First and solely BTK inhibitor to display favorable general survival pattern vs. standard-of-care chemoimmunotherapy on this setting

WILMINGTON, Del.–(BUSINESS WIRE)–Optimistic outcomes from the ECHO Section III trial confirmed AstraZeneca (NASDAQ:)’s CALQUENCE ® (acalabrutinib) together with bendamustine and rituximab demonstrated a statistically important and clinically significant enchancment in progression-free survival (PFS) and confirmed a positive pattern in general survival (OS) in comparison with standard-of-care chemoimmunotherapy (bendamustine plus rituximab) in beforehand untreated sufferers with mantle cell lymphoma (MCL).

These outcomes have been offered at the moment in a late-breaking oral presentation on the European Hematology Affiliation (EHA) 2024 Hybrid Congress in Madrid, Spain (#LBA3439).

Outcomes confirmed the CALQUENCE mixture routine decreased the chance of illness development or dying by 27% in comparison with standard-of-care chemoimmunotherapy (hazard ratio [HR] 0.73; 95% confidence interval [CI] 0.57-0.94; p=0.016). Median PFS was 66.4 months for sufferers handled with the CALQUENCE mixture (n=299) versus 49.6 months with standard-of-care chemoimmunotherapy (n=299).

The secondary endpoint of OS confirmed a positive pattern for the CALQUENCE mixture in comparison with standard-of-care chemoimmunotherapy, additional supporting the medical good thing about this mixture (HR 0.86; 95% CI 0.65-1.13; p=0.2743). The OS knowledge weren’t mature on the time of this analysis and the trial will proceed to evaluate OS as a key secondary endpoint.

The ECHO trial enrolled in the course of the pandemic interval, and a pre-specified analysis censoring for COVID-19-related deaths was carried out to evaluate the influence. PFS was additional improved in each arms, with the CALQUENCE mixture lowering the chance of illness development or dying by 36% (HR 0.64; 95% CI 0.48-0.84; p=0.0017). Median PFS was not reached amongst sufferers handled with the CALQUENCE mixture versus 61.6 months for standard-of-care chemoimmunotherapy (HR 0.64; 95% CI 0.48-0.84; p=0.0017). A good pattern was seen for OS on this analysis for the CALQUENCE mixture (HR 0.75; 95% CI 0.53-1.04; p=0.0797).

Michael Wang, MD, Puddin Clarke Endowed Professor, Director of Mantle Cell Lymphoma Program of Excellence, Co-Director of Scientific Trials at MD Anderson Most cancers Heart in Houston, US and principal investigator within the trial, stated: For folks dwelling with mantle cell lymphoma, a sometimes aggressive type of non-Hodgkin’s lymphoma, the ECHO outcomes provide promise of a brand new, efficient therapy choice for adults older than 65, who characterize the vast majority of MCL sufferers. The improved progression-free survival seen in sufferers handled with the CALQUENCE mixture in comparison with chemoimmunotherapy display its potential to vary the usual of care as the one BTK inhibitor on this first-line setting.

Susan Galbraith, Govt Vice President, Oncology R&D, AstraZeneca, stated: The ECHO trial knowledge display necessary progress in enhancing outcomes for sufferers with mantle cell lymphoma. The 16.8 months of extra time sufferers can reside with out their illness progressing is extremely clinically significant, along with a pattern to enchancment in general survival. We due to this fact imagine CALQUENCE plus chemoimmunotherapy might be an necessary new choice for sufferers dwelling with this illness.

Abstract of Outcomes: ECHO

The protection and tolerability of CALQUENCE was in line with its recognized security profile, and no new security alerts have been recognized. Grade 3 or greater hostile occasions (AEs) because of any trigger occurred in 88.9% (n=264) of sufferers handled with the CALQUENCE mixture and 88.2% (n=262) of sufferers handled with standard-of-care chemoimmunotherapy, together with Grade 3 or greater atrial fibrillation in 3.7% (n=11) and 1.7% (n=5) of sufferers, Grade 3 or greater hypertension in 5.4% (n=16) and eight.4% (n=25), Grade 3 or greater main bleeding in 2.0% (n=6) and three.4% (n=10), and Grade 3 or greater infections in 41.1% (n=122) and 34.0% (n=101), respectively. Critical AEs and Grade 5 occasions have been balanced throughout arms (69% [n=205] versus 62% [n=184], and 12.1% [n=36] versus 10.1% [n=30], respectively). AEs resulting in discontinuation have been noticed in 10.4% (n=31) and 6.4% (n=19) of sufferers for the CALQUENCE mixture and placebo arms respectively. AEs associated to COVID-19 have been seen within the trial, together with Grade 5 occasions which occurred in 9.4% (n=28) of sufferers handled with the CALQUENCE mixture and 6.7% (n=20) of sufferers handled with standard-of-care chemoimmunotherapy.

