Investigating the Addition of Ianalumab (VAY736) to Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL) on Ibrutinib Therapy: Results from a Phase Ib Study
Introduction: B-cell activating factor receptor (BAFF-R) enhances the survival and regulation of normal and malignant B cells. VAY736 is a human monoclonal antibody (mAb) targeting BAFF-R that targets BAFF-R+ B cells for elimination by antibody-dependent cell-mediated cytotoxicity (ADCC). VAY736 has...
Gespeichert in:
Veröffentlicht in: | Blood 2021-11, Vol.138 (Supplement 1), p.2631-2631 |
---|---|
Hauptverfasser: | , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 2631 |
---|---|
container_issue | Supplement 1 |
container_start_page | 2631 |
container_title | Blood |
container_volume | 138 |
creator | Rogers, Kerry A. Flinn, Ian W. Stephens, Deborah M. Kipps, Thomas J. Larson, Sarah McGarry, Carolyn Hassounah, Nadia B. Gou, Liangke Connie Woo, Janghee Byrd, John C. |
description | Introduction:
B-cell activating factor receptor (BAFF-R) enhances the survival and regulation of normal and malignant B cells. VAY736 is a human monoclonal antibody (mAb) targeting BAFF-R that targets BAFF-R+ B cells for elimination by antibody-dependent cell-mediated cytotoxicity (ADCC). VAY736 has anti-leukemia activity in preclinical CLL models that is superior to that of anti-CD20 mAbs (McWilliams EM, et al. Blood Adv 2019;3:447-460). Although Bruton's tyrosine kinase inhibitors (BTKis; acalabrutinib, ibrutinib) are the current standard of care for CLL, the indefinite length of monotherapy required may result in cumulative clinical or economic toxicity and/or acquired treatment resistance. In preclinical models, adding VAY736 to ibrutinib significantly improved survival and reduced disease burden, suggesting that this combination may augment the anti-leukemia response and allow patients (pts) to discontinue ibrutinib.
Methods:
This dose escalation/expansion trial (NCT03400176) enrolled pts with CLL undergoing either first- or second-line therapy with ibrutinib and whose disease failed to achieve a complete response (CR) after >1 year of therapy or who had CLL with a mutation associated with ibrutinib resistance. Pts received oral ibrutinib (420 mg) once daily and VAY736 IV at 0.3, 1, 3, or 9 mg/kg once every 2 weeks. In the expansion, pts were enrolled into 2 arms depending on whether ibrutinib resistance mutations were present at baseline. Pts received VAY736 + ibrutinib for up to 6 28-day cycles. After 6 cycles, pts with a CR discontinued VAY736 and received ibrutinib for an additional 2 cycles; all other pts continued VAY736 + ibrutinib for those 2 cycles. Pts achieving undetectable minimal residual disease (uMRD) at C9D1 could discontinue ibrutinib at the investigator's discretion. This study aimed to characterize the safety and tolerability of VAY736 + ibrutinib, determine the recommended dose for expansion (RDE), and explore the efficacy of this combination.
Results:
A total of 32 pts (median age 65 years; ECOG PS 0: 91%) were treated prior to data cutoff (May 10, 2021). Overall, 19 pts completed therapy and 4 discontinued VAY736 + ibrutinib (primarily due to disease progression); 4 pts remain on VAY736 + ibrutinib and 5 pts continue to receive ibrutinib. Of the enrolled pts, 44% had CLL cells with mutations associated with ibrutinib resistance (mainly [71%] BTKC481); the median number of prior regimens was 1 (range: 0.0-14.0); median duration of |
doi_str_mv | 10.1182/blood-2021-147775 |
format | Article |
