Differentiating Between BTK Inhibitors in CLL: Same Class, Distinctly Dissimilar Agents
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May 13, 2024
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About This Presentation
Lindsey Roeker, MD discusses chronic lymphocytic leukaemia in this CME activity titled "Differentiating Between BTK Inhibitors in CLL: Same Class, Distinctly Dissimilar Agents." For the full presentation, please visit us at www.peervoice.com/HZH870.
Slide Content
PeerVoice
Differentiating Between BTK Inhibitors in CLL: Same Class,
Distinctly Dissimilar Agents
Learning Objectives
Recall available safety and efficacy data evaluating the use of BTK inhibitors in
the management of chronic lymphocytic leukaemia (CLL)
Implement evidence-based best practices for the management of CLL with BTK
inhibitors, including sequencing alongside other agents (such as BCL-2 inhibitors)
and switching between BTK inhibitors following adverse event (AE)-related
discontinuation
www.peervoice.com/HZH870
Differentiating Between BTK Inhibitors in CLL: Same Class,
Distinctly Dissimilar Agents
Learning Objectives
Recall available safety and efficacy data evaluating the use of BTK inhibitors in
the management of chronic lymphocytic leukaemia (CLL)
Implement evidence-based best practices for the management of CLL with BTK
inhibitors, including sequencing alongside other agents (such as BCL-2 inhibitors)
and switching between BTK inhibitors following adverse event (AE)-related
discontinuation
www.peervoice.com/HZH870
PeerVoice
Part 1 of 2: BTK Inhibitors for Management of CLL: Similarities and Stark Differences
MIA Lindsey Roeker, MD
si Assistant Member and Assistant Attending Physician
ye] Memorial Sloan Kettering Cancer Center
New York, New York, USA
Copyright © 201
Part 1 of 2: BTK Inhibitors for Management of CLL: Similarities and Stark Differences
MIA Lindsey Roeker, MD
si Assistant Member and Assistant Attending Physician
ye] Memorial Sloan Kettering Cancer Center
New York, New York, USA
Copyright © 201
PeerVoice
Disclosures
2] Lindsey Roeker, MD, has a financial interest/relationship or affiliation in the
form of:
Consultant for AbbVie Inc.; Ascentage Pharma Group International;
AstraZeneca; BeiGene; Janssen Inc.; Loxo Oncology, Inc.; Pfizer Inc.;
Pharmacyclics LLC; and TG Therapeutics.
Grant/Research Support from AbbVie Inc.; Adaptive Biotechnologies
Corporation; Aptose Biosciences Inc.; AstraZeneca; Dren Bio, Inc.; Genentech,
Inc.; Loxo Oncology, Inc.; Pfizer Inc.; and Qilu Puget Sound Biotherapeutics Corp.
Stock Shareholder in Abbott Laboratories.
Other Financial or Material Support from Loxo Oncology, Inc.
Advisory Board or Panel for Ascentage Pharma Group International.
4
www.peervoice.com/HZH870 Copyright © 2010-2024, PeerVoice
Disclosures
2] Lindsey Roeker, MD, has a financial interest/relationship or affiliation in the
form of:
Consultant for AbbVie Inc.; Ascentage Pharma Group International;
AstraZeneca; BeiGene; Janssen Inc.; Loxo Oncology, Inc.; Pfizer Inc.;
Pharmacyclics LLC; and TG Therapeutics.
Grant/Research Support from AbbVie Inc.; Adaptive Biotechnologies
Corporation; Aptose Biosciences Inc.; AstraZeneca; Dren Bio, Inc.; Genentech,
Inc.; Loxo Oncology, Inc.; Pfizer Inc.; and Qilu Puget Sound Biotherapeutics Corp.
Stock Shareholder in Abbott Laboratories.
Other Financial or Material Support from Loxo Oncology, Inc.
Advisory Board or Panel for Ascentage Pharma Group International.
4
www.peervoice.com/HZH870 Copyright © 2010-2024, PeerVoice
PeerVoice
L Evolving Ther:
FDA | EMA | FDA | em EMA | FDA FDA
2014 -------- 2019 2020
2021
Ne ws
S © 14
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L Evolving Ther:
FDA | EMA | FDA | em EMA | FDA FDA
2014 -------- 2019 2020
2021
Ne ws
S © 14
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PeerVoice
BTK Inhibitors: Characteristics and Mechanism of Action
Covalent Binding B cell Receptor Complex and BTK Inhibitors
(Irreversible)
ri Non-covalent,
¡paria non-C48te
+ Specificity: Low dependent binding.
