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BTK inhibition in mantle cell and diffuse large cell lymphoma: the next steps

BTK inhibition in mantle cell and diffuse large cell lymphoma: the next steps. Kristie A. Blum, MD Associate Professor of Medicine Section Head, OSU Lymphoma Program. Discussion topics. Single agent ibrutinib trials Combination ibrutinib trials Prognostic factors in MCL and DLCL

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BTK inhibition in mantle cell and diffuse large cell lymphoma: the next steps

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  1. BTK inhibition in mantle cell and diffuse large cell lymphoma: the next steps Kristie A. Blum, MD Associate Professor of Medicine Section Head, OSU Lymphoma Program

  2. Discussion topics • Single agent ibrutinib trials • Combination ibrutinib trials • Prognostic factors in MCL and DLCL • Identification of high risk groups where novel treatment strategies required

  3. Mantle Cell Lymphoma • MCL is a rare type of B-cell non-Hodgkin’s lymphoma • Presentation can be indolent or aggressive • No standard front-line regimen: • R-HyperCVAD1 • R-CHOP2,6 or alternating RCHOP/RDHAP7 • Methotrexate with augmented R-CHOP3 • Nordic regimen4 • R-Bendamustine5 • Consolidation with autologous transplant in first remission may prolong progression-free survival6 • Options at relapse include ibrutinib, bortezomib, R-bendamustine, lenalidomide 1Romaguera et al. BJH (2010) 2Lenz et al. J Clin Oncol (2005) 3Damon et al. J Clin Oncol (2009) 4 Geisler et al. BJH 2012 5 Rummel et al. Lancet (2013) 6Dreyling et al. Blood (2005) 7 Hermine et al (ASH 2012, abstract 151)

  4. Bruton’s Tyrosine Kinase (BTK):A Critical Kinase in B-cell receptor mediated Lymphoma Cell Survival and Proliferation

  5. PCI-32765 (Ibrutinib): A First-in-Class Inhibitor of BTK • Forms covalent bond with cysteine-481 in BTK • High BTK specificity • IC50 = 0.5 nM • Daily oral dosing produces 24-hr BTK inhibition • Off target effects: • Blocks pERK, pJNK, NF-κB 1Chang, ASH. 2011.

  6. The New England JournalofMedicine established in 1812 august 8, 2013 vol. 369 no. 6 Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma Michael L. Wang, M.D., Simon Rule, M.D., Peter Martin, M.D., Andre Goy, M.D., Rebecca Auer, M.D., Ph.D., Brad S. Kahl, M.D., Wojciech Jurczak, M.D., Ph.D., Ranjana H. Advani, M.D., Jorge E. Romaguera, M.D., Michael E. Williams, M.D., Jacqueline C. Barrientos, M.D., Ewa Chmielowska, M.D., John Radford, M.D., Stephan Stilgenbauer, M.D., Martin Dreyling, M.D., Wieslaw Wiktor Jedrzejczak, M.D., Peter Johnson, M.D., Stephen E. Spurgeon, M.D., Lei Li, Ph.D., Liang Zhang, M.D., Ph.D., Kate Newberry, Ph.D., Zhishuo Ou, M.D., Nancy Cheng, M.S., Bingliang Fang, Ph.D., Jesse McGreivy, M.D., Fong Clow, Sc.D., Joseph J. Buggy, Ph.D., Betty Y. Chang, Ph.D., Darrin M. Beaupre, M.D., Ph.D., Lori A. Kunkel, M.D., and Kristie A. Blum, M.D.

  7. Patient Characteristics *4 of the original 115 patients never started therapy due to PD

  8. Best Response (Investigator assessed)Efficacy Population n=111, Median Follow Up ~15.3 months (range, 1.9-22.3) Percent of patients (%) 68% 68% 68% Bortezomib-naïve(n=63) Bortezomib-exposed(n=48) Total(n=111)

  9. Treatment Related and Unrelated AEs Occurring in >10% of Patients (1014 cycles administered to all pts) Hematogenous AE: Non-Hematogenous AE:

  10. Time to Response • Median time to response: 1.9 mos (range 1.4-13.7) • Median time to complete response: 5.5 mos (range 1.7 -11.5) • Median response duration: 17.5 mos (95% CI 15.8-NR) • Median PFS: 13.9 mos (95% CI: 7.0-NR)