fullrecord | <record><control><sourceid>elsevier_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1182_blood_2021_147775</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0006497121045766</els_id><sourcerecordid>S0006497121045766</sourcerecordid><originalsourceid>FETCH-LOGICAL-c1855-345dd743d256babe2e8358edb9fa04616feb39438ac8a795144ffeee07620d8e3</originalsourceid><addsrcrecordid>eNp9kMtKxDAUQIMoOD4-wN1d6qKapEnb0dUw-BgoKL7AVUmbWxudNkOSKv0g_9OOI7hzde_insPlEHLE6CljGT8rl9bqiFPOIibSNJVbZMIkzyJKOd0mE0ppEolpynbJnvdvlDIRczkhX4vuA30wryqY7hVCgzDT2gRjO7A1LFSnln2rSjh-nr2kcXICwcKidP14bkowHdyNJHbBw6cJDcwbZztTQT60q8ZWQ1jv2L9jaxQcz_P8BEbzn-CxQadWwznco--Xo6V2tgUFd43yON7BQ-j1cEB2arX0ePg798nT1eXj_CbKb68X81keVSyTMoqF1DoVseYyKVWJHLNYZqjLaa2oSFhSYxlPRZypKlPpVDIh6hoRaZpwqjOM9wnbeCtnvXdYFytnWuWGgtFi3bn46VysOxebziNzsWFwfOzDoCt8NQapUBuHVSi0Nf_Q3y3dhyU</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Investigating the Addition of Ianalumab (VAY736) to Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL) on Ibrutinib Therapy: Results from a Phase Ib Study</title><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><creator>Rogers, Kerry A. ; Flinn, Ian W. ; Stephens, Deborah M. ; Kipps, Thomas J. ; Larson, Sarah ; McGarry, Carolyn ; Hassounah, Nadia B. ; Gou, Liangke Connie ; Woo, Janghee ; Byrd, John C.</creator><creatorcontrib>Rogers, Kerry A. ; Flinn, Ian W. ; Stephens, Deborah M. ; Kipps, Thomas J. ; Larson, Sarah ; McGarry, Carolyn ; Hassounah, Nadia B. ; Gou, Liangke Connie ; Woo, Janghee ; Byrd, John C.</creatorcontrib><description>Introduction:
B-cell activating factor receptor (BAFF-R) enhances the survival and regulation of normal and malignant B cells. VAY736 is a human monoclonal antibody (mAb) targeting BAFF-R that targets BAFF-R+ B cells for elimination by antibody-dependent cell-mediated cytotoxicity (ADCC). VAY736 has anti-leukemia activity in preclinical CLL models that is superior to that of anti-CD20 mAbs (McWilliams EM, et al. Blood Adv 2019;3:447-460). Although Bruton's tyrosine kinase inhibitors (BTKis; acalabrutinib, ibrutinib) are the current standard of care for CLL, the indefinite length of monotherapy required may result in cumulative clinical or economic toxicity and/or acquired treatment resistance. In preclinical models, adding VAY736 to ibrutinib significantly improved survival and reduced disease burden, suggesting that this combination may augment the anti-leukemia response and allow patients (pts) to discontinue ibrutinib.
Methods:
This dose escalation/expansion trial (NCT03400176) enrolled pts with CLL undergoing either first- or second-line therapy with ibrutinib and whose disease failed to achieve a complete response (CR) after >1 year of therapy or who had CLL with a mutation associated with ibrutinib resistance. Pts received oral ibrutinib (420 mg) once daily and VAY736 IV at 0.3, 1, 3, or 9 mg/kg once every 2 weeks. In the expansion, pts were enrolled into 2 arms depending on whether ibrutinib resistance mutations were present at baseline. Pts received VAY736 + ibrutinib for up to 6 28-day cycles. After 6 cycles, pts with a CR discontinued VAY736 and received ibrutinib for an additional 2 cycles; all other pts continued VAY736 + ibrutinib for those 2 cycles. Pts achieving undetectable minimal residual disease (uMRD) at C9D1 could discontinue ibrutinib at the investigator's discretion. This study aimed to characterize the safety and tolerability of VAY736 + ibrutinib, determine the recommended dose for expansion (RDE), and explore the efficacy of this combination.
Results:
A total of 32 pts (median age 65 years; ECOG PS 0: 91%) were treated prior to data cutoff (May 10, 2021). Overall, 19 pts completed therapy and 4 discontinued VAY736 + ibrutinib (primarily due to disease progression); 4 pts remain on VAY736 + ibrutinib and 5 pts continue to receive ibrutinib. Of the enrolled pts, 44% had CLL cells with mutations associated with ibrutinib resistance (mainly [71%] BTKC481); the median number of prior regimens was 1 (range: 0.0-14.0); median duration of prior ibrutinib therapy was 3.5 years (range: 0.2-8.3). Baseline cytogenetics were (not mutually exclusive): 19% del(17)(p13.1), 75% unmutated IGHV, 59% stimulated complex karyotypes (≥3 abnormalities), 34% del(11)(q22.3), 44% del(13)(q14), and 6% +12.