Further AstraZeneca knowledge at EHA

Along with these compelling knowledge, AstraZeneca knowledge at EHA 2024 reveals how the Firm is advancing a various and revolutionary pipeline spanning a number of modalities together with next-generation T cell engagers, cell remedy and antibody drug conjugates, to allow the creation of novel mixture regimens throughout a variety of blood cancers.

Outcomes from the continuing Section I, dose-escalation trial of AZD0486, a novel CD19xCD3 T cell engager, confirmed sturdy responses in sufferers with closely pretreated relapsed/refractory follicular lymphoma with a median observe up of 11 months. Full response charges of 84% have been seen at doses of AZD0486 of two.4 mg and above. Knowledge additionally confirmed how cytokine launch syndrome (CRS) occasions have been successfully mitigated by the double step-up dosing schedule and no immune effector cell-associated neurotoxicity syndrome (ICANS) occasions have been noticed.

In an oral presentation, preliminary knowledge was shared from an investigator-initiated trial of AstraZeneca’s first hematology cell remedy, GC012F (AZD0120), in sufferers with transplant-eligible high-risk, newly identified a number of myeloma. Early outcomes confirmed that GC012F had an general response fee of 100%, a minimal residual disease-negative stringent full response fee of 95%, and was effectively tolerated. Grade 1-2 CRS was skilled by 27% (6/22) of sufferers and no ICANS or neurotoxicity was noticed. GC012F is a novel BCMAxCD19 dual-targeting autologous chimeric antigen receptor T remedy (CAR-T) created utilizing the next-day FasTCAR manufacturing platform pioneered by Gracell Biotechnologies, a completely owned subsidiary of AstraZeneca.

INDICATIONS AND USAGE

CALQUENCE is a Bruton tyrosine kinase (BTK) inhibitor indicated for the therapy of grownup sufferers with mantle cell lymphoma (MCL) who’ve obtained no less than one prior remedy.

This indication is authorised below accelerated approval based mostly on general response fee. Continued approval for this indication could also be contingent upon verification and outline of medical profit in confirmatory trials.

CALQUENCE can also be indicated for the therapy of grownup sufferers with persistent lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

IMPORTANT SAFETY INFORMATION ABOUT CALQUENCE ® (acalabrutinib) tablets

Critical and Opportunistic Infections

Deadly and critical infections, together with opportunistic infections, have occurred in sufferers with hematologic malignancies handled with CALQUENCE.

Critical or Grade 3 or greater infections (bacterial, viral, or fungal) occurred in 19% of 1029 sufferers uncovered to CALQUENCE in medical trials, most frequently because of respiratory tract infections (11% of all sufferers, together with pneumonia in 6%). These infections predominantly occurred within the absence of Grade 3 or 4 neutropenia, with neutropenic an infection reported in 1.9% of all sufferers. Opportunistic infections in recipients of CALQUENCE have included, however are usually not restricted to, hepatitis B virus reactivation, fungal pneumonia, Pneumocystis jirovecii pneumonia, Epstein-Barr virus reactivation, cytomegalovirus, and progressive multifocal leukoencephalopathy (PML). Take into account prophylaxis in sufferers who’re at elevated threat for opportunistic infections. Monitor sufferers for indicators and signs of an infection and deal with promptly.

Hemorrhage

Deadly and critical hemorrhagic occasions have occurred in sufferers with hematologic malignancies handled with CALQUENCE. Main hemorrhage (critical or Grade 3 or greater bleeding or any central nervous system bleeding) occurred in 3.0% of sufferers, with deadly hemorrhage occurring in 0.1% of 1029 sufferers uncovered to CALQUENCE in medical trials. Bleeding occasions of any grade, excluding bruising and petechiae, occurred in 22% of sufferers.

Use of antithrombotic brokers concomitantly with CALQUENCE could additional improve the chance of hemorrhage. In medical trials, main hemorrhage occurred in 2.7% of sufferers taking CALQUENCE with out antithrombotic brokers and three.6% of sufferers taking CALQUENCE with antithrombotic brokers. Take into account the dangers and advantages of antithrombotic brokers when co-administered with CALQUENCE. Monitor sufferers for indicators of bleeding.

Take into account the benefit-risk of withholding CALQUENCE for 3-7 days pre- and post-surgery relying upon the kind of surgical procedure and the chance of bleeding.