  11. A tale of 2 patients • WV • 63 yo, relapsed stage IVA MCL • Diagnosed in 1993 • Pathology (CD20+, CD5+ (faint), Cyclin D1+, Ki-67 <10%). FISH for 11;14 is positive • Treatment history • 1993: Chlorambucil x 1 month • 1993-1994: Cytoxan and prednisone for 10 cycles • 1999: Rituximab x 4 weeks • 2002: Rituximab and IL-2 on clinical trial (Toxicity) • 2004-2008: Maintenance R • 2009: RCHOP X 4 followed by Auto SCT • 2011: Progressive adenopathy diffusely with abdominal mass of 6 cm, BM biopsy negative for involvement

  12. CT abdomen: 6/2011 (4.4 x 6.9 cm and 4.4 x 5.3 cm)

  13. 6 months on study (3.3 x 2.5 cm) - PR 12 months on study

  14. At 2 years on study achieves CRu, Currently receiving cycle 34

  15. A tale of 2 patients • VV • 67 yo, relapsed stage IVB MCL • Diagnosed in 2008 • Pathology (CD20+, CD5+, Cyclin D1+, Ki-67 50%). FISH for 11;14 is positive • Treatment history • 10/2008-7/2009: RCHOP x 6 cycles (CR) + Maintenance rituxan x 2 doses (PD) • 6/2010: Bortezomib x 6 cycles (PR) • 6/2011: Lenalidomide x 2 cycles (PD) • 8/2011: Progressive cervical, axillary, inguinal adenopathy

  16. Extensive retroperitoneal adenopathy 10.6 x 5.6 cm iliac mass

  17. 2 months: 8.7 x 4.1 cm, SD 4 months: 9.7 x 4.2 cm, SD *6 months: new pleural effusions, off study, dies 1 month later due to PD

  18. 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 StudyASH Annual Meeting Abstracts 2012: 686 Wyndham H. Wilson MD, PhD1, John F. Gerecitano MD, PhD2, Andre Goy MD3, Sven de Vos MD, PhD4, Vaishalee P. Kenkr, MD5, Paul Barr MD6, Kristie A. Blum MD7, Andrei R. Shustov MD8, Ranjana H. Advani MD9, Jason Lih PhD10, Mickey Williams PhD10, Roland Schmitz PhD1, Yandan Yang PhD1, Stefania Pittaluga MD, PhD1, George Wright PhD1, Lori A. Kunkel MD11, Jesse McGreivy MD11, Sriram Balasubramanian PhD11, Mei Cheng PhD11, Davina Moussa11, Joseph J. Buggy PhD11, and Louis M. Staudt MD, PhD1 1National Cancer Institute, Bethesda, MD; 2Memorial Sloan-Kettering Cancer Center, New York, NY 3The John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ; 4UCLA Medical Center, Los Angeles, CA; 5Department of Medicine - Hematology/Oncology, University of Wisconsin, Madison, WI; 6Hematology/Oncology, University of Rochester Medical Center, Rochester, NY 7The Ohio State University Medical Center, Columbus, OH; 8Seattle Cancer Care Alliance, Seattle, WA; 9Division of Oncology, Department of Medicine, Stanford, CA; 10NCI/NIH, SAIC Frederick National Laboratory for Cancer Research, Frederick, MD; 11Pharmacyclics, Inc., Sunnyvale, CA

  19. Molecular Subtypes of Diffuse Large B-Cell Lymphoma (DLBCL) Lenz et al, N Engl J Med. 2008 Nov 27;359(22):2313-23.

  20. Chronic Active B-Cell Receptor Signaling Activates NFκB in ABC DLBCL 21% have CD79A/B mutations 10% have CARD11 mutations Davis et al, Nature 2010:463;88-93.

  21. Patient Characteristics by GEP Analysis (Total 70 pts, 29 ABC, 20 GCB, 16 Unclassifiable, 5 Unknown) * No statistically significant differences between ABC and GCB were observed (p-values > 0.05)

  22. Waterfall Plot of Maximum Decrease inBi-dimensional Measurements (66 evaluable) ORR: 26% ABC 12/29 (41%) GCB 2/18 (11%) UNK 3/4 (75%)

  23. Grade 3 or Higher AEs >3% Incidence (Unrelated and related) Hematologic AEs Non-Hematologic AEs

  24. CD79B Mutant ABC DLBCL Predicts a High Rate of Response to Ibrutinib Percent Response (CR + PR) 4/5 5/7 10/29 CD79B: WT MYD88: WT Mutant Mutant CARD11: WT WT WT WT Mutant