No dose-limiting toxicities were observed and the RDE was 3 mg/kg, based on pharmacokinetics, exposure-to-response relationship, pharmacodynamics, safety, and in vitro ADCC. Twelve (38%) pts experienced AEs of Grade ≥3, most common (occurring in ≥2 pts) were neutrophil count decreased (n=5), lymphocyte count decreased (n=2), hypophosphatemia (n=2), and elevated lipase (n=2).
The overall response at C9D1 for evaluable pts (n=21) was 38% CR, 5% CRi, 14% PR, 24% SD, and 19% PD (Fig. 1A). Thirteen (41%) pts achieved uMRD in blood. Eight pts (42%, 8/19) and 8 pts (42%, 8/19) had uMRD in blood and bone marrow (BM) at end of treatment (EoT), respectively. Among those, 6 pts were elected to discontinue ibrutinib and remained off treatment for 0.2-26.2 months and were still off therapy at the data cutoff. The median percentage change from baseline in MRD was -99.0% (range: -100.0% to -16.7%) and -97.3% (range: -100.0% to 1346.3%) in blood and BM, respectively. None of the pts who enrolled with CLL cells lacking mutations associated with ibrutinib resistance (11/11) developed mutations by C9D1. Although 1 pt with PLCG2 mutation eradicated mutant clones at EoT with VAY736, the response may vary depending on the type of mutation (Fig. 1B).
Conclusions:
VAY736 + ibrutinib was well tolerated with an acceptable safety profile enabling dose expansion. Clinical activity was observed including multiple pts attaining uMRD status in blood and BM, allowing 6 to discontinue ibrutinib therapy for an extended period. These data provide clinical evidence of the potent anti-leukemia activity of VAY736 and the potential to safely discontinue ibrutinib or other BTKi by VAY736 add-on therapy.
[Display omitted]
Rogers: AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Pharmacyclics: Consultancy; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Janssen: Research Funding. Flinn: TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to S</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2021-147775</identifier><language>eng</language><publisher>Elsevier Inc</publisher><ispartof>Blood, 2021-11, Vol.138 (Supplement 1), p.2631-2631</ispartof><rights>2021 American Society of Hematology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c1855-345dd743d256babe2e8358edb9fa04616feb39438ac8a795144ffeee07620d8e3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,27929,27930</link.rule.ids></links><search><creatorcontrib>Rogers, Kerry A.</creatorcontrib><creatorcontrib>Flinn, Ian W.</creatorcontrib><creatorcontrib>Stephens, Deborah M.</creatorcontrib><creatorcontrib>Kipps, Thomas J.</creatorcontrib><creatorcontrib>Larson, Sarah</creatorcontrib><creatorcontrib>McGarry, Carolyn</creatorcontrib><creatorcontrib>Hassounah, Nadia B.</creatorcontrib><creatorcontrib>Gou, Liangke Connie</creatorcontrib><creatorcontrib>Woo, Janghee</creatorcontrib><creatorcontrib>Byrd, John C.</creatorcontrib><title>Investigating the Addition of Ianalumab (VAY736) to Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL) on Ibrutinib Therapy: Results from a Phase Ib Study</title><title>Blood</title><description>Introduction:
B-cell activating factor receptor (BAFF-R) enhances the survival and regulation of normal and malignant B cells. VAY736 is a human monoclonal antibody (mAb) targeting BAFF-R that targets BAFF-R+ B cells for elimination by antibody-dependent cell-mediated cytotoxicity (ADCC). VAY736 has anti-leukemia activity in preclinical CLL models that is superior to that of anti-CD20 mAbs (McWilliams EM, et al. Blood Adv 2019;3:447-460). Although Bruton's tyrosine kinase inhibitors (BTKis; acalabrutinib, ibrutinib) are the current standard of care for CLL, the indefinite length of monotherapy required may result in cumulative clinical or economic toxicity and/or acquired treatment resistance. In preclinical models, adding VAY736 to ibrutinib significantly improved survival and reduced disease burden, suggesting that this combination may augment the anti-leukemia response and allow patients (pts) to discontinue ibrutinib.