Cytopenias

Grade 3 or 4 cytopenias, together with neutropenia (23%), anemia (8%), thrombocytopenia (7%), and lymphopenia (7%), developed in sufferers with hematologic malignancies handled with CALQUENCE. Grade 4 neutropenia developed in 12% of sufferers. Monitor full blood counts recurrently throughout therapy. Interrupt therapy, scale back the dose, or discontinue therapy as warranted.

Second Major Malignancies

Second main malignancies, together with pores and skin cancers and different strong tumors, occurred in 12% of 1029 sufferers uncovered to CALQUENCE in medical trials. Essentially the most frequent second main malignancy was pores and skin most cancers, reported in 6% of sufferers. Monitor sufferers for pores and skin cancers and advise safety from solar publicity.

Cardiac Arrhythmias

Critical cardiac arrhythmias have occurred in sufferers handled with CALQUENCE. Grade 3 atrial fibrillation or flutter occurred in 1.1% of 1029 sufferers handled with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 4.1% of all sufferers. Grade 3 or greater ventricular arrhythmia occasions have been reported in 0.9% of sufferers. The chance could also be elevated in sufferers with cardiac threat components, hypertension, earlier arrhythmias, and acute an infection. Monitor for signs of arrhythmia (eg, palpitations, dizziness, syncope, dyspnea) and handle as acceptable.

Hepatotoxicity, Together with Drug-Induced Liver Harm

Hepatotoxicity, together with extreme, life-threatening, and probably deadly instances of drug-induced liver damage (DILI), has occurred in sufferers handled with Bruton tyrosine kinase inhibitors, together with CALQUENCE.

Consider bilirubin and transaminases at baseline and all through therapy with CALQUENCE. For sufferers who develop irregular liver exams after CALQUENCE, monitor extra steadily for liver take a look at abnormalities and medical indicators and signs of hepatic toxicity. If DILI is suspected, withhold CALQUENCE. Upon affirmation of DILI, discontinue CALQUENCE.

ADVERSE REACTIONS

The commonest hostile reactions ( ‰¥20%) of any grade in sufferers with relapsed or refractory MCL have been anemia, thrombocytopenia, headache (39%), neutropenia, diarrhea (31%), fatigue (28%), myalgia (21%), and bruising (21%). The commonest Grade ‰¥3 non-hematological hostile response (reported in no less than 2% of sufferers) was diarrhea (3.2%).

Remedy-emergent decreases (all grades) of hemoglobin (46%), platelets (44%), and neutrophils (36%) have been based mostly on laboratory measurements and hostile reactions.

Dose reductions or discontinuations because of any hostile response have been reported in 1.6% and 6.5% of sufferers, respectively. Will increase in creatinine to 1.5 to three occasions the higher restrict of regular (ULN) occurred in 4.8% of sufferers.

The commonest hostile reactions ( ‰¥30%) of any grade in sufferers with CLL have been anemia, neutropenia, thrombocytopenia, headache, higher respiratory tract an infection, and diarrhea.

Remedy-emergent decreases (all grades) of hemoglobin, platelets, and neutrophils have been based mostly on laboratory measurements and hostile reactions.

In sufferers with beforehand untreated CLL uncovered to CALQUENCE, deadly hostile reactions that occurred within the absence of illness development and with onset inside 30 days of the final examine therapy have been reported in 2% for every therapy arm, most frequently from an infection. Critical hostile reactions have been reported in 39% of sufferers within the CALQUENCE plus obinutuzumab arm and 32% within the CALQUENCE monotherapy arm, most frequently because of occasions of pneumonia (7% and a couple of.8%, respectively).

Hostile reactions led to CALQUENCE dose discount in 7% and 4% of sufferers within the CALQUENCE plus obinutuzumab arm (N=178) and CALQUENCE monotherapy arm (N=179), respectively. Hostile occasions led to discontinuation in 11% and 10% of sufferers, respectively. Will increase in creatinine to 1.5 to three occasions ULN occurred in 3.9% and a couple of.8% of sufferers within the CALQUENCE mixture arm and monotherapy arm, respectively.

In sufferers with relapsed/refractory CLL uncovered to CALQUENCE, critical hostile reactions occurred in 29% of sufferers. Critical hostile reactions in >5% of sufferers who obtained CALQUENCE included decrease respiratory tract an infection (6%). Deadly hostile reactions inside 30 days of the final dose of CALQUENCE occurred in 2.6% of sufferers, together with from second main malignancies and an infection.

