CALQUENCE plus venetoclax with obinutuzumab diminished the chance of illness development or dying by 58% versus customary of care on this setting
CALQUENCE plus venetoclax poised to change into first all-oral fixed-duration routine of a second-generation BTK inhibitor plus venetoclax in 1st-line CLL
WILMINGTON, Del.–(BUSINESS WIRE)–Optimistic outcomes from the AMPLIFY Section III trial confirmed AstraZeneca (NASDAQ:)’s CALQUENCE ® (acalabrutinib) together with venetoclax demonstrated a statistically important and clinically significant enchancment in progression-free survival (PFS) in comparison with standard-of-care chemoimmunotherapy in beforehand untreated grownup sufferers with continual lymphocytic leukemia (CLL).
These outcomes shall be introduced on the American Society of Hematology (ASH) 2024 Annual Assembly in San Diego, CA.
At a median observe up of 41 months, outcomes confirmed CALQUENCE plus venetoclax diminished the chance of illness development or dying by 35% in comparison with 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% discount within the threat of illness development or dying in comparison with standard-of-care chemoimmunotherapy (HR 0.42; 95% CI 0.30-0.59; p
Interim general survival (OS) information demonstrated a good pattern which was nominally statistically important for CALQUENCE plus venetoclax (HR 0.33; 95% CI 0.18-0.56; p
Jennifer R. Brown, MD, PhD, Director of the CLL Heart of the Division of Hematologic Malignancies, Dana-Farber Most cancers Institute, and the Worthington and Margaret Collette Professor of Medication at Harvard Medical (TASE:) Faculty, and principal investigator of the trial, stated: Continual lymphocytic leukemia is taken into account an incurable most cancers and sufferers reside with the illness and the long-term results of their therapies for a few years. The AMPLIFY outcomes present the promise of a brand new all-oral fixed-duration remedy method which might permit sufferers to take breaks from remedy, lowering the chance of long-term hostile occasions and drug resistance.
Susan Galbraith, Government Vice President, Oncology R&D, AstraZeneca, stated: Primarily based on these spectacular information from the AMPLIFY trial, CALQUENCE is the one second-generation BTK inhibitor to show efficacy within the front-line remedy of sufferers with continual lymphocytic leukemia as each a treat-to-progression and a fixed-duration method. This advance is a crucial improvement for sufferers and their physicians who search new choices and extra flexibility in managing this illness in the long run.
Each investigational arms demonstrated sturdy responses, with estimated 36-month PFS charges of 76.5% for CALQUENCE plus venetoclax and 83.1% with the addition of obinutuzumab in comparison with 66.5% for chemoimmunotherapy. Sufferers additionally demonstrated a strong response in each investigational arms with an general response charge (ORR) of 92.8% for CALQUENCE plus venetoclax and 92.7% with the addition of obinutuzumab, in comparison with 75.2% for chemoimmunotherapy.
Abstract of Outcomes: AMPLIFY
|
CALQUENCE plus venetoclax |
CALQUENCE plus venetoclax and obinutuzumab |
Management arm |
|
|
Affected person inhabitants (n) |
291 |
286 |
290 |
|
Median PFS (months) |
NR |
NR |
47.6 |
|
PFS HR vs. management (95% CI) |
0.65 p=0.0038 |
0.42 p |
Reference |
|
36-month PFS charge |
76.5% |
83.1% |
66.5% |
|
ORR (95% CI) |
92.8% (89.4-95.4) p |
92.7% (89.2-95.3) p |
75.2% (70.0-79.9) |
|
OS HR vs. management (95% CI) |
0.33 (0.18-0.56) p |
0.76 (0.49-1.18) p=0.2224 |
Reference |
|
NR=Not reached |
|||
|
Management arm = Investigator’s selection of fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab |
|||
The security and tolerability of CALQUENCE was according to its recognized security profile, and no new security indicators have been recognized. Grade 3 or larger hostile occasions (AEs) occurred in 53.6% of sufferers handled with CALQUENCE plus venetoclax, 69.4% of sufferers handled with CALQUENCE plus venetoclax with obinutuzumab and 60.6% for sufferers handled with standard-of-care chemoimmunotherapy. The most typical Grade 3 or larger AE was neutropenia throughout all arms, seen in 26.8%, 35.2% and 32.4% of sufferers respectively. There have been over twice as many COVID-19 associated deaths within the CALQUENCE plus venetoclax with obinutuzumab arm in contrast with the CALQUENCE plus venetoclax arm.