Methods:
This dose escalation/expansion trial (NCT03400176) enrolled pts with CLL undergoing either first- or second-line therapy with ibrutinib and whose disease failed to achieve a complete response (CR) after >1 year of therapy or who had CLL with a mutation associated with ibrutinib resistance. Pts received oral ibrutinib (420 mg) once daily and VAY736 IV at 0.3, 1, 3, or 9 mg/kg once every 2 weeks. In the expansion, pts were enrolled into 2 arms depending on whether ibrutinib resistance mutations were present at baseline. Pts received VAY736 + ibrutinib for up to 6 28-day cycles. After 6 cycles, pts with a CR discontinued VAY736 and received ibrutinib for an additional 2 cycles; all other pts continued VAY736 + ibrutinib for those 2 cycles. Pts achieving undetectable minimal residual disease (uMRD) at C9D1 could discontinue ibrutinib at the investigator's discretion. This study aimed to characterize the safety and tolerability of VAY736 + ibrutinib, determine the recommended dose for expansion (RDE), and explore the efficacy of this combination.
Results:
A total of 32 pts (median age 65 years; ECOG PS 0: 91%) were treated prior to data cutoff (May 10, 2021). Overall, 19 pts completed therapy and 4 discontinued VAY736 + ibrutinib (primarily due to disease progression); 4 pts remain on VAY736 + ibrutinib and 5 pts continue to receive ibrutinib. Of the enrolled pts, 44% had CLL cells with mutations associated with ibrutinib resistance (mainly [71%] BTKC481); the median number of prior regimens was 1 (range: 0.0-14.0); median duration of prior ibrutinib therapy was 3.5 years (range: 0.2-8.3). Baseline cytogenetics were (not mutually exclusive): 19% del(17)(p13.1), 75% unmutated IGHV, 59% stimulated complex karyotypes (≥3 abnormalities), 34% del(11)(q22.3), 44% del(13)(q14), and 6% +12.
No dose-limiting toxicities were observed and the RDE was 3 mg/kg, based on pharmacokinetics, exposure-to-response relationship, pharmacodynamics, safety, and in vitro ADCC. Twelve (38%) pts experienced AEs of Grade ≥3, most common (occurring in ≥2 pts) were neutrophil count decreased (n=5), lymphocyte count decreased (n=2), hypophosphatemia (n=2), and elevated lipase (n=2).
The overall response at C9D1 for evaluable pts (n=21) was 38% CR, 5% CRi, 14% PR, 24% SD, and 19% PD (Fig. 1A). Thirteen (41%) pts achieved uMRD in blood. Eight pts (42%, 8/19) and 8 pts (42%, 8/19) had uMRD in blood and bone marrow (BM) at end of treatment (EoT), respectively. Among those, 6 pts were elected to discontinue ibrutinib and remained off treatment for 0.2-26.2 months and were still off therapy at the data cutoff. The median percentage change from baseline in MRD was -99.0% (range: -100.0% to -16.7%) and -97.3% (range: -100.0% to 1346.3%) in blood and BM, respectively. None of the pts who enrolled with CLL cells lacking mutations associated with ibrutinib resistance (11/11) developed mutations by C9D1. Although 1 pt with PLCG2 mutation eradicated mutant clones at EoT with VAY736, the response may vary depending on the type of mutation (Fig. 1B).
Conclusions:
VAY736 + ibrutinib was well tolerated with an acceptable safety profile enabling dose expansion. Clinical activity was observed including multiple pts attaining uMRD status in blood and BM, allowing 6 to discontinue ibrutinib therapy for an extended period. These data provide clinical evidence of the potent anti-leukemia activity of VAY736 and the potential to safely discontinue ibrutinib or other BTKi by VAY736 add-on therapy.
