise of a new all-oral fixed-duration therapy approach which would allow patients to take breaks from treatment, reducing the risk of long-term adverse events and drug resistance.”

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “Based on these impressive data from the AMPLIFY trial, Calquence is the only second-generation BTK inhibitor to demonstrate efficacy in the front-line treatment of patients with chronic lymphocytic leukaemia as both a treat-to-progression and a fixed-duration approach. This advance is an important development for patients and their physicians who seek new options and more flexibility in managing this disease in the long term.”  

Both investigational arms demonstrated durable responses, with estimated 36-month PFS rates of 76.5% for Calquence plus venetoclax and 83.1% with the addition of obinutuzumab compared to 66.5% for chemoimmunotherapy. Patients also demonstrated a robust response in both investigational arms with an overall response rate (ORR) of 92.8% for Calquence plus venetoclax and 92.7% with the addition of obinutuzumab, compared to 75.2% for chemoimmunotherapy.

Summary of Results: AMPLIFY

	Calquence plus venetoclax	Calquence plus venetoclax and obinutuzumab	Control arm
Patient population (n)	291	286	290
Median PFS(months)	NR	NR	47.6
PFS HR vs. control (95% CI)	0.65p=0.0038	0.42p<0.0001	Reference
36-month PFS rate	76.5%	83.1%	66.5%
ORR (95% CI)	92.8% (89.4-95.4)p<0.0001	92.7% (89.2-95.3)p<0.0001	75.2% (70.0-79.9)
OS HR vs. control (95% CI)	0.33 (0.18-0.56)p<0.0001	0.76 (0.49-1.18)p=0.2224	Reference

NR=Not reached

Control arm = Investigator’s choice of fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab

The safety and tolerability of Calquence was consistent with its known safety profile, and no new safety signals were identified. Grade 3 or higher adverse events (AEs) occurred in 53.6% of patients treated with Calquence plus venetoclax, 69.4% of patients treated with Calquence plus venetoclax with obinutuzumab and 60.6% for patients treated with standard-of-care chemoimmunotherapy. The most common Grade 3 or higher AE was neutropenia across all arms, seen in 26.8%, 35.2% and 32.4% of patients respectively. There were over twice as many COVID related deaths in the Calquence plus venetoclax with obinutuzumab arm compared with the Calquence plus venetoclax arm.  

Notably, low rates of tumour lysis syndrome (TLS) were observed in both Calquence arms with events of any grade seen in 0.3% of patients treated with Calquence plus venetoclax and 0.4% with the addition of obinutuzumab, compared to 3.1% for patients treated with chemoimmunotherapy. No cases of clinical TLS were observed across Calquence treatment arms.

Calquence has been used to treat more than 85,000 patients worldwide[i] 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.

Notes

Chronic Lymphocytic Leukaemia (CLL)

CLL is the most prevalent type of leukaemia in adults, with over 100,000 new cases globally in 2019.[ii] Although some people with CLL may not experience any symptoms at diagnosis, others may experience symptoms, such as weakness, fatigue, weight loss, chills, fever, night sweats, swollen lymph nodes and abdominal pain.[iii] In CLL, there is an accumulation of abnormal lymphocytes within the blood, bone marrow and lymph nodes. As the number of abnormal cells increases, there is less room within the marrow for the production of normal white blood cells, red blood cells and platelets.[iv] This could result in infection, anaemia and bleeding. B-cell receptor signalling through BTK is one of the essential growth pathways for CLL.

AMPLIFY

AMPLIFY is a randomised, global, multi-centre, open-label Phase III trial evaluating the efficacy and safety of Calquence in combination with venetoclax with and without obinutuzumab compared to investigator's choice of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) in adult patients with previously untreated CLL without del(17p) or TP53 mutation.[v] Patients were randomised 1:1:1 to receive either Calquence plus venetoclax, Calquence  plus venetoclax with obinutuzumab for a fixed duration or standard-of-care chemoimmunotherapy.⁵ Both the Calquence containing arms were administered for a fixed duration of 14 cycles (each 28 days), and the standard-of-care chemoimmunotherapy was for 6 cycles.⁵

The primary endpoint is PFS in the Calquence and venetoclax arm as assessed by an Independent Review Committee and PFS in the Calquence plus venetoclax with obinutuzumab is a key secondary endpoint. Other key secondary endpoints include OS and undetectable measurable residual disease.⁵ The trial includes 27 countries across North and South America, Europe, Asia and Oceania.⁵

The AMPLIFY trial enrolled patients from 2019 to 2021, continuing through the COVID-19 pandemic.⁵ 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.[vi]

Calquence

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

Calquence is also approved in the US, China and several other countries for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Calquence is not currently approved for the treatment of MCL in Japan or the EU.

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 in 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. 

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 in 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.

AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca’s innovative medicines are sold in more than 125 countries and used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on Social Media @AstraZeneca.

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