Notably, low charges of tumor lysis syndrome (TLS) have been noticed in each CALQUENCE arms with occasions of any grade seen in 0.3% of sufferers handled with CALQUENCE plus venetoclax and 0.4% with the addition of obinutuzumab, in comparison with 3.1% for sufferers handled with chemoimmunotherapy. No circumstances of scientific TLS have been noticed throughout CALQUENCE remedy arms.
CALQUENCE has been used to deal with greater than 85,000 sufferers worldwide1 and is authorised for the remedy of CLL and small lymphocytic lymphoma (SLL) within the US and Japan, authorised for CLL within the EU and plenty of different nations worldwide and authorised in China for relapsed or refractory CLL and SLL.
INDICATION AND USAGE
CALQUENCE is a Bruton tyrosine kinase (BTK) inhibitor indicated for the remedy of grownup sufferers with continual lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
IMPORTANT SAFETY INFORMATION ABOUT CALQUENCE ® (acalabrutinib) tablets
Severe and Opportunistic Infections
Deadly and severe infections, together with opportunistic infections, have occurred in sufferers with hematologic malignancies handled with CALQUENCE.
Severe or Grade 3 or larger infections (bacterial, viral, or fungal) occurred in 19% of 1029 sufferers uncovered to CALQUENCE in scientific trials, most frequently attributable to 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 will not be 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 severe hemorrhagic occasions have occurred in sufferers with hematologic malignancies handled with CALQUENCE. Main hemorrhage (severe or Grade 3 or larger 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 could additional enhance the chance 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 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 frequently throughout remedy. Interrupt remedy, scale back the dose, or discontinue remedy as warranted.
Second Main Malignancies
Second main malignancies, together with pores and skin cancers and different stable tumors, occurred in 12% of 1029 sufferers uncovered to CALQUENCE in scientific trials. Probably 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
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 larger ventricular arrhythmia occasions have been reported in 0.9% of sufferers. The chance 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 Damage
Hepatotoxicity, together with extreme, life-threatening, and doubtlessly deadly circumstances 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 remedy with CALQUENCE. For sufferers who develop irregular liver checks after CALQUENCE, monitor extra continuously for liver check abnormalities and scientific indicators and signs of hepatic toxicity. If DILI is suspected, withhold CALQUENCE. Upon affirmation of DILI, discontinue CALQUENCE.
ADVERSE REACTIONS
The most typical 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 remedy have been reported in 2% for every remedy arm, most frequently from an infection. Severe hostile reactions have been reported in 39% of sufferers within the CALQUENCE plus obinutuzumab arm and 32% within the CALQUENCE monotherapy arm, most frequently attributable to occasions of pneumonia (7% and a pair 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 the higher restrict of regular (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, severe hostile reactions occurred in 29% of sufferers. Severe hostile reactions in >5% of sufferers who acquired 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 attributable to respiratory tract infections adopted by neutropenia, and discontinuation in 10% of sufferers, most continuously attributable to 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 acquired CALQUENCE.
DRUG INTERACTIONS
Sturdy CYP3A Inhibitors: Keep away from co-administration of CALQUENCE with a powerful CYP3A inhibitor. If these inhibitors shall be used short-term, interrupt CALQUENCE. After discontinuation of robust CYP3A inhibitor for no less than 24 hours, resume earlier dosage of CALQUENCE.
Average CYP3A Inhibitors: Cut back the dosage of CALQUENCE to 100 mg as soon as each 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, enhance the dosage of CALQUENCE to 200 mg roughly each 12 hours.
SPECIFIC POPULATIONS
Primarily based on findings in animals, CALQUENCE could trigger fetal hurt and dystocia when administered to a pregnant girl. There aren’t any accessible 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 remedy 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 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 Info, together with Affected person Info.
Notes
Continual Lymphocytic Leukemia (CLL)
CLL is essentially the most prevalent sort of leukemia in adults, with over 100,000 new circumstances globally in 2019.2 Though some folks with CLL could not expertise any signs at analysis, others could expertise signs, resembling weak spot, fatigue, weight reduction, chills, fever, night time sweats, swollen lymph nodes and stomach ache.3 In CLL, there may be an accumulation of irregular lymphocytes throughout the blood, bone marrow and lymph nodes. Because the variety of irregular cells will increase, there may be much less room throughout the marrow for the manufacturing of regular white blood cells, pink blood cells and platelets.4 This might lead to an infection, anemia and bleeding. B-cell receptor signaling via BTK is among the important progress pathways for CLL.
