First and solely BTK inhibitor to show favorable total survival pattern vs. standard-of-care chemoimmunotherapy on this setting
WILMINGTON, Del.–(BUSINESS WIRE)–Constructive outcomes from the ECHO Section III trial confirmed AstraZeneca (NASDAQ:)’s CALQUENCE ® (acalabrutinib) together with bendamustine and rituximab demonstrated a statistically vital and clinically significant enchancment in progression-free survival (PFS) and confirmed a positive pattern in total survival (OS) in comparison with standard-of-care chemoimmunotherapy (bendamustine plus rituximab) in beforehand untreated sufferers with mantle cell lymphoma (MCL).
These outcomes had been introduced right now 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 diminished the danger of illness development or demise 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 scientific advantage of this mixture (HR 0.86; 95% CI 0.65-1.13; p=0.2743). The OS information weren’t mature on the time of this evaluation 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 evaluation censoring for COVID-19-related deaths was performed to evaluate the affect. PFS was additional improved in each arms, with the CALQUENCE mixture decreasing the danger of illness development or demise 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 positive pattern was seen for OS on this evaluation 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 Medical Trials at MD Anderson Most cancers Middle in Houston, US and principal investigator within the trial, stated: For folks dwelling with mantle cell lymphoma, a usually aggressive type of non-Hodgkin’s lymphoma, the ECHO outcomes supply promise of a brand new, efficient therapy choice for adults older than 65, who symbolize the vast majority of MCL sufferers. The improved progression-free survival seen in sufferers handled with the CALQUENCE mixture in comparison with chemoimmunotherapy show 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 information show necessary progress in bettering outcomes for sufferers with mantle cell lymphoma. The 16.8 months of further time sufferers can reside with out their illness progressing is very clinically significant, along with a pattern to enchancment in total survival. We subsequently imagine CALQUENCE plus chemoimmunotherapy will probably be an necessary new choice for sufferers dwelling with this illness.
Abstract of Outcomes: ECHO
CALQUENCE plus bendamustine and rituximab (n=299) |
Placebo plus bendamustine and rituximab (n=299) |
|
Median PFS (months) |
66.4 |
49.6 |
PFS HR (95% CI) |
0.73 (0.57-0.94) |
|
PFS p-value |
0.0160 |
|
OS HR (95% CI) |
0.86 (0.65-1.13) |
|
OS p-value |
0.2743 |
|
Censoring for COVID-19 deaths |
||
Median PFS |
NR |
61.6 |
PFS HR (95% CI) |
0.64 (0.48-0.84) |
|
PFS p-value |
0.0017 |
|
OS HR (95% CI) |
0.75 (0.53-1.04) |
|
OS p-value |
0.0797 |
|
NR=Not reached |
The protection and tolerability of CALQUENCE was according to its identified security profile, and no new security indicators had been recognized. Grade 3 or increased opposed occasions (AEs) on account 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 increased atrial fibrillation in 3.7% (n=11) and 1.7% (n=5) of sufferers, Grade 3 or increased hypertension in 5.4% (n=16) and eight.4% (n=25), Grade 3 or increased main bleeding in 2.0% (n=6) and three.4% (n=10), and Grade 3 or increased infections in 41.1% (n=122) and 34.0% (n=101), respectively. Severe AEs and Grade 5 occasions had 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 had 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 had 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.
Extra AstraZeneca information at EHA
Along with these compelling information, AstraZeneca information at EHA 2024 exhibits how the Firm is advancing a various and progressive 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 continued 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% had been seen at doses of AZD0486 of two.4 mg and above. Information additionally confirmed how cytokine launch syndrome (CRS) occasions had been successfully mitigated by the double step-up dosing schedule and no immune effector cell-associated neurotoxicity syndrome (ICANS) occasions had been noticed.
In an oral presentation, preliminary information was shared from an investigator-initiated trial of AstraZeneca’s first hematology cell remedy, GC012F (AZD0120), in sufferers with transplant-eligible high-risk, newly recognized a number of myeloma. Early outcomes confirmed that GC012F had an total 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 not less than one prior remedy.
This indication is permitted underneath accelerated approval based mostly on total response fee. Continued approval for this indication could also be contingent upon verification and outline of scientific 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
Severe and Opportunistic Infections
Deadly and critical infections, together with opportunistic infections, have occurred in sufferers with hematologic malignancies handled with CALQUENCE.
Severe or Grade 3 or increased infections (bacterial, viral, or fungal) occurred in 19% of 1029 sufferers uncovered to CALQUENCE in scientific trials, most frequently on account 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 should 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 increased 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 scientific trials. Bleeding occasions of any grade, excluding bruising and petechiae, occurred in 22% of sufferers.