+ Short half-life Pirtobrutinib
Acalabrutinib and Zanubruti
+ Specificity: High
+ Short half-life
Non-Covalent Binding y Ibrutinib
(Reversible) Acalabrutinib O
Zanubrutinib
Pirtobr Salant
+ Specificity: Very high Casi-dependent
Binding
+ Long half-life (20 hours)
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BTK Inhibitors: Characteristics and Mechanism of Action
Covalent Binding B cell Receptor Complex and BTK Inhibitors
(Irreversible)
ri Non-covalent,
¡paria non-C48te
+ Specificity: Low dependent binding.
+ Short half-life Pirtobrutinib
Acalabrutinib and Zanubruti
+ Specificity: High
+ Short half-life
Non-Covalent Binding y Ibrutinib
(Reversible) Acalabrutinib O
Zanubrutinib
Pirtobr Salant
+ Specificity: Very high Casi-dependent
Binding
+ Long half-life (20 hours)
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Approved Covalent BTK Inhibitors for Treatment-Naive CLL
Phase
Open-Label Trials
RESONATE-2
(NCTO1722487;
NCTOI724346)
N= 269
Follow-up: 827 mo
ELEVATE-TN
(NCTO2475681)
N= 535
Follow-up: 46.9 mo
SEQUOIA
(NCTO3336333)
N= 479
Follow-up: 26.2 mo
al Design
Randomised 1:
‘Arm 1: Ibrutir
Arm 2: Chlorambucil
Randomised
Arm 1: Acalabruti
Arm 2: Acalabruti
+ obinutuzumab
Arm 3: Obinutuzumab
+ chlorambucil
b
Cohort 1:
Randomised
Arm 1: Zanubrut
‘Arm 2: Bendamustine
+ rituximab
Patient Eligibility
TN patients with
CLL/SLL
Patients 265 y
Without del(17p)
TN patients with
CLL/SLL
Patients 265 y
TN patients with
CLL/SLL
Patients 265 y or 218 y.
with comorbidities
Without del(17p)
(cohort 1)
Primary Outcome
PFS
(ibrutinib vs chlorambucil):
NE vs 15 mo (HR 0.154; 95% Cl, 0.108
to 0.220)
PFS
(acalabrutinib-containing arms vs
obinutuzumab + chlorambucil):
NE vs 27.8 mo (both P < 0001)
PFS
(zanubrutinib vs bendamustine +
rituximab):
Both NE (95% Cl, NE to NE vs 28.1 mo
to NE) (HR 0.42; 95% Cl, 0.28 to 0.63;
P<.0001)
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Approved Covalent BTK Inhibitors for Treatment-Naive CLL
Phase
Open-Label Trials
RESONATE-2
(NCTO1722487;
NCTOI724346)
N= 269
Follow-up: 827 mo
ELEVATE-TN
(NCTO2475681)
N= 535
Follow-up: 46.9 mo
SEQUOIA
(NCTO3336333)
N= 479
Follow-up: 26.2 mo
al Design
Randomised 1:
‘Arm 1: Ibrutir
Arm 2: Chlorambucil
Randomised
Arm 1: Acalabruti
Arm 2: Acalabruti
+ obinutuzumab
Arm 3: Obinutuzumab
+ chlorambucil
b
Cohort 1:
Randomised
Arm 1: Zanubrut
‘Arm 2: Bendamustine
+ rituximab
Patient Eligibility
TN patients with
CLL/SLL
Patients 265 y
Without del(17p)
TN patients with
CLL/SLL
Patients 265 y
TN patients with
CLL/SLL
Patients 265 y or 218 y.