[Display omitted]
Rogers: AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Pharmacyclics: Consultancy; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Janssen: Research Funding. Flinn: TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to S</description><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kMtKxDAUQIMoOD4-wN1d6qKapEnb0dUw-BgoKL7AVUmbWxudNkOSKv0g_9OOI7hzde_insPlEHLE6CljGT8rl9bqiFPOIibSNJVbZMIkzyJKOd0mE0ppEolpynbJnvdvlDIRczkhX4vuA30wryqY7hVCgzDT2gRjO7A1LFSnln2rSjh-nr2kcXICwcKidP14bkowHdyNJHbBw6cJDcwbZztTQT60q8ZWQ1jv2L9jaxQcz_P8BEbzn-CxQadWwznco--Xo6V2tgUFd43yON7BQ-j1cEB2arX0ePg798nT1eXj_CbKb68X81keVSyTMoqF1DoVseYyKVWJHLNYZqjLaa2oSFhSYxlPRZypKlPpVDIh6hoRaZpwqjOM9wnbeCtnvXdYFytnWuWGgtFi3bn46VysOxebziNzsWFwfOzDoCt8NQapUBuHVSi0Nf_Q3y3dhyU</recordid><startdate>20211123</startdate><enddate>20211123</enddate><creator>Rogers, Kerry A.</creator><creator>Flinn, Ian W.</creator><creator>Stephens, Deborah M.</creator><creator>Kipps, Thomas J.</creator><creator>Larson, Sarah</creator><creator>McGarry, Carolyn</creator><creator>Hassounah, Nadia B.</creator><creator>Gou, Liangke Connie</creator><creator>Woo, Janghee</creator><creator>Byrd, John C.</creator><general>Elsevier Inc</general><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20211123</creationdate><title>Investigating the Addition of Ianalumab (VAY736) to Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL) on Ibrutinib Therapy: Results from a Phase Ib Study</title><author>Rogers, Kerry A. ; Flinn, Ian W. ; Stephens, Deborah M. ; Kipps, Thomas J. ; Larson, Sarah ; McGarry, Carolyn ; Hassounah, Nadia B. ; Gou, Liangke Connie ; Woo, Janghee ; Byrd, John C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1855-345dd743d256babe2e8358edb9fa04616feb39438ac8a795144ffeee07620d8e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rogers, Kerry A.</creatorcontrib><creatorcontrib>Flinn, Ian W.</creatorcontrib><creatorcontrib>Stephens, Deborah M.</creatorcontrib><creatorcontrib>Kipps, Thomas J.</creatorcontrib><creatorcontrib>Larson, Sarah</creatorcontrib><creatorcontrib>McGarry, Carolyn</creatorcontrib><creatorcontrib>Hassounah, Nadia B.</creatorcontrib><creatorcontrib>Gou, Liangke Connie</creatorcontrib><creatorcontrib>Woo, Janghee</creatorcontrib><creatorcontrib>Byrd, John C.</creatorcontrib><collection>CrossRef</collection><jtitle>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rogers, Kerry A.</au><au>Flinn, Ian W.</au><au>Stephens, Deborah M.</au><au>Kipps, Thomas J.</au><au>Larson, Sarah</au><au>McGarry, Carolyn</au><au>Hassounah, Nadia B.</au><au>Gou, Liangke Connie</au><au>Woo, Janghee</au><au>Byrd, John C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Investigating the Addition of Ianalumab (VAY736) to Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL) on Ibrutinib Therapy: Results from a Phase Ib Study</atitle><jtitle>Blood</jtitle><date>2021-11-23</date><risdate>2021</risdate><volume>138</volume><issue>Supplement 1</issue><spage>2631</spage><epage>2631</epage><pages>2631-2631</pages><issn>0006-4971</issn><eissn>1528-0020</eissn><abstract>Introduction:
B-cell activating factor receptor (BAFF-R) enhances the survival and regulation of normal and malignant B cells. VAY736 is a human monoclonal antibody (mAb) targeting BAFF-R that targets BAFF-R+ B cells for elimination by antibody-dependent cell-mediated cytotoxicity (ADCC). VAY736 has anti-leukemia activity in preclinical CLL models that is superior to that of anti-CD20 mAbs (McWilliams EM, et al. Blood Adv 2019;3:447-460). Although Bruton's tyrosine kinase inhibitors (BTKis; acalabrutinib, ibrutinib) are the current standard of care for CLL, the indefinite length of monotherapy required may result in cumulative clinical or economic toxicity and/or acquired treatment resistance. In preclinical models, adding VAY736 to ibrutinib significantly improved survival and reduced disease burden, suggesting that this combination may augment the anti-leukemia response and allow patients (pts) to discontinue ibrutinib.
Methods:
This dose escalation/expansion trial (NCT03400176) enrolled pts with CLL undergoing either first- or second-line therapy with ibrutinib and whose disease failed to achieve a complete response (CR) after >1 year of therapy or who had CLL with a mutation associated with ibrutinib resistance. Pts received oral ibrutinib (420 mg) once daily and VAY736 IV at 0.3, 1, 3, or 9 mg/kg once every 2 weeks. In the expansion, pts were enrolled into 2 arms depending on whether ibrutinib resistance mutations were present at baseline. Pts received VAY736 + ibrutinib for up to 6 28-day cycles. After 6 cycles, pts with a CR discontinued VAY736 and received ibrutinib for an additional 2 cycles; all other pts continued VAY736 + ibrutinib for those 2 cycles. Pts achieving undetectable minimal residual disease (uMRD) at C9D1 could discontinue ibrutinib at the investigator's discretion. This study aimed to characterize the safety and tolerability of VAY736 + ibrutinib, determine the recommended dose for expansion (RDE), and explore the efficacy of this combination.
