Updated results from the ELEVATE-TN Phase III trial showed AstraZeneca’s Calquence (acalabrutinib) maintained a statistically significant progression-free survival (PFS) benefit versus chlorambucil plus obinutuzumab and a safety and tolerability profile consistent with the known profile for Calquence at a median follow up of approximately five years in combination and as a monotherapy in chronic lymphocytic leukaemia (CLL).¹

Results also showed longer overall survival (OS) for Calquence combined with obinutuzumab compared with chlorambucil combined with obinutuzumab in previously untreated adults with CLL.¹ CLL is the most prevalent type of leukaemia in adults, with over 100,000 patients diagnosed globally in 2019.²

At a median follow-up of 58.2 months, Calquence plus obinutuzumab reduced the risk of disease progression or death by 89% (based on a hazard ratio [HR] of 0.11, 95% confidence interval [CI] 0.07-0.16) and as a monotherapy by 79% (based on a HR of 0.21, 95% CI 0.15-0.30), compared with chlorambucil plus obinutuzumab.¹ OS data are immature, and medians were not yet reached in any treatment arm.¹ The relative risk for death was 45% lower in the Calquence plus obinutuzumab arm (based on a HR of 0.55, 95% CI 0.30-0.99).¹ An estimated 90% of patients treated with the Calquence combination were alive at five years versus 84% for Calquence alone and 82% for chlorambucil plus obinutuzumab.¹

Separately, follow-up data from the ASCEND Phase III trial showed Calquence demonstrated a sustained PFS benefit at four years based on investigator assessment compared with investigator’s choice of rituximab combined with either idelalisib (IdR) or bendamustine (BR) in adults with relapsed or refractory CLL.³ At 42 months, an estimated 62% of patients treated with Calquence were alive and had not progressed in comparison with 19% of patients treated with IdR/BR.³ The median follow-up was 46.5 months for Calquence and 45.3 months for IdR/BR.³

The safety and tolerability of Calquence in the ELEVATE-TN and ASCEND trials were consistent with earlier findings, with no new safety signals identified.^1,3

Jeff P. Sharman, MD, Director of Research at Willamette Valley Cancer Institute, Medical Director of Hematology Research for the US Oncology Network, and a lead investigator of the ELEVATE-TN trial, said: “These data from ELEVATE-TN, with nearly five years of follow-up, support what I have seen in clinical practice and provide clinicians with further reassurance when prescribing this therapy. Patients with chronic lymphocytic leukaemia often remain on therapy for many years, so long-term efficacy and tolerability are critical factors that physicians consider when deciding on a treatment plan. These data show that acalabrutinib combined with obinutuzumab helped previously untreated patients live longer compared with chlorambucil plus obinutuzumab and was generally well-tolerated.”

Anas Younes, Senior Vice President, Haematology R&D, AstraZeneca, said: “We are committed to bringing efficacious and safe treatments to patients with haematological diseases. With chronic lymphocytic leukaemia, these two factors are particularly important due to the chronic nature of the disease and the likelihood of patients having comorbidities. The totality of our longer-term data at ASCO show Calquence’s efficacy benefits and sustained safety profile in key treatment settings, providing more options for patients and their physicians.”

The results were presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting on 4 June 2022.

Summary of key efficacy results from the ELEVATE-TN trial¹
Median follow-up of 58.2 months (range: 0.0-72.0)

NR, not reached; ORR, overall response rate
*Investigator-assessed
^†P-values are descriptive and not adjusted for multiplicity

Treatment is ongoing in 65% of patients on Calquence plus obinutuzumab and 60% of patients on Calquence monotherapy.¹ The most common reasons for treatment discontinuation were adverse events (AEs) (17%, 16% and 14% for Calquence plus obinutuzumab, Calquence monotherapy and chlorambucil plus obinutuzumab, respectively) and progressive disease (6%, 10% and 2%, respectively).¹

Median treatment exposures were 58.1 months and 5.5 months, respectively, for Calquence and obinutuzumab in the Calquence combination arm; 58.0 months for Calquence in the monotherapy arm; and 5.5 months and 5.6 months, respectively, for chlorambucil and obinutuzumab in the chlorambucil plus obinutuzumab arm.¹ Selected AEs of interest of any grade in the Calquence combination arm, Calquence monotherapy arm and chlorambucil plus obinutuzumab arm included bleeding (49.4%, 43.6% and 11.8%, respectively), hypertension (9.6%, 8.9% and 3.6%, respectively) and atrial fibrillation (6.2%, 7.3% and 0.6%, respectively).¹ Common AEs (any grade, greater than or equal to 30% of patients) observed with Calquence with or without obinutuzumab included diarrhoea, headache, arthralgia and neutropenia.¹