with comorbidities
Without del(17p)
(cohort 1)
Primary Outcome
PFS
(ibrutinib vs chlorambucil):
NE vs 15 mo (HR 0.154; 95% Cl, 0.108
to 0.220)
PFS
(acalabrutinib-containing arms vs
obinutuzumab + chlorambucil):
NE vs 27.8 mo (both P < 0001)
PFS
(zanubrutinib vs bendamustine +
rituximab):
Both NE (95% Cl, NE to NE vs 28.1 mo
to NE) (HR 0.42; 95% Cl, 0.28 to 0.63;
P<.0001)
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Approved Covalent BTK Inhibitors for R/R CLL
Phase
Open-Label Tri
RESONATE Randomised 11 Must have received at least 1
(NCTO1578707) ‘Arm E Ibrutinib prior therapy for CLL/SLL (ibrutinib vs ofatumumab):
N=361 44.1 vs 8.1 mo (HR 0.148; 95% CI, 0.13
Follow-up: 65.3 mo to 0.196; P <.001)
Trial Design
‘ASCEND ised 1 RIR to at least 1 prior systemic PFS
(NCTO2970318) Arm 1: Acalabrutinib therapy for CLL (acalabrutinib vs idelalisib +
N= 310 ‘Arm 2: Idelalisib + rituximab rituximab or bendamustine +
Follow-up: 46.5 mo or bendamustine + rituximab):
rituximab NR vs 16.8 mo (HR 0.28; 95% CI, 0.20
to 0.38; P< 001)
ELEVATE-RR Randomised 11 Must have received at least 1 PFS
(NCTO2477696) Arm 1: Acalabrutinib prior therapy for CLL (in both arms):
N= 533 ‘Arm 2: Ibrutinib Must have centrally confirmed 38.4 mo (HR 100; 95% CI, 0.79 to 1.27)
Follow-up: 40.9 mo del(17)(p13.1) or del(1Xq22.3)
ALPINE Randomised 11 R/R to at least 1 prior systemic ‘ORR
(NCTO3734016) Arm: Zanubrutinib therapy for CLL/SLL (zanubrutinib vs ibrutinib):
N = 415 (first interim ‘Arm 2: Ibrutinib 78.3% (95% Cl, 72.0 to 83.7) vs 62.5%
analysis) (95% Cl, 55.5 to 69.1, P « .001)
Follow-up: 15 mo
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Approved Covalent BTK Inhibitors for R/R CLL
Phase
Open-Label Tri
RESONATE Randomised 11 Must have received at least 1
(NCTO1578707) ‘Arm E Ibrutinib prior therapy for CLL/SLL (ibrutinib vs ofatumumab):
N=361 44.1 vs 8.1 mo (HR 0.148; 95% CI, 0.13
Follow-up: 65.3 mo to 0.196; P <.001)
Trial Design
‘ASCEND ised 1 RIR to at least 1 prior systemic PFS
(NCTO2970318) Arm 1: Acalabrutinib therapy for CLL (acalabrutinib vs idelalisib +
N= 310 ‘Arm 2: Idelalisib + rituximab rituximab or bendamustine +
Follow-up: 46.5 mo or bendamustine + rituximab):
rituximab NR vs 16.8 mo (HR 0.28; 95% CI, 0.20
to 0.38; P< 001)
ELEVATE-RR Randomised 11 Must have received at least 1 PFS
(NCTO2477696) Arm 1: Acalabrutinib prior therapy for CLL (in both arms):
N= 533 ‘Arm 2: Ibrutinib Must have centrally confirmed 38.4 mo (HR 100; 95% CI, 0.79 to 1.27)
Follow-up: 40.9 mo del(17)(p13.1) or del(1Xq22.3)
ALPINE Randomised 11 R/R to at least 1 prior systemic ‘ORR
(NCTO3734016) Arm: Zanubrutinib therapy for CLL/SLL (zanubrutinib vs ibrutinib):
N = 415 (first interim ‘Arm 2: Ibrutinib 78.3% (95% Cl, 72.0 to 83.7) vs 62.5%
analysis) (95% Cl, 55.5 to 69.1, P « .001)
Follow-up: 15 mo
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Binding of BTK Inhibitors to BTK: Mechanisms of Resistance
Covalent Binding Non-Covalent Binding
Non-covalent
BTK inhibitor
Covalent
Site of BTK BTK inhibitor
C481S mutation
bond
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Binding of BTK Inhibitors to BTK: Mechanisms of Resistance
Covalent Binding Non-Covalent Binding
Non-covalent
BTK inhibitor
Covalent
Site of BTK BTK inhibitor
C481S mutation
bond
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Approved Non-Covalent BTK Inhibitor for R/R CLL
Outcomes
Trial Design Patient Eligibility (Previous BTK Inhibitor;
n= 247)
BRUIN Single-arm R/R to 22 prior ORR:
(NCTO3740529) pirtobrutinib standard of care 73.3% (95% CI, 67.3 to 78.7)
N = 317 regimens given in PFS:
Follow-up: 19.4 mo combination or 19.6 mo (95% Cl, 16.9 to
sequentially 22.1)
FDA Accelerated Approval (Dec 2023):
For adults with CLL/SLL who have received at least two prior lines of therapy,
including a BTK inhibitor and a BCL-2 inhibitor
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Approved Non-Covalent BTK Inhibitor for R/R CLL
Outcomes
Trial Design Patient Eligibility (Previous BTK Inhibitor;
n= 247)
BRUIN Single-arm R/R to 22 prior ORR:
(NCTO3740529) pirtobrutinib standard of care 73.3% (95% CI, 67.3 to 78.7)
N = 317 regimens given in PFS:
Follow-up: 19.4 mo combination or 19.6 mo (95% Cl, 16.9 to
sequentially 22.1)
FDA Accelerated Approval (Dec 2023):
For adults with CLL/SLL who have received at least two prior lines of therapy,
including a BTK inhibitor and a BCL-2 inhibitor
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Abbreviations and References
CLL Evolving Therapeutic Landscape: BTK Inhibitor Approvals
Abbreviation(s): BTK: Bruton's tyrosine kinase; CLL: chronic lymphocytic leukaemia.