Results:
A total of 32 pts (median age 65 years; ECOG PS 0: 91%) were treated prior to data cutoff (May 10, 2021). Overall, 19 pts completed therapy and 4 discontinued VAY736 + ibrutinib (primarily due to disease progression); 4 pts remain on VAY736 + ibrutinib and 5 pts continue to receive ibrutinib. Of the enrolled pts, 44% had CLL cells with mutations associated with ibrutinib resistance (mainly [71%] BTKC481); the median number of prior regimens was 1 (range: 0.0-14.0); median duration of prior ibrutinib therapy was 3.5 years (range: 0.2-8.3). Baseline cytogenetics were (not mutually exclusive): 19% del(17)(p13.1), 75% unmutated IGHV, 59% stimulated complex karyotypes (≥3 abnormalities), 34% del(11)(q22.3), 44% del(13)(q14), and 6% +12.
No dose-limiting toxicities were observed and the RDE was 3 mg/kg, based on pharmacokinetics, exposure-to-response relationship, pharmacodynamics, safety, and in vitro ADCC. Twelve (38%) pts experienced AEs of Grade ≥3, most common (occurring in ≥2 pts) were neutrophil count decreased (n=5), lymphocyte count decreased (n=2), hypophosphatemia (n=2), and elevated lipase (n=2).
The overall response at C9D1 for evaluable pts (n=21) was 38% CR, 5% CRi, 14% PR, 24% SD, and 19% PD (Fig. 1A). Thirteen (41%) pts achieved uMRD in blood. Eight pts (42%, 8/19) and 8 pts (42%, 8/19) had uMRD in blood and bone marrow (BM) at end of treatment (EoT), respectively. Among those, 6 pts were elected to discontinue ibrutinib and remained off treatment for 0.2-26.2 months and were still off therapy at the data cutoff. The median percentage change from baseline in MRD was -99.0% (range: -100.0% to -16.7%) and -97.3% (range: -100.0% to 1346.3%) in blood and BM, respectively. None of the pts who enrolled with CLL cells lacking mutations associated with ibrutinib resistance (11/11) developed mutations by C9D1. Although 1 pt with PLCG2 mutation eradicated mutant clones at EoT with VAY736, the response may vary depending on the type of mutation (Fig. 1B).
Conclusions:
VAY736 + ibrutinib was well tolerated with an acceptable safety profile enabling dose expansion. Clinical activity was observed including multiple pts attaining uMRD status in blood and BM, allowing 6 to discontinue ibrutinib therapy for an extended period. These data provide clinical evidence of the potent anti-leukemia activity of VAY736 and the potential to safely discontinue ibrutinib or other BTKi by VAY736 add-on therapy.
[Display omitted]
Rogers: AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Pharmacyclics: Consultancy; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Janssen: Research Funding. Flinn: TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to S</abstract><pub>Elsevier Inc</pub><doi>10.1182/blood-2021-147775</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0006-4971 |
ispartof | Blood, 2021-11, Vol.138 (Supplement 1), p.2631-2631 |
issn | 0006-4971 1528-0020 |
language | eng |
recordid | cdi_crossref_primary_10_1182_blood_2021_147775 |
source | Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
title | Investigating the Addition of Ianalumab (VAY736) to Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL) on Ibrutinib Therapy: Results from a Phase Ib Study |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-12T02%3A52%3A08IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-elsevier_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Investigating%20the%20Addition%20of%20Ianalumab%20(VAY736)%20to%20Ibrutinib%20in%20Patients%20with%20Chronic%20Lymphocytic%20Leukemia%20(CLL)%20on%20Ibrutinib%20Therapy:%20Results%20from%20a%20Phase%20Ib%20Study&rft.jtitle=Blood&rft.au=Rogers,%20Kerry%20A.&rft.date=2021-11-23&rft.volume=138&rft.issue=Supplement%201&rft.spage=2631&rft.epage=2631&rft.pages=2631-2631&rft.issn=0006-4971&rft.eissn=1528-0020&rft_id=info:doi/10.1182/blood-2021-147775&rft_dat=%3Celsevier_cross%3ES0006497121045766%3C/elsevier_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/&rft_els_id=S0006497121045766&rfr_iscdi=true |