  25. Patient example • JN • 64 yo female • Diagnosed in 2007 with stage IVA DLCL • RCHOP x 8 cycles 9/2007-3/2008 • 6/2009: Palpable new r cervical node • Biopsy: recurrent DLCL: Large and small lymphocytes that were CD20, CD79a, bcl-2 staining. Negative for bcl-6, CD10. MUM-1 not tested. FISH 14;18 negative • RICE x 2 cycles and ASCT (BEAM preparative regimen) in 9/2009 • 12/2011: Relapses with PET avid periaortic, aortocaval and iliac nodes, BM involved with large CD20 positive cells

  26. - PET/CT at 2 months demonstrates CR, repeat PET/CT and BM biopsy at 6 months confirms CR. - Remains on study, now on cycle 26 without recurrence - Has an available sibling donor, do you transplant and when?

  27. Questions from these two ibrutinib trials • Can we identify a subgroup of patients with MCL where ibrutinib isn’t active? • Does the disease rapidly worsen with withdrawal of ibrutinib in patients with MCL, particularly after initial period of SD? • Is the activity of ibrutinib truly restricted to the ABC subtype or are there selected GCB patients who could respond? • What are the relevant signaling pathways in the responding GCB patients? • Is the lack of activity in GCB patients simply due to a refractory patient population? • Does combination therapy improve efficacy of ibrutinib in MCL and DLCL?

  28. OSU 10052: Phase I Trial of the Bruton’s Tyrosine Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765), in Combination with Rituximab and Bendamustine in Patients with Relapsed/Refractory Non-Hodgkin’s Lymphoma Blum KA, Christian B, Flynn JM, Jaglowski SM, Jones JA, Maddocks K, and Byrd JC. ASH Annual Meeting Abstracts, 2012, abstract 1643

  29. Eligibility Criteria • Relapsed or refractory NHL including follicular, MZL, DLCL, transformed, MCL • After phase I study, 3 expansion cohorts planned with 10 pts each with MCL, DLCL, FL • Previously untreated MCL who are not transplant candidates also eligible • Prior bendamustine permitted • Required Laboratory • ANC > 1000/mm3 • platelets > 50,000/mm3 • Creatinine < 2.0 mg/dl • AST/ALT < 2.5 x ULN • Bilirubin < 1.5 x ULN • Patients requiring anti-coagulation with warfarin or LMWH excluded

  30. Treatment Schema D1 D28 Cycles 1-6 D28 D1 Cycles 7+ Continue until PD *Stepped up dosing of rituximab with 100 mg day 1 and 375 mg/m2 on day 2 permitted in cycle 1 for patients at high risk of infusion reactions ** Ibrutinib dosing per Dose Escalation Schema

  31. Treatment Summary All Patients

  32. Treatment Summary MCL Patients

  33. Patient example • GW • 62 yo female • Diagnosed in 2005 with stage IVA MCL • Observed • 6/2012 – rising WBC from 20,000 to 50,000. New Fe def anemia, colonoscopy demonstrates large mass consistent with MCL • Enrolls on R-bendamustine + ibrutinib • Cycle 1 day 1, WBC 52,000 (ALC 51,780), post treatment 14,000 (ALC 9800) • Cycle 1 day 2, WBC 156,000 (ALC 143,890) • Cycle 1 day 8, WBC 4.3 (ALC 170) • Cycle 1 day 15, WBC 3.3 (ALC 310) • Cycle 2 day 1, WBC 0.5 (ALC 230) - has prolonged neutropenia for 2 more weeks. Per protocol has to come off study • Completes 4 more cycles of BR - CR x 9 months

  34. Patient example • RK • 68 yo male • Diagnosed in 2007 with stage IVB MCL, blastic variant • 2 cycles of augmented RCHOP and methotrexate (CALGB regimen) and autologous transplant in 8/2007 • 9/2012 – New L supraclavicular, L subpectoral, L axillary adenopathy • BM biopsy: uninvolved • Enrolls on R-bendamustine + ibrutinib

  35. After cycle 3: CR, no residual adenopathy Pre-treatment: 3.6 x 2.7 cm L axillary node *Completed all 6 cycles, remains on ibrutinib alone now at cycle 13