Reference(s): lbrutinib: FDA Approval. Angelo de Claro R et al. Clin Cancer Res. 201
Ibrutinib: EMA Authorisation. https://www.ema.europa.eu/en/medicines/human/EPAR/imbruvica. Accessed 25 April
2024,
Acalabrutinib: FDA Approval. https://www.fda.gov/drugs/resources-information-approved-drugs/project-orbis-fda-
approves-acalabrutinib-cll-and-sll. Accessed 25 April 2024.
Acalabrutinib: EMA Authorisation. https://www.ema.europa.eu/en/medicines/human/EPAR/calquence. Accessed 25
April 2024.
Zanubrutinib: FDA Approval. https://wwwfda.gov/drugs/resources-information-approved-drugs/fda-approves-
zanubrutinib~chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma, Accessed 25 April 2024.
Zanubrutinib: EMA Authorisation. https://www.ema.europa.eu/en/medicines/human/EPAR/brukinsa. Accessed 25 April
2024,
Pirtobrutinib: FDA Approval. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-
accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic. Accessed 25 April 2024.
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Abbreviations and References
CLL Evolving Therapeutic Landscape: BTK Inhibitor Approvals
Abbreviation(s): BTK: Bruton's tyrosine kinase; CLL: chronic lymphocytic leukaemia.
Reference(s): lbrutinib: FDA Approval. Angelo de Claro R et al. Clin Cancer Res. 201
Ibrutinib: EMA Authorisation. https://www.ema.europa.eu/en/medicines/human/EPAR/imbruvica. Accessed 25 April
2024,
Acalabrutinib: FDA Approval. https://www.fda.gov/drugs/resources-information-approved-drugs/project-orbis-fda-
approves-acalabrutinib-cll-and-sll. Accessed 25 April 2024.
Acalabrutinib: EMA Authorisation. https://www.ema.europa.eu/en/medicines/human/EPAR/calquence. Accessed 25
April 2024.
Zanubrutinib: FDA Approval. https://wwwfda.gov/drugs/resources-information-approved-drugs/fda-approves-
zanubrutinib~chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma, Accessed 25 April 2024.
Zanubrutinib: EMA Authorisation. https://www.ema.europa.eu/en/medicines/human/EPAR/brukinsa. Accessed 25 April
2024,
Pirtobrutinib: FDA Approval. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-
accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic. Accessed 25 April 2024.
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Abbreviations and References (Cont'd)
BTK Inhibitors: Characteristics and Mechanism of Action
Abbreviation(s): CXCL12: stromal-derived factor la; IgH: immunoglobulin H; PCLy: phospholipase C-y;
PI3K: phosphoinositide 3-kinase; P: phosphorylation; PKCf: protein kinase C-f.
Reference(s): Lewis KL, Cheah CY. J Pers Med. 2021:1:764.
Approved Covalent BTK Inhibitors for Treatment-Naive CLL
Abbreviation(s): Del: deletion; NE: not estimated; SLL: small lymphocytic lymphoma; TN: treatment-naive.
Reference(s): Barr PM et al. Blood Adv. 2022:6:3440-3450.
Sharman JP et al. Leukemia, 2022;36:171-1175.
Tam CS et al. Lancet Oncol. 2022;23:1031-1043.
Approved Covalent BTK Inhibitors for R/R CLL
Abbreviation(s): ORR: overall response rate; R/R: relapsed/refractory.
Reference(: L
Ghia P et al. J Clin Oncol. 2020;
Ghia P et al. Hemasphere. 2022;6:
Byrd JC et al. J Clin Oncol. 2021;39:3441-3452.
Hillmen P et al. J Clin Oncol. 202: 1035-1045.
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Abbreviations and References (Cont'd)
BTK Inhibitors: Characteristics and Mechanism of Action
Abbreviation(s): CXCL12: stromal-derived factor la; IgH: immunoglobulin H; PCLy: phospholipase C-y;
PI3K: phosphoinositide 3-kinase; P: phosphorylation; PKCf: protein kinase C-f.
Reference(s): Lewis KL, Cheah CY. J Pers Med. 2021:1:764.
Approved Covalent BTK Inhibitors for Treatment-Naive CLL
Abbreviation(s): Del: deletion; NE: not estimated; SLL: small lymphocytic lymphoma; TN: treatment-naive.
Reference(s): Barr PM et al. Blood Adv. 2022:6:3440-3450.