Hostile reactions led to CALQUENCE dose discount in 3.9% of sufferers (N=154), dose interruptions in 34% of sufferers, most frequently because of respiratory tract infections adopted by neutropenia, and discontinuation in 10% of sufferers, most steadily because of second main malignancies adopted by an infection. Will increase in creatinine to 1.5 to three occasions ULN occurred in 1.3% of sufferers who obtained CALQUENCE.

DRUG INTERACTIONS

Sturdy CYP3A Inhibitors: Keep away from co-administration of CALQUENCE with a powerful CYP3A inhibitor. If these inhibitors might be used short-term, interrupt CALQUENCE. After discontinuation of robust CYP3A inhibitor for no less than 24 hours, resume earlier dosage of CALQUENCE.

Reasonable CYP3A Inhibitors: Scale back the dosage of CALQUENCE to 100 mg as soon as day by day when co-administered with a average CYP3A inhibitor.

Sturdy CYP3A Inducers: Keep away from co-administration of CALQUENCE with a powerful CYP3A inducer. If co-administration is unavoidable, improve the dosage of CALQUENCE to 200 mg roughly each 12 hours.

SPECIFIC POPULATIONS

Based mostly on findings in animals, CALQUENCE could trigger fetal hurt and dystocia when administered to a pregnant girl. There are not any out there knowledge in pregnant ladies to tell the drug-associated threat. Advise pregnant ladies of the potential threat to a fetus.

Being pregnant testing is advisable for females of reproductive potential previous to initiating CALQUENCE remedy. Advise feminine sufferers of reproductive potential to make use of efficient contraception throughout therapy with CALQUENCE and for 1 week following the final dose of CALQUENCE.

It isn’t recognized if CALQUENCE is current in human milk. Advise lactating ladies to not breastfeed whereas taking CALQUENCE and for two weeks after the final dose.

Keep away from use of CALQUENCE in sufferers with extreme hepatic impairment (Youngster-Pugh class C). No dosage adjustment of CALQUENCE is advisable in sufferers with gentle (Youngster-Pugh class A) or average (Youngster-Pugh class B) hepatic impairment.

Please see full Prescribing Data, together with Affected person Data.

Notes

Mantle cell lymphoma

MCL is a uncommon and sometimes aggressive type of non-Hodgkin lymphoma (NHL), typically identified as a late-stage illness, ensuing when B-lymphocytes mutate into malignant cells inside a area of the lymph node often known as the mantle zone.1,2 Whereas MCL sufferers initially reply to therapy, sufferers do are likely to relapse.3 MCL includes about 3-6% of non-Hodgkin lymphomas, with an annual incidence of 0.5 per 100,000 inhabitants in Western international locations; within the US, it’s estimated that roughly 4,000 new sufferers are identified with MCL every year.3,4 It’s estimated that there are greater than 27,500 folks dwelling with MCL worldwide.5,6

ECHO

ECHO is a randomized, double-blind, placebo-controlled, multi-center Section III trial evaluating the efficacy and security of CALQUENCE plus bendamustine and rituximab in comparison with customary of care chemoimmunotherapy (bendamustine and rituximab) in grownup sufferers at or over 65 years of age (n=635) with beforehand untreated MCL.7 Sufferers have been randomized 1:1 to obtain both CALQUENCE or placebo administered orally twice per day, on 28 day therapy cycles, plus bendamustine on days 1 and a couple of and rituximab on day 1 of every cycle. After six cycles of induction remedy, all sufferers continued CALQUENCE or placebo together with bendamustine and rituximab, sufferers obtain CALQUENCE or placebo plus upkeep rituximab for 2 years after which both CALQUENCE or placebo solely till illness development.7

The first endpoint is PFS assessed by an Unbiased Overview Committee and key secondary endpoints embody OS, general response fee (ORR), period of response (DoR) and time to response (TTR).7 The trial contains 27 international locations throughout North and South America, Europe, Asia and Oceania.7

The ECHO trial enrolled sufferers from Could 2017 to March 2023, persevering with via the COVID-19 pandemic. Sufferers with blood most cancers stay at a disproportionately excessive threat of extreme outcomes from COVID-19, together with hospitalization and dying in comparison with the final inhabitants.8

CALQUENCE

CALQUENCE (acalabrutinib) is a next-generation, selective inhibitor of Bruton’s tyrosine kinase (BTK). CALQUENCE binds covalently to BTK, thereby inhibiting its exercise.9 In B-cells, BTK signaling leads to activation of pathways obligatory for B-cell proliferation, trafficking, chemotaxis and adhesion.