Summary of key efficacy results from the ASCEND trial³
Median follow-up of 46.5 months for Calquence and 45.3 months for IdR/BR

*Investigator-assessed

Median treatment exposures were 44.2 months for Calquence; 11.5 months and 5.5 months, respectively, for idelalisib and rituximab in the IdR arm; and 5.6 months and 5.5 months, respectively, for bendamustine and rituximab in the BR arm.³ AEs led to treatment discontinuation in 23% of patients in the Calquence arm, 67% of patients in the IdR arm and 17% of patients in the BR arm.³ Events of clinical interest for Calquence versus comparators included atrial fibrillation/flutter (all grade, 8% and 3%, respectively), hypertension (all grade, 8% and 5%, respectively), major haemorrhage (all grade, 3% in both arms) and infections (greater than or equal to grade 3, 29% in both arms).³ Common AEs (any grade, greater than or equal to 15% of patients; or grade 3 or higher, greater than or equal to 5% of patients) observed with Calquence included neutropenia, headache, diarrhoea and upper respiratory tract infection.³

Notes

CLL
CLL is the most prevalent type of leukaemia in adults, with over 100,000 new cases globally in 2019 and an estimated 20,160 new cases in the US in 2022.^2,4 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.⁵

In CLL, too many blood stem cells in the bone marrow become abnormal lymphocytes and these abnormal cells have difficulty fighting infections.⁶ As the number of abnormal cells grows, there is less room for healthy white blood cells, red blood cells and platelets.⁶ This could result in anaemia, infection and bleeding.⁶ B-cell receptor signalling through Bruton’s tyrosine kinase (BTK) is one of the essential growth pathways for CLL.⁶

ELEVATE-TN
ELEVATE-TN (ACE-CL-007) is a randomised, multicentre, open-label Phase III trial evaluating the safety and efficacy of Calquence alone or in combination with obinutuzumab versus chlorambucil in combination with obinutuzumab in previously untreated patients with CLL. In the trial, 535 patients were randomised (1:1:1) into three arms.⁷ Patients in the first arm received chlorambucil in combination with obinutuzumab.⁷ Patients in the second arm received Calquence (100mg twice daily until disease progression) in combination with obinutuzumab.⁷ Patients in the third arm received Calquence monotherapy (100mg twice daily until disease progression).⁷

The primary endpoint was PFS in the Calquence and obinutuzumab arm compared to the chlorambucil and obinutuzumab arm, assessed by an independent review committee (IRC), and a key secondary endpoint was IRC-assessed PFS in the Calquence monotherapy arm compared to the chlorambucil and obinutuzumab arm.⁷ Other secondary endpoints included overall response rate, time to next treatment, OS and investigator assessed PFS.⁷ After interim analysis, assessments were by investigator only.^7,8

Initial results from the ELEVATE-TN Phase III trial were presented in December 2019 at the American Society of Hematology Annual Meeting and Exhibition.⁹ The trial met its primary endpoint (IRC-assessed PFS with Calquence plus obinutuzumab versus chlorambucil plus obinutuzumab) at the data cut-off for the interim analysis after a median follow-up of 28.3 months.⁸ The findings, along with previously reported data from the Phase III ASCEND trial in relapsed or refractory CLL, supported the approvals of Calquence by the US FDA and the Australian Therapeutic Goods Administration for the treatment of adult patients with CLL or small lymphocytic lymphoma (SLL) and by the European Medicines Agency (EMA) and Health Canada for CLL.

ASCEND
ASCEND (ACE-CL-309) is a global, randomised, multicentre, open-label Phase III trial evaluating the efficacy of Calquence in patients with relapsed or refractory CLL.¹⁰

In the trial, 310 patients were randomised (1:1) into two treatment arms.¹⁰ Patients in the first arm received Calquence monotherapy (100mg twice-daily until disease progression or unacceptable toxicity).¹⁰ Patients in the second arm received physician’s choice of either rituximab, a CD20 monoclonal antibody, in combination with idelalisib, a PI3-kinase inhibitor, or rituximab in combination with bendamustine, a chemotherapy.¹⁰

The primary endpoint at the interim analysis was PFS assessed by an IRC, and key secondary endpoints included investigator-assessed PFS, IRC and investigator-assessed overall response rate, and duration of response, as well as overall survival, patient-reported outcomes and time to next treatment.^10,11

ASCEND is the first randomised Phase III trial to directly compare a BTK inhibitor as monotherapy to these combinations in relapsed or refractory CLL.¹¹

Calquence
Calquence (acalabrutinib) is a next-generation, selective inhibitor of BTK. Calquence binds covalently to BTK, thereby inhibiting its activity.^12,13 In B cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis and adhesion.¹³

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. A Phase I trial is currently underway in Japan for the treatment of front-line CLL.