Sharman JP et al. Leukemia, 2022;36:171-1175.
Tam CS et al. Lancet Oncol. 2022;23:1031-1043.
Approved Covalent BTK Inhibitors for R/R CLL
Abbreviation(s): ORR: overall response rate; R/R: relapsed/refractory.
Reference(: L
Ghia P et al. J Clin Oncol. 2020;
Ghia P et al. Hemasphere. 2022;6:
Byrd JC et al. J Clin Oncol. 2021;39:3441-3452.
Hillmen P et al. J Clin Oncol. 202: 1035-1045.
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Abbreviations and References (Cont'd)
Binding of BTK Inhibitors to BTK: Mechanisms of Resistance
Reference(s): Gu D et al. J Hematol Oncol. 2021:14:40.
Approved Non-Covalent BTK Inhibitor for R/R CLL
Abbreviation(s): BCL-2: B cell lymphoma 2.
Reference(s): Mato AR et al. N Engl J Med. 2023;389:33-44.
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Abbreviations and References (Cont'd)
Binding of BTK Inhibitors to BTK: Mechanisms of Resistance
Reference(s): Gu D et al. J Hematol Oncol. 2021:14:40.
Approved Non-Covalent BTK Inhibitor for R/R CLL
Abbreviation(s): BCL-2: B cell lymphoma 2.
Reference(s): Mato AR et al. N Engl J Med. 2023;389:33-44.
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Part 2 of 2: Clinical Considerations for Offering BTK Inhibitors: Which Agent for Which Patient?
MEM Lindsey Roeker, MD
Assistant Member and Assistant Attending Physician
Memorial Sloan Kettering Cancer Center
New York, New York, USA
Copyright © 201
Part 2 of 2: Clinical Considerations for Offering BTK Inhibitors: Which Agent for Which Patient?
MEM Lindsey Roeker, MD
Assistant Member and Assistant Attending Physician
Memorial Sloan Kettering Cancer Center
New York, New York, USA
Copyright © 201
PeerVoice
Disclosures
2] Lindsey Roeker, MD, has a financial interest/relationship or affiliation in the
form of:
Consultant for AbbVie Inc.; Ascentage Pharma Group International;
AstraZeneca; BeiGene; Janssen Inc.; Loxo Oncology, Inc.; Pfizer Inc.;
Pharmacyclics LLC; and TG Therapeutics.
Grant/Research Support from AbbVie Inc.; Adaptive Biotechnologies
Corporation; Aptose Biosciences Inc.; AstraZeneca; Dren Bio, Inc.; Genentech,
Inc.; Loxo Oncology, Inc.; Pfizer Inc.; and Qilu Puget Sound Biotherapeutics Corp.
Stock Shareholder in Abbott Laboratories.
Other Financial or Material Support from Loxo Oncology, Inc.
Advisory Board or Panel for Ascentage Pharma Group International.
4
www.peervoice.com/HZH870 Copyright © 2010-2024, PeerVoice
Disclosures
2] Lindsey Roeker, MD, has a financial interest/relationship or affiliation in the
form of:
Consultant for AbbVie Inc.; Ascentage Pharma Group International;
AstraZeneca; BeiGene; Janssen Inc.; Loxo Oncology, Inc.; Pfizer Inc.;
Pharmacyclics LLC; and TG Therapeutics.
Grant/Research Support from AbbVie Inc.; Adaptive Biotechnologies
Corporation; Aptose Biosciences Inc.; AstraZeneca; Dren Bio, Inc.; Genentech,
Inc.; Loxo Oncology, Inc.; Pfizer Inc.; and Qilu Puget Sound Biotherapeutics Corp.
Stock Shareholder in Abbott Laboratories.
Other Financial or Material Support from Loxo Oncology, Inc.
Advisory Board or Panel for Ascentage Pharma Group International.
4
www.peervoice.com/HZH870 Copyright © 2010-2024, PeerVoice
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Approved BTK Inhibitors for CLL
Year of First Approval for CLL
BTK Inhibitor Indication
FDA EMA
Ibrutinib la Feb 2014 Oct 2014
+ RR .
* TNasa monotherapy or in combo with
Acalabrutinib obinutuzumab Nov 2019 Nov 2020
“RR
2 + TN
Zanubrutinib Jan 2023 Nov 2022
+ RR
+ R/R patients who have received at least Dec 2023
Pirtobrutinib two prior lines of therapy, including a BTK (accelerated N/A?
inhibitor and a BCL-2 inhibitor approval)
* Information is accurate as of activity launch date.
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Approved BTK Inhibitors for CLL
Year of First Approval for CLL
BTK Inhibitor Indication
FDA EMA
Ibrutinib la Feb 2014 Oct 2014
+ RR .
