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Novel Agents for Indolent L ymphoma and Mantle Cell Lymphoma

Novel Agents for Indolent L ymphoma and Mantle Cell Lymphoma. Stephen Ansell, MD, PhD Mayo Clinic. Would we expect mantle cell lymphoma and follicular lymphoma to respond to similar agents?. Tiacci et al, Nature Reviews Cancer 6, 437- 448, 2006.

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Novel Agents for Indolent L ymphoma and Mantle Cell Lymphoma

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  1. Novel Agents for Indolent Lymphoma and Mantle Cell Lymphoma Stephen Ansell, MD, PhD Mayo Clinic

  2. Would we expect mantle cell lymphoma and follicular lymphoma to respond to similar agents? Tiacci et al, Nature Reviews Cancer 6, 437-448, 2006.

  3. Major aberrant pathways susceptible to targeted therapies. Humala, Younes. LeukLymphoma. 2013 May;54(5):912-21.

  4. Wnt signalling pathway is activated in Mantle Cell Lymphoma. Ansell SM. Blood 2008;112:4783-4784

  5. Novel Agents for Mantle Cell Lymphoma

  6. What are we comparing new agents to? Bortezomib in Relapsed Mantle Cell Lymphoma • 155 previously treated patients. • Response rate in 141 patients was 33% including 8% CRs. • Median DOR was 9.2 months. • Median TTP was 6.2 months. • Median OS not reached after a median follow-up of 13.4 months. Fisher R I et al. JCO 2006;24:4867-4874

  7. What are we comparing new agents to? Bendamustine in Relapsed Mantle Cell Lymphoma • 58 previously treated patients. • Response rate in 57 patients was 86% including 55% CRs. • Median PFS was 16 months (12m for prior). • Median PFS for patients with CR after bendamustine was 33 months • Median OS was 32.4 months. García-NoblejasA et al. Ann Hematol. 2014;93(9):1551-8

  8. Treatment options for Relapsed Mantle Cell Lymphoma Humala, Younes. LeukLymphoma. 2013 May;54(5):912-21.

  9. Efficacy of Lenalidomide in Relapsed Mantle Cell Lymphoma • 134 patients were enrolled (EMERGE study). • All bortezomib failures. • Median age of 67 years and median of 4 prior therapies. • The ORR was 28% (7.5% CR) • Median DOR of 16.6 months. • Median PFS was 4 months • Median OS was 19.0 months. Goy A et al. JCO 2013;31:3688-3695

  10. Efficacy of mTOR inhibition – Everolimus - in Relapsed Mantle Cell Lymphoma • 58 patients were enrolled (PILLAR-1 study). • All bortezomib failures • ORR – 8·6%. • 5 PRs (ORR 8.6%) • Study did not meet the objective of ≥8 responses among 57 patients. • Median PFS and OS were 4·4 months and 16·9 months Wang et al. Br J Haematol. 2014; 165(4):510-8.

  11. Efficacy of CDK4/6 inhibition – PD0332991 - in Relapsed Mantle Cell Lymphoma • 17 patients with relapsed/refractory disease • ORR – 18% with 1 complete and 2 partial responses. • Five patients achieved progression-free survival time of > 1 year • Responding patients demonstrated > 70%, > 90%, and ≥ 87.5% reductions in FLT SUV(max) and expression of Ki67 Leonard J P et al. Blood 2012;119:4597-4607

  12. Efficacy of PI3kinase inhibition – Idelalisib - in Relapsed Mantle Cell Lymphoma • 40 patients with relapsed/refractory MCL • 17/40 (43%) were refractory to bortezomib • ORR was 16/40 (40%), with CR in 2/40 (5%) patients. • ORR 69% in patients getting 150 mg twice daily or higher • Median DOR was 2.7 months, median PFS was 3.7 months • 1-year PFS was 22%. Kahl et al. Blood. 2014; 123(22):3398-405.

  13. Efficacy of BTK inhibition – Ibrutinib - in Relapsed Mantle Cell Lymphoma Wang ML et al. N Engl J Med 2013;369:507-516. • 111 patients enrolled. • ORR – 68% (75 patients), complete response rate of 21% and a partial response rate of 47%. • Prior treatment with bortezomib had no effect on the response rate. • Median response duration was 17.5 months. • Median progression-free survival was 13.9 months • Estimated rate of overall survival was 58% at 18 months.