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

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 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.

AstraZeneca in haematology
AstraZeneca is pushing the boundaries of science to redefine care in haematology. We have expanded our commitment to patients with haematologic conditions, not only in oncology but also in rare diseases with the acquisition of Alexion, allowing us to reach more patients with the greatest unmet needs. By applying our deep understanding of blood cancers, leveraging our strength in solid tumour oncology and delivering on Alexion’s pioneering legacy in complement science to provide transformative medicines for rare diseases, we are pursuing the end-to-end development of novel therapies designed to target underlying drivers of disease.

By targeting haematological conditions with high unmet medical needs, we aim to deliver innovative medicines and approaches to improve patient outcomes. Our goal is to transform the lives of patients living with malignant, rare and other related haematologic diseases, shaped by insights from patients, caregivers and physicians to have the most meaningful impact.  

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 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. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± Obinutuzumab vs

Obinutuzumab + Chlorambucil in Treatment-Naïve Chronic Lymphocytic Leukemia: 5-Year Follow-up of ELEVATE-TN [abstract and poster]. Presented at: American Society for Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2022. Abstract ID: 7539.

2. Yao Y, Lin X, Li F, et al. The global burden and attributable risk factors of chronic lymphocytic leukemia in 204 countries and territories from 1990 to 2019: analysis based on the global burden of disease study 2019. Biomed Eng Online. 2022;1: 4. doi: 10.1186/s12938-021-00973-6.

3. Jurczak W, Pluta A, Wach M, et al. Acalabrutinib vs Rituximab Plus Idelalisib or Bendamustine in Relapsed/Refractory Chronic Lymphocytic Leukemia: ASCEND Results at ~4 Years of Follow-up [abstract and poster]. American Society for Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2022. Abstract ID: 7538.

4. National Cancer Institute. Cancer stat facts: leukemia — chronic lymphocytic leukemia (CLL). https://seer.cancer.gov/statfacts/html/clyl.html. Accessed May 2022.

5. American Cancer Society. What is chronic lymphocytic leukemia. https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/about/what-is-cll.html. Accessed May 2022.

6. National Cancer Institute.  Chronic Lymphocytic Leukemia Treatment (PDQ®)–Patient Version. https://www.cancer.gov/types/leukemia/patient/cll-treatment-pdq. Accessed May 2022.

7. ClinicalTrials.gov. ELEVATE CLL TN: Study of Obinutuzumab + Chlorambucil, Acalabrutinib (ACP-196) + Obinutuzumab, and Acalabrutinib in Subjects With Previously Untreated CLL. NCT identifier: NCT02475681. https://clinicaltrials.gov/ct2/show/NCT02475681. Accessed May 2022.

8. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE-TN): a randomized, controlled, phase 3 trial. Lancet. 2020;395:1278-1291. doi:10.1182/blood-2019-128404.

9. Sharman JP, Egyed M, Jurczak W, et al. ELEVATE-TN: Phase 3 Study of Acalabrutinib Combined with Obinutuzumab (O) or Alone vs O Plus Chlorambucil (Clb) in Patients (Pts) With Treatment-Naive Chronic Lymphocytic Leukemia (CLL). Oral presentation at: American Society of Hematology 2019 Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL.

10. ClinicalTrials.gov. A Study of Acalabrutinib vs Investigator's Choice of Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in R/R CLL. NCT identifier: NCT02970318. https://clinicaltrials.gov/ct2/show/NCT02970318. Accessed May 2022.

11. Ghia P, Pluta A, Wach M, et al. Acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia (ASCEND): a randomized phase 3 trial. J Clin Oncol. 2020;25: 2849-2861. doi: 10.1200/JCO.19.03355.

12. CALQUENCE®(acalabrutinib) [prescribing information]. Wilmington, DE; AstraZeneca Pharmaceuticals LP; 2019.14.

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