* TNasa monotherapy or in combo with
Acalabrutinib obinutuzumab Nov 2019 Nov 2020
“RR
2 + TN
Zanubrutinib Jan 2023 Nov 2022
+ RR
+ R/R patients who have received at least Dec 2023
Pirtobrutinib two prior lines of therapy, including a BTK (accelerated N/A?
inhibitor and a BCL-2 inhibitor approval)
* Information is accurate as of activity launch date.
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ibrut
Safety Profile of BTK Inhibitors: Acalabrutinib vs Ibrutinib
Acalabrutinib
Ibrutinib
Any Grade AE, % 266) (n=263) Any Grade AE, %* (n= 266) (n=263)
‘Anaemia 220 19.0 Arthralgia 16.0 23.09
Neutropenia 210 25.0 Myalgia 90 10.0
Thrombocytopenia 15.0 13.0 Back pain 80 13.0
Diarrhoea 35.0 46.0 Muscle spasms 60 13.0°
Nausea 18.0 19.0 Headache 35.08 20.0
Constipation 120 14.0 Dizziness 110 10.0
Vomiting 110 14.0 Cough 29.0? 210 ]
Dyspepsia 40 12.0 Dyspnoea 140 9.0
(ye BER El AEs of Clinical Interest, %*
Fatigue 20.0 17.0° Saas
Atrial fibrillation/flutter 90 16.0°
Peripheral oedema 10.0 14.0
Hypertension 9.0 23.0°
“Incidence (%) of AEs based on the results of the ELEVATE-RR trial
(NCTO2477696). * Two-sided P value <.05 Bleeding 38.0 51.0°
Infections 78.0 81.0
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ibrut
Safety Profile of BTK Inhibitors: Acalabrutinib vs Ibrutinib
Acalabrutinib
Ibrutinib
Any Grade AE, % 266) (n=263) Any Grade AE, %* (n= 266) (n=263)
‘Anaemia 220 19.0 Arthralgia 16.0 23.09
Neutropenia 210 25.0 Myalgia 90 10.0
Thrombocytopenia 15.0 13.0 Back pain 80 13.0
Diarrhoea 35.0 46.0 Muscle spasms 60 13.0°
Nausea 18.0 19.0 Headache 35.08 20.0
Constipation 120 14.0 Dizziness 110 10.0
Vomiting 110 14.0 Cough 29.0? 210 ]
Dyspepsia 40 12.0 Dyspnoea 140 9.0
(ye BER El AEs of Clinical Interest, %*
Fatigue 20.0 17.0° Saas
Atrial fibrillation/flutter 90 16.0°
Peripheral oedema 10.0 14.0
Hypertension 9.0 23.0°
“Incidence (%) of AEs based on the results of the ELEVATE-RR trial
(NCTO2477696). * Two-sided P value <.05 Bleeding 38.0 51.0°
Infections 78.0 81.0
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Safety Profile of BTK Inhibitors: Zanubrutinib vs Ibrutinib
A”: Zanubrutinib Ibrutinib event, 06 Zanubrutinib Ibrutinib
if (n= 204) (n=207) 2 (n= 204) (n=207)
‘Any grade AE 95.6 99.0 ‘Any AEs of interest 83.8 86.0
Diarrhoea 16.7 193 Ansernla 22 =>
Upper respiratory tract a6 En Atrial fibrillation/ flutter
Infection 2 2 (key 2° endpoint)
Neutropenia us DS Haemorrhage 358 36.2
Hypertension 157 Bo Hypertension 16.7 16.4
Anaemia 13.2 15.0 Infections 59.8 63.3
arthralgia 93 14.0 Neutropenia 28.4 217
Confusion 103 87 2° primary malignancies 83 63
Cp a es Skin cancers 34 48
Urinary tract infection 108 82 Thrombocytopenia 93 12.6
CAE i) ree Tumour lysis syndrome 05 0.0
“Incidence (%) of AEs based on the results of the ALPINE trial (NCTO3734016).
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Safety Profile of BTK Inhibitors: Zanubrutinib vs Ibrutinib
A”: Zanubrutinib Ibrutinib event, 06 Zanubrutinib Ibrutinib
if (n= 204) (n=207) 2 (n= 204) (n=207)
‘Any grade AE 95.6 99.0 ‘Any AEs of interest 83.8 86.0
Diarrhoea 16.7 193 Ansernla 22 =>
Upper respiratory tract a6 En Atrial fibrillation/ flutter
Infection 2 2 (key 2° endpoint)
Neutropenia us DS Haemorrhage 358 36.2
Hypertension 157 Bo Hypertension 16.7 16.4
Anaemia 13.2 15.0 Infections 59.8 63.3
arthralgia 93 14.0 Neutropenia 28.4 217
Confusion 103 87 2° primary malignancies 83 63
Cp a es Skin cancers 34 48
Urinary tract infection 108 82 Thrombocytopenia 93 12.6
CAE i) ree Tumour lysis syndrome 05 0.0
“Incidence (%) of AEs based on the results of the ALPINE trial (NCTO3734016).