Use of antithrombotic brokers concomitantly with CALQUENCE might additional enhance the danger of hemorrhage. In scientific 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 danger 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 often throughout therapy. Interrupt therapy, scale back the dose, or discontinue therapy as warranted.
Second Major Malignancies
Second major malignancies, together with pores and skin cancers and different strong tumors, occurred in 12% of 1029 sufferers uncovered to CALQUENCE in scientific trials. Essentially the most frequent second major 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
Severe 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 increased ventricular arrhythmia occasions had been reported in 0.9% of sufferers. The danger could also be elevated in sufferers with cardiac threat elements, hypertension, earlier arrhythmias, and acute an infection. Monitor for signs of arrhythmia (eg, palpitations, dizziness, syncope, dyspnea) and handle as applicable.
Hepatotoxicity, Together with Drug-Induced Liver Harm
Hepatotoxicity, together with extreme, life-threatening, and doubtlessly deadly instances of drug-induced liver harm (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 checks after CALQUENCE, monitor extra continuously for liver take a look at abnormalities and scientific indicators and signs of hepatic toxicity. If DILI is suspected, withhold CALQUENCE. Upon affirmation of DILI, discontinue CALQUENCE.
ADVERSE REACTIONS
The commonest opposed reactions ( ‰¥20%) of any grade in sufferers with relapsed or refractory MCL had been anemia, thrombocytopenia, headache (39%), neutropenia, diarrhea (31%), fatigue (28%), myalgia (21%), and bruising (21%). The commonest Grade ‰¥3 non-hematological opposed response (reported in not less than 2% of sufferers) was diarrhea (3.2%).
Remedy-emergent decreases (all grades) of hemoglobin (46%), platelets (44%), and neutrophils (36%) had been based mostly on laboratory measurements and opposed reactions.
Dose reductions or discontinuations on account of any opposed response had been reported in 1.6% and 6.5% of sufferers, respectively. Will increase in creatinine to 1.5 to three instances the higher restrict of regular (ULN) occurred in 4.8% of sufferers.
The commonest opposed reactions ( ‰¥30%) of any grade in sufferers with CLL had been anemia, neutropenia, thrombocytopenia, headache, higher respiratory tract an infection, and diarrhea.
Remedy-emergent decreases (all grades) of hemoglobin, platelets, and neutrophils had been based mostly on laboratory measurements and opposed reactions.
In sufferers with beforehand untreated CLL uncovered to CALQUENCE, deadly opposed reactions that occurred within the absence of illness development and with onset inside 30 days of the final examine therapy had been reported in 2% for every therapy arm, most frequently from an infection. Severe opposed reactions had been reported in 39% of sufferers within the CALQUENCE plus obinutuzumab arm and 32% within the CALQUENCE monotherapy arm, most frequently on account of occasions of pneumonia (7% and a pair of.8%, respectively).
Antagonistic 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. Antagonistic occasions led to discontinuation in 11% and 10% of sufferers, respectively. Will increase in creatinine to 1.5 to three instances ULN occurred in 3.9% and a pair of.8% of sufferers within the CALQUENCE mixture arm and monotherapy arm, respectively.
In sufferers with relapsed/refractory CLL uncovered to CALQUENCE, critical opposed reactions occurred in 29% of sufferers. Severe opposed reactions in >5% of sufferers who obtained CALQUENCE included decrease respiratory tract an infection (6%). Deadly opposed reactions inside 30 days of the final dose of CALQUENCE occurred in 2.6% of sufferers, together with from second major malignancies and an infection.
Antagonistic reactions led to CALQUENCE dose discount in 3.9% of sufferers (N=154), dose interruptions in 34% of sufferers, most frequently on account of respiratory tract infections adopted by neutropenia, and discontinuation in 10% of sufferers, most continuously on account of second major malignancies adopted by an infection. Will increase in creatinine to 1.5 to three instances ULN occurred in 1.3% of sufferers who obtained CALQUENCE.
DRUG INTERACTIONS
Robust CYP3A Inhibitors: Keep away from co-administration of CALQUENCE with a robust CYP3A inhibitor. If these inhibitors will probably be used short-term, interrupt CALQUENCE. After discontinuation of robust CYP3A inhibitor for not less than 24 hours, resume earlier dosage of CALQUENCE.
Average CYP3A Inhibitors: Cut back the dosage of CALQUENCE to 100 mg as soon as every day when co-administered with a average CYP3A inhibitor.
Robust CYP3A Inducers: Keep away from co-administration of CALQUENCE with a robust CYP3A inducer. If co-administration is unavoidable, enhance the dosage of CALQUENCE to 200 mg roughly each 12 hours.
