Presentation on theme: "Wilson WH et al. Proc ASH 2012;Abstract 686."— Presentation transcript:
1Wilson WH et al. Proc ASH 2012;Abstract 686. The Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765), Has Preferential Activity in the ABC Subtype of Relapsed/Refractory De Novo Diffuse Large B-Cell Lymphoma (DLBCL): Interim Results of a Multicenter, Open-Label, Phase 2 StudyWilson WH et al.Proc ASH 2012;Abstract 686.
2BackgroundSurvival of activated B-cell-like (ABC) but not germinal center B-cell-like (GCB) DLBCL cell lines is sustained by “chronic active” B-cell receptor (BCR) signaling.Constitutive activation of NFkB leads to activation of a prosurvival program in ABC DLBCL.Mutations in the BCR subunit CD79B and in the adaptor protein for toll-like receptors, MYD88, occur more frequently in ABC than GCB DLBCL and could lead to the activation of NFkB and chronic BCR signaling in ABC DLBCL.Ibrutinib is a first-in-class oral inhibitor of Bruton tyrosine kinase (BTK), a kinase in the BCR pathway.Study objective: Evaluate the efficacy and safety of ibrutinib in relapsed/refractory DLBCL.Wilson WH et al. Proc ASH 2012;Abstract 686.
3Phase II Study Design Eligibility (N = 70) Relapsed/refractory de novo DLBCLProgressive disease (PD) after ASCT or ineligible for ASCTArchival tissue for central reviewNo primary mediastinal DLBCL, transformed DLBCL or CNS involvementIbrutinib:560 mg/d, POASCT = autologous stem cell transplantGene expression profiling of biopsy tissues using Affymetrix arrays to identify DLBCL subtype (ABC, GCB, unclassifiable)Mutations in tumor samples analyzed by PCR and DNA sequencingABC DLBCL tumors analyzed for mutations in CD79B, MYD88 and CARD11 genesWilson WH et al. Proc ASH 2012;Abstract 686.
4Waterfall Plot of Maximum Decrease in Bidimensional Measurements ABC (N = 23)GCB (N = 12)Unclassifiable (N = 8)Unknown (N = 3)% Change from Baseline SPDOnly includes pts with post baseline LN measurements* Best response was PD due to clinical progressionWith permission from Wilson WH et al. Proc ASH 2012;Abstract 686.
5Percent of patients (%) Response to IbrutinibITT populationABC versus GCB DLBCL50100908070605040302010PRCRp = 0.007403023% (16/70)41% (12/29)% Response (CR + PR)Percent of patients (%)2014%PR 24%10PR 5% (1/20)9%CR 17%ORRABC DLBCLGCB DLBCLORR = overall response rate; PR = partial response; CR = complete responseWith permission from Wilson WH et al. Proc ASH 2012;Abstract 686.
6Overall Survival in ABC and GCB DLBCL Probability of Survivalp =Overall Survival (months)ABC (n = 29)GCB (n = 20)Median OS9.76 mo3.35 moWith permission from Wilson WH et al. Proc ASH 2012;Abstract 686.
7Response of CD79B-, MYD88- and CARD11-Mutant ABC DLBCL to Ibrutinib 1008060402080%71%Percent Response (CR + PR)34%5/710/294/50/50/4CD79B:MYD88 L265P:CARD11:Mutant—WT—Mutant—WTMutant——MutantWith permission from Wilson WH et al. Proc ASH 2012;Abstract 686.
8Grade ≥3 Adverse Events Hematologic AEs* Non-Hematologic AEs* Grade 3 Lymphocyte count decreasedNeutropeniaThrombocytopeniaAnemiaPlatelet count decreasedWhite blood cell count decreased0%1%2%3%4%5%6%7%8%9%10%Grade 3Grade 4Grade 5Non-Hematologic AEs*FatigueHyponatremia SepsisBlood bilirubin increasedDehydrationDyspnea PneumoniaVomiting0%1%2%3%4%5%6%7%8%9%10%* >3% incidence (unrelated and related to ibrutinib)With permission from Wilson WH et al. Proc ASH 2012;Abstract 686.
9Author ConclusionsIbrutinib induced a high response rate in relapsed/refractory ABC DLBCL.Ibrutinib had marginal activity in GCB DLBCL, supporting the ABC DLBCL molecular subtype as a biomarker for activity.CD79B-mutant tumors responded frequently to ibrutinib, suggesting that it inhibits “chronic active” BCR signaling in ABC DLBCL.Ibrutinib response did not require CD79B mutation, suggesting that BCR pathway addiction can occur by other means in ABC DLBCL.CARD11-mutant tumors were resistant, suggesting that ibrutinib response requires upstream BCR signaling.Tumors harboring only MYD88 L265P mutation were resistant to ibrutinib, suggesting a BCR-independent pathway to ABC DLBCL.Ibrutinib was associated with a favorable safety profile.Wilson WH et al. Proc ASH 2012;Abstract 686.
10Investigator Commentary: Phase II Study of Ibrutinib in the ABC Subtype of Relapsed/Refractory DLBCL The oral BTK inhibitor ibrutinib is one of the most dynamite drugs in lymphoid cancers. The drug is active in chronic lymphocytic leukemia/small lymphocytic lymphoma and mantle-cell lymphoma. Its activity in follicular lymphoma is less well defined.In DLBCL, the activity of ibrutinib is selective based on the cell of origin. The overall activity of ibrutinib in an unselected population in this study was not impressive. However, when patients were classified according to the cell of origin subtype, the overall response rate (ORR) for those with the ABC subtype was approximately 40%, whereas the ORR for those with the GCB subtype was 5%.This is an example of how a better understanding of the biology of the disease can lead to a more rational selection of patients for treatment with targeted agents. The preferential activity of ibrutinib in ABC DLBCL has implications not only for relapsed/refractory disease but also for the design of trials that may be initiated with ibrutinib in the front-line treatment of the disease.Interview with Brad S Kahl, MD, January 17, 2013