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PeerVoice
Safety Profile of BTK Inhibitors: Pirtobrutinib
Any Grade AE, %°
Fatigue
Diarrhoea
Confusion
Cough
covip-19
Nausea
‘Abdominal pain
Dyspnoea
Headache
Upper respiratory tract infection
Back pain
Anaemia
Pirtobrutinib
(N= 317)
315
26.5
243
243
240
18.9
18.0
174
174
164
161
151
AEs of Special Interest, %°
Atrial fibrillation/flutter
Bleeding
Bruising
Haemorrhage
Hypertension
Infections
Neutropenia
Pirtobrutinib
(N = 317)
38
426
303
211
142
710
325
“Incidence (%) of AEs based on the results of the BRUIN trial (NCTO3740529).
www.peervoice.com/HZH870
Copyright © 2010-2024, PeerVoice
Safety Profile of BTK Inhibitors: Pirtobrutinib
Any Grade AE, %°
Fatigue
Diarrhoea
Confusion
Cough
covip-19
Nausea
‘Abdominal pain
Dyspnoea
Headache
Upper respiratory tract infection
Back pain
Anaemia
Pirtobrutinib
(N= 317)
315
26.5
243
243
240
18.9
18.0
174
174
164
161
151
AEs of Special Interest, %°
Atrial fibrillation/flutter
Bleeding
Bruising
Haemorrhage
Hypertension
Infections
Neutropenia
Pirtobrutinib
(N = 317)
38
426
303
211
142
710
325
“Incidence (%) of AEs based on the results of the BRUIN trial (NCTO3740529).
www.peervoice.com/HZH870
Copyright © 2010-2024, PeerVoice
PeerVoice
Sequencing Therapies in R/R CLL
Initial Therapy Subsequent Therapy Progression/Relapse
Venetoclax-based therapy
A different OR
tatolerance BTK inhibitor Pirtobrutinib
OR (if previous therapy was
Venetoclax-based therapy venetoclax-based and
where available)
BTK
Inhibitor?
Pirtobrutinib
Progression Venetoclax-based (where available)
8 therapy OR
Clinical trial
28TK inhibitors include ibrutinib, acalabrutinib, or zanubrutinib.
www.peervoice.com/HZH870 Copyright © 2010-2024, PeerVoice
Sequencing Therapies in R/R CLL
Initial Therapy Subsequent Therapy Progression/Relapse
Venetoclax-based therapy
A different OR
tatolerance BTK inhibitor Pirtobrutinib
OR (if previous therapy was
Venetoclax-based therapy venetoclax-based and
where available)
BTK
Inhibitor?
Pirtobrutinib
Progression Venetoclax-based (where available)
8 therapy OR
Clinical trial
28TK inhibitors include ibrutinib, acalabrutinib, or zanubrutinib.
www.peervoice.com/HZH870 Copyright © 2010-2024, PeerVoice
PeerVoice
Sequencing Therapies in R/R CLL (Cont’d)
Initial Therapy
Early
Relapse
Venetoclax-Based
Therapy
Late
Relapse
Subsequent Therapy
=>. BTK inhibitor? En
Progression/Relapse
Pirtobrutinib
{where available)
OR
Clinical trial
Venetoclax-based therapy
(if no BCL-2 resistance)
OR
mm}, BTKimhibitor" => Pirtobrutinib
(where available)
OR
of Clinical trial
Venetoclax-based
therapy BTK inhibitor
(if no BCL-2 OR
resistance) Clinical trial
*BTK inhibitors include ibrutinib, acalabrutinib, or zanubrutinib.
www.peervoice.com/HZH870
Copyright © 2010-2024, PeerVoice
Sequencing Therapies in R/R CLL (Cont’d)
Initial Therapy
Early
Relapse
Venetoclax-Based
Therapy
Late
Relapse
Subsequent Therapy
=>. BTK inhibitor? En
Progression/Relapse
Pirtobrutinib
{where available)
OR
Clinical trial
Venetoclax-based therapy
(if no BCL-2 resistance)
OR
mm}, BTKimhibitor" => Pirtobrutinib
(where available)
OR
of Clinical trial
Venetoclax-based
therapy BTK inhibitor
(if no BCL-2 OR
resistance) Clinical trial
*BTK inhibitors include ibrutinib, acalabrutinib, or zanubrutinib.