SPECIFIC POPULATIONS
Based mostly on findings in animals, CALQUENCE might trigger fetal hurt and dystocia when administered to a pregnant lady. There aren’t any obtainable information in pregnant girls to tell the drug-associated threat. Advise pregnant girls of the potential threat to a fetus.
Being pregnant testing is really useful 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’s not identified if CALQUENCE is current in human milk. Advise lactating girls 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 (Little one-Pugh class C). No dosage adjustment of CALQUENCE is really useful in sufferers with gentle (Little one-Pugh class A) or average (Little one-Pugh class B) hepatic impairment.
Please see full Prescribing Data, together with Affected person Data.
Notes
Mantle cell lymphoma
MCL is a uncommon and usually aggressive type of non-Hodgkin lymphoma (NHL), usually recognized 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 nations; within the US, it’s estimated that roughly 4,000 new sufferers are recognized 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 commonplace of care chemoimmunotherapy (bendamustine and rituximab) in grownup sufferers at or over 65 years of age (n=635) with beforehand untreated MCL.7 Sufferers had 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 pair 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 Impartial Evaluate Committee and key secondary endpoints embody OS, total response fee (ORR), length of response (DoR) and time to response (TTR).7 The trial consists of 27 nations throughout North and South America, Europe, Asia and Oceania.7
The ECHO trial enrolled sufferers from Might 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 demise in comparison with the overall 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 crucial for B-cell proliferation, trafficking, chemotaxis and adhesion.
CALQUENCE has been used to deal with greater than 80,000 sufferers worldwide and is permitted for the therapy of CLL and small lymphocytic lymphoma (SLL) within the US and Japan, permitted for CLL within the EU and plenty of different nations worldwide and permitted in China for relapsed or refractory CLL and SLL. CALQUENCE can also be permitted within the US, China and several other different nations for the therapy of grownup sufferers with MCL who’ve obtained not less than one prior remedy. CALQUENCE is just not at present permitted for the therapy of MCL in Japan or the EU.
As a part of an in depth scientific 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 progressive 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 latest acquisitions of Alexion (NASDAQ:), with experience in uncommon, non-malignant blood issues, and Gracell Biotechnologies Inc., targeted on cell therapies for hematologic malignancies, develop our hematology pipeline and allow us to achieve 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 a number of the most difficult cancers. It’s via persistent innovation that AstraZeneca has constructed probably the most various portfolios and pipelines within the trade, 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 reason behind demise.
AstraZeneca
AstraZeneca is a worldwide, science-led biopharmaceutical firm that focuses on the invention, growth, and commercialization of prescription medicines in Oncology, Uncommon Ailments and BioPharmaceuticals, together with Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based mostly in Cambridge, UK, AstraZeneca’s progressive medicines are offered in additional than 125 nations and utilized by tens of millions of sufferers worldwide. Please go to www.astrazeneca-us.com and observe the Firm on social media @AstraZeneca.
References
- Lymphoma Analysis Basis. Mantle Cell Lymphoma. Obtainable at: https://lymphoma.org/aboutlymphoma/nhl/mcl/. Accessed Might 2024.
- Nationwide Group for Uncommon Problems. Mantle Cell Lymphoma. Obtainable at: https://rarediseases.org/rare-diseases/mantle-cell-lymphoma/. Accessed Might 2024.
- Cheah C, Seymour J, Wang ML. Mantle cell lymphoma. J Clin Oncol. 2016;34(11):1256-1269. doi: 10.1200/JCO.2015.63.5904.
- MD Anderson Most cancers Middle. What to learn about mantle cell lymphoma. Obtainable at: https://www.mdanderson.org/cancerwise/what-to-know-about-mantle-cell-lymphoma-symptoms-diagnosis-and-treatment.h00-159385101.html. Accessed Might 2024.
- GLOBOCAN. Non-Hodgkin Lymphoma. Obtainable at: https://gco.iarc.who.int/media/globocan/factsheets/cancers/34-non-hodgkin-lymphoma-fact-sheet.pdf. Accessed Might 2024.
- Lynch DT, Koya S, Acharya U, et al. Mantle Cell Lymphoma. Obtainable at: https://www.ncbi.nlm.nih.gov/books/NBK536985/. Accessed Might 2024.
- ClinicalTrials.gov. A Research of BR Alone Versus in Mixture With Acalabrutinib in Topics With Beforehand Untreated MCL. Obtainable at: https://clinicaltrials.gov/examine/NCT02972840. Accessed Might 2024.
- Dube S, et al. Continued Elevated Danger of COVID-19 Hospitalisation and Loss of life in Immunocompromised People Regardless of Receipt of ‰¥4 Vaccine Doses: Up to date 2023 Outcomes from INFORM, a Retrospective Well being Database Research in England. Poster P0409 at ECCMID 2024.
- 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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