CALQUENCE has been used to deal with greater than 80,000 sufferers worldwide and is authorised for the therapy of CLL and small lymphocytic lymphoma (SLL) within the US and Japan, authorised for CLL within the EU and lots of different international locations worldwide and authorised in China for relapsed or refractory CLL and SLL. CALQUENCE can also be authorised within the US, China and a number of other different international locations for the therapy of grownup sufferers with MCL who’ve obtained no less than one prior remedy. CALQUENCE just isn’t at present authorised for the therapy of MCL in Japan or the EU.

As a part of an intensive medical growth program, CALQUENCE is at present being evaluated as a single therapy and together with standard-of-care chemoimmunotherapy for sufferers with a number of B-cell blood cancers, together with CLL, MCL, diffuse massive B-cell lymphoma and follicular lymphoma.

AstraZeneca in hematology

AstraZeneca is pushing the boundaries of science to redefine care in hematology. Our aim is to assist remodel the lives of sufferers dwelling with malignant, uncommon and different associated hematologic illnesses via revolutionary medicines and approaches which might be formed by insights from sufferers, caregivers and physicians.

Along with our marketed merchandise, we’re spearheading the event of novel therapies designed to focus on underlying drivers of illness throughout six scientific platforms. Our current acquisitions of Alexion (NASDAQ:), with experience in uncommon, non-malignant blood issues, and Gracell Biotechnologies Inc., centered on cell therapies for hematologic malignancies, broaden our hematology pipeline and allow us to succeed in extra sufferers with excessive unmet wants via the end-to-end growth and supply of novel therapies.

AstraZeneca in oncology

AstraZeneca is main a revolution in oncology with the ambition to supply cures for most cancers in each kind, following the science to grasp most cancers and all its complexities to find, develop and ship life-changing medicines to sufferers.

The Firm’s focus is on among the most difficult cancers. It’s via persistent innovation that AstraZeneca has constructed probably the most numerous portfolios and pipelines within the business, with the potential to catalyze modifications within the apply of medication and remodel the affected person expertise.

AstraZeneca has the imaginative and prescient to redefine most cancers care and, in the future, get rid of most cancers as a explanation for dying.

AstraZeneca

AstraZeneca is a world, science-led biopharmaceutical firm that focuses on the invention, growth, and commercialization of prescription medicines in Oncology, Uncommon Illnesses and BioPharmaceuticals, together with Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based mostly in Cambridge, UK, AstraZeneca’s revolutionary medicines are offered in additional than 125 international locations and utilized by thousands and thousands of sufferers worldwide. Please go to www.astrazeneca-us.com and observe the Firm on social media @AstraZeneca.

References

1. Lymphoma Analysis Basis. Mantle Cell Lymphoma. Accessible at: https://lymphoma.org/aboutlymphoma/nhl/mcl/. Accessed Could 2024.
2. Nationwide Group for Uncommon Issues. Mantle Cell Lymphoma. Accessible at: https://rarediseases.org/rare-diseases/mantle-cell-lymphoma/. Accessed Could 2024.
3. Cheah C, Seymour J, Wang ML. Mantle cell lymphoma. J Clin Oncol. 2016;34(11):1256-1269. doi: 10.1200/JCO.2015.63.5904.
4. MD Anderson Most cancers Heart. What to learn about mantle cell lymphoma. Accessible at: https://www.mdanderson.org/cancerwise/what-to-know-about-mantle-cell-lymphoma-symptoms-diagnosis-and-treatment.h00-159385101.html. Accessed Could 2024.
5. GLOBOCAN. Non-Hodgkin Lymphoma. Accessible at: https://gco.iarc.who.int/media/globocan/factsheets/cancers/34-non-hodgkin-lymphoma-fact-sheet.pdf. Accessed Could 2024.
6. Lynch DT, Koya S, Acharya U, et al. Mantle Cell Lymphoma. Accessible at: https://www.ncbi.nlm.nih.gov/books/NBK536985/. Accessed Could 2024.
7. ClinicalTrials.gov. A Examine of BR Alone Versus in Mixture With Acalabrutinib in Topics With Beforehand Untreated MCL. Accessible at: https://clinicaltrials.gov/examine/NCT02972840. Accessed Could 2024.
8. Dube S, et al. Continued Elevated Danger of COVID-19 Hospitalisation and Dying in Immunocompromised People Regardless of Receipt of ‰¥4 Vaccine Doses: Up to date 2023 Outcomes from INFORM, a Retrospective Well being Database Examine in England. Poster P0409 at ECCMID 2024.
9. Wu J, Zhang M, Liu D. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol. 2016;9(21).

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