AMPLIFY
AMPLIFY is a randomized, international, multi-center, open-label Section III trial evaluating the efficacy and security of CALQUENCE together with venetoclax with and with out obinutuzumab in comparison with investigator’s selection of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) in grownup sufferers with beforehand untreated CLL with out del(17p) or TP53 mutation.5 Sufferers have been randomized 1:1:1 to obtain both CALQUENCE plus venetoclax, CALQUENCE plus venetoclax with obinutuzumab for a set period or standard-of-care chemoimmunotherapy.5 Each the CALQUENCE containing arms have been administered for a set period of 14 cycles (every 28 days), and the standard-of-care chemoimmunotherapy was for six cycles.5
The first endpoint is PFS within the CALQUENCE and venetoclax arm as assessed by an Impartial (LON:) Assessment Committee and PFS within the CALQUENCE plus venetoclax with obinutuzumab is a key secondary endpoint. Different key secondary endpoints embrace OS and undetectable measurable residual illness.5 The trial contains 27 nations throughout North and South America, Europe, Asia and Oceania.5
The AMPLIFY trial enrolled sufferers from 2019 to 2021, persevering with via the COVID-19 pandemic.5 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 overall inhabitants.6
CALQUENCE ®
CALQUENCE (acalabrutinib) is a second-generation, selective inhibitor of Bruton’s tyrosine kinase (BTK). CALQUENCE binds covalently to BTK, thereby inhibiting its exercise.7 In B-cells, BTK signaling leads to activation of pathways essential for B-cell proliferation, trafficking, chemotaxis and adhesion.
CALQUENCE can also be authorised within the US, China and a number of other different nations for the remedy of grownup sufferers with mantle cell lymphoma (MCL) who’ve acquired no less than one prior remedy. CALQUENCE isn’t presently authorised for the remedy of MCL in Japan or the EU.
As a part of an intensive scientific improvement program, CALQUENCE is presently being evaluated as a single remedy and together with standard-of-care chemoimmunotherapy for sufferers with a number of B-cell blood cancers, together with CLL, MCL and diffuse massive B-cell lymphoma.
AstraZeneca in hematology
AstraZeneca is pushing the boundaries of science to redefine care in hematology. Our purpose is to assist rework the lives of sufferers dwelling with malignant, uncommon and different associated hematologic illnesses via revolutionary medicines and approaches which are 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 a number of scientific platforms. Our acquisitions of Alexion (NASDAQ:), with experience in uncommon, non-malignant blood issues, and Gracell Biotechnologies Inc., pioneers of autologous cell therapies, develop our hematology pipeline and allow us to succeed in extra sufferers with excessive unmet wants via the end-to-end discovery, improvement and supply of novel therapies.
AstraZeneca in oncology
AstraZeneca is main a revolution in oncology with the ambition to offer 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 few of the most difficult cancers. It’s via persistent innovation that AstraZeneca has constructed one of the numerous portfolios and pipelines within the trade, with the potential to catalyze modifications within the apply of drugs and rework 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
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References
- Information on File, REF-236261. AstraZeneca Prescribed drugs LP.
- Yao Y, et al. The worldwide burden and attributable threat elements of continual lymphocytic leukemia in 204 nations and territories from 1990 to 2019: evaluation based mostly on the worldwide burden of illness examine 2019. Biomed Eng On-line. 2022;1:4.
- American Most cancers Society. Indicators and Signs of Continual Lymphocytic Leukemia. Accessed November 2024. Obtainable at: https://www.most cancers.org/most cancers/varieties/chronic-lymphocytic-leukemia/detection-diagnosis-staging/signs-symptoms.html.
- Nationwide Most cancers Institute. Continual lymphocytic leukemia remedy (PDQ ®)“Affected person model. Accessed November 2024. Obtainable at: https://www.most cancers.gov/varieties/leukemia/affected person/cll-treatment-pdq.
- ClinicalTrials.gov. Examine of Acalabrutinib (ACP-196) in Mixture With Venetoclax (ABT-199), With and With out Obinutuzumab (GA101) Versus Chemoimmunotherapy for Beforehand Untreated CLL (AMPLIFY). Accessed November 2024. Obtainable at: https://clinicaltrials.gov/examine/NCT03836261.
- Dube S, et al. Continued Elevated Danger of COVID-19 Hospitalization 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.
- Wu J, et al. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol. 2016;9(21).
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