  36. Treatment Summary DLCL Patients

  37. Patient example • MO • 61 yo female • Diagnosed in 9/2011 with stage IIIA DLCL • RCHOP x 3 cycles – persistent disease in inguinal nodes on PET • RICE x 3 cycles, IFXRT to L inguinal, Auto SCT 6/2012 - CR • 10/2012: Palpable new bilateral cervical nodes and tonsil enlargement • Biopsy: recurrent DLCL: MUM1, CD20, CD5 positive. Negative for bcl-6, CD10. FISH myc negative • Enrolls on R-bendamustine + ibrutinib • Cycle 1 d8: resolution of all palpable cervical nodes and tonsil enlargement • 3 cycles: CR based on PET, develops prolonged neutropenia – to allo transplant

  38. Patient example • DB • 59 yo female • Diagnosed in 7/2007 with stage IIA DLCL • REPOCH on CALGB trial x 6 cycles – CR • 3/2011, new L axillary adenopathy, biopsy confirms relapse • RICE x 2 cycles and Auto SCT 8/2011 - CR • 11/2012: Palpable new L axillary and L breast mass • Biopsy: recurrent DLCL: MUM1, CD20, bcl-2 positive. Negative for CD10. Ki-70%. FISH myc negative • Enrolls on R-bendamustine + ibrutinib • Cycle 1 day 8: Gr 3 macular-papular rash, resolution of breast mass and axillary node • Cycle 1 day 15 – rechallenge 420 mg ibrutinib, rash and fever within 4 hours of dosing • Off study due to severe, recurrent rash/DRESS

  39. Cycle 1, week 3 Pre-treatment

  40. Conclusions • R-Bendamustine + Ibrutinib is well tolerated in this cohort of patients • Higher incidence of gr. 3 rash (27%) than previously reported • Most of pts with rash had FL or DLCL (only 1 MCL) • Gr. 3 Rash in a R-B-ibrutinib trial in CLL pts was 10% • Bendamustine dose 70 mg/m2 and ibrutinib was 420 mg/d • Brown, et al. ASH 2013, abstract 525 • Responses seen in all subtypes (FL, MZL, transformed, MCL and DLBC) • Excellent ORR in evaluable MCL patients • ORR of 100% and CR of 81% compared to 68% and 21%, respectively, in single agent trial • 3/4 CRs seen in DLBC were of the ABC subtype • ORR of 30% similar to single agent

  41. NCI 9426/OSU 13022: A phase I study of ibrutinib and lenalidomide in relapsed NHL (PI: Christian) Eligibility • Relapsed or refractory B-cell NHL after at least one prior therapy • PS 0-2 • No prior lenalidomide or ibrutinib permitted • Required Laboratory • ANC > 1000/mm3 • platelets > 50,000/mm3 • Creatinine < 2.0 mg/dl • AST/ALT < 2.5 x ULN • Bilirubin < 1.5 x ULN • Patients requiring anti-coagulation with warfarin or LMWH excluded

  42. NCI 9426/OSU 13022: A phase I study of ibrutinib and lenalidomide in relapsed NHL (PI: Christian) Study Design: Phase 1 standard 3 + 3 dose escalation

  43. Future Directions • Randomized phase 3 trial of R-bendamustine + ibrutinib vs. R-bendamustine + placebo in patients > 65 yo with previously untreated MCL (accruing patients) • Randomized phase 3 trial of RCHOP +/- ibrutinib in ABC type DLCL • Phase 1 trial with 100% ORR, CR60% with 60% rates of neutropenia and thrombocytopenia(Younes et al. ASH 2013, abstract 852) • A051306 Randomized Phase II trial of R-lenalidomide + ibrutinib vs. R-bendamustine + ibrutinib in pts < 65 with previously untreated MCL • Based on our 10052 study, the success of R-lenalidomide in untreated MCL (ORR 77%, CR 40%, Ruan et al., ASH 2013, abstract 247), and an ongoing phase I of R-lenalidomide-ibrutinib in untreated follicular NHL (A051103) • Determine 3-year PFS of BRI induction + RI maintenance (Arm A) and RLI induction + RI maintenance (Arm B), • Aim to take most successful arm to randomized phase III study vs. transplant containing arm

  44. A051306: PI: K. Maddocks, P. Martin, K. Blum Patients age 18-65 with previously untreated stage II-IV MCL Arm A: Rituximab+Bendamustine+Ibrutinib (BRI) x 6 cycles Arm B: Rituximab+lenalidomide+Ibrutinib (LRI) x 12 cycles Re-stage including repeat BM biopsy with MRD assessments if initially involved CR or PR CR or PR Rituximab+Ibrutinib (RI) maintenance x 18 months Rituximab+Ibrutinib (RI) maintenance x 12 months

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