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Copyright © 2010-2024, PeerVoice
PeerVoice
Abbreviations and References
Approved BTK Inhibitors for CLL
Abbreviation(s): BCL-2: B cell lymphoma 2; BTK: Bruton’s tyrosine kinase; CLL: chronic lymphocytic leukaemia;
TN: treatment naive; R/R: relapsed/refractory.
Reference(s): lbrutinib: FDA Approval. Angelo de Claro R et al. Clin Cancer Res. 2015:21:3586-3590.
inib: EMA Authorisation. https://www.ema.europa.eu/en/medicines/human/EPAR/imbruvica. Accessed 25 April
Acalabrutinib: FDA Approval. https://www.fda.gov/drugs/resources-information-approved-drugs/project-orbis-fda-
approves-acelabrutinib-cll-and-sll. Accessed 25 April 2024.
Acalabrutinib: EMA Authorisation. https://www.ema.europa.eu/en/medicines/human/EPAR/calquence. Accessed 25
April 2024,
Zanubrutinib: FDA Approval. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-
zanubrutinib-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma. Accessed 25 April 2024.
Zanubrutinib: EMA Authorisation. https://www.ema.europa.eu/en/medieines/human/EPAR/brukinsa. Accessed 25 April
2024,
Pirtobrutinib: FDA Approval. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-
accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic. Accessed 25 April 2024.
www.peervoice.com/HZH870 Copyright © 2010-2024, PeerVoice
Abbreviations and References
Approved BTK Inhibitors for CLL
Abbreviation(s): BCL-2: B cell lymphoma 2; BTK: Bruton’s tyrosine kinase; CLL: chronic lymphocytic leukaemia;
TN: treatment naive; R/R: relapsed/refractory.
Reference(s): lbrutinib: FDA Approval. Angelo de Claro R et al. Clin Cancer Res. 2015:21:3586-3590.
inib: EMA Authorisation. https://www.ema.europa.eu/en/medicines/human/EPAR/imbruvica. Accessed 25 April
Acalabrutinib: FDA Approval. https://www.fda.gov/drugs/resources-information-approved-drugs/project-orbis-fda-
approves-acelabrutinib-cll-and-sll. Accessed 25 April 2024.
Acalabrutinib: EMA Authorisation. https://www.ema.europa.eu/en/medicines/human/EPAR/calquence. Accessed 25
April 2024,
Zanubrutinib: FDA Approval. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-
zanubrutinib-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma. Accessed 25 April 2024.
Zanubrutinib: EMA Authorisation. https://www.ema.europa.eu/en/medieines/human/EPAR/brukinsa. Accessed 25 April
2024,
Pirtobrutinib: FDA Approval. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-
accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic. Accessed 25 April 2024.
www.peervoice.com/HZH870 Copyright © 2010-2024, PeerVoice
PeerVoice
Abbreviations and References (Cont'd)
Safety Profile of BTK Inhibitors: Acalabrutinib vs Ibrutinib
Reference(s): Seymour JF et al. Blood. 2023;142:687-699.
Safety Profile of BTK Inhibitors: Zanubrutinib vs Ibrutinib
Reference(s): Hillmen P et al. J Clin Oncol. 2023;41:1035-1045.
Safety Profile of BTK Inhibitors: Pirtobrutinib
Reference(s): Mato AR et al. N Engl J Med. 2023;389:33-44.
‘Sequencing Therapies in R/R CLL
Reference(s): Odetola O, Ma S. Curr Hematol Malig Rep. 2023;18:130-143.
Sequencing Therapies in R/R CLL (Cont'd)
Reference(s): Odetola O, Ma S. Curr Hematol Malig Rep. 2023;18:130-143.
www.peervoice.com/HZH870 Copyright © 2010-2024, PeerVoice
Abbreviations and References (Cont'd)
Safety Profile of BTK Inhibitors: Acalabrutinib vs Ibrutinib
Reference(s): Seymour JF et al. Blood. 2023;142:687-699.
Safety Profile of BTK Inhibitors: Zanubrutinib vs Ibrutinib
Reference(s): Hillmen P et al. J Clin Oncol. 2023;41:1035-1045.
Safety Profile of BTK Inhibitors: Pirtobrutinib
Reference(s): Mato AR et al. N Engl J Med. 2023;389:33-44.
‘Sequencing Therapies in R/R CLL
Reference(s): Odetola O, Ma S. Curr Hematol Malig Rep. 2023;18:130-143.
Sequencing Therapies in R/R CLL (Cont'd)
Reference(s): Odetola O, Ma S. Curr Hematol Malig Rep. 2023;18:130-143.
www.peervoice.com/HZH870 Copyright © 2010-2024, PeerVoice
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