  14. Novel Agents for Follicular Lymphoma

  15. What are we comparing new agents to? Rituximab retreatment in Relapsed Follicular Lymphoma • 52 patients with relapsed or refractory patients post previous rituximab • eight weekly infusions of rituximab • ORR - 69% with 47% CRs • Median PFS: 15.6 months • Davis study with 4 doses – ORR 40% (11% CR and 30% PR) Tobinai K, et al. CancerSci. 2011 Sep;102(9):1698-705.

  16. What are we comparing new agents to? Bendamustine in Relapsed Follicular Lymphoma • Multicenter study - bendamustine 120 mg/m2 Days 1 + 2 every 21 days • ORR In 62 follicular lymphoma patients - 74% with 20% CRs • Median DOR: 9.2 mo • Median PFS: 9.3 mo Kahl B, et al. Cancer. 2010 Jan 1;116(1):106-14.

  17. GA101 (obinutumumab)for Relapsed Follicular Lymphoma • Phase II study- 40 patients with relapsed indolent non-Hodgkin lymphoma, 34 with follicular • ORR - 55% in the 1,600/800-mg group (9% CRs) and 17% in the 400/400-mg group (no CRs). • Median PFS - 11.9 months in the 1,600/800-mg group and 6 months in the 400/400-mg group. Salles G A et al. JCO 2013;31:2920-2926

  18. Lenalidomide in Relapsed/Refractory Indolent NHL: Phase II Results 43 patients – follicular and other indolent lymphomas • Median PFS 4.4 months • Median DOR > 16.5 months • 7/10 responses ongoing at 15-28 months Witzig et al. J ClinOnc 2009;27:5404.

  19. Ibrutinibin Relapsed Indolent Lymphoma • Btk downstream of BCR signalling • PCI-32765 – oral inhibitor given daily. Phase 1 study • 56 patients (16 FL, 16 SLL, 7 DLBCL, 9 MCL, 4 Marginal zone lymphoma, 4 Waldenstrommacroglobulinemia) • ORR 54% (MCL -7/9, SLL – 11/16, FL – 6/16, DLBCL – 4/7, WM – 3/4, MZL – 1/4. • Well tolerated Advani et al,J ClinOncol. 2013;31(1):88-94.

  20. Efficacy of PI3kinase inhibition – Idelalisib - in Relapsed Indolent Lymphoma • Phase I study- 64 patients with relapsed indolent non-Hodgkin lymphoma • FL, 38 pts(59%); SLL, 11 pts(17%); MZL, 6 pts(9%); and LPL, 9 pts(14%) • Disease regression in 46/54 (85%) • ORR - 30/64 (47%), with 1 patient having a complete response (1.6%)r • Median DOR - 18.4 months • Median PFS - 7.6 months. Flinn I W et al. Blood 2014;123:3406-3413

  21. Idelalisib – Phase II study in Relapsed Indolent Lymphoma • 125 patients with relapsed indolent NHL • Idelalisib 150mg bid • FL n=72 (58%), SLL n=28 (22%), MZL n=15 (12%) LPL/WM n=10 (8%). • ORR– 57%. 7 CRs (6%), 63 PRs (50%) • FL (54%), SLL (61%), LPL/WM (80%), and MZL (47%). • Median DOR – 12.5 months • Median PFS – 11 months. Gopal AJ et al. ASH 2013; abstract 85

  22. Phase I/II study of InotuzumabOzogamicin With Rituximab (R-INO) in patients with lymphoma • Targets CD22. Conjugated to calicheamycin • 118 patients enrolled and received one or more cycles of R-INO (median, four cycles). • ORR 87% for relapsed FL (n = 39). • CR in 62% of patients with FL • 2-year PFS 68% for FL. Fayad L et al. JCO 2013;31:573-583

  23. Pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma • Pidilizumab targets PD-1 on T-cells • 32 patients enrolled. • The combination was well tolerated. • Of 29 evaluable patients, 19 (66%) achieved an objective response: CRs in 15 (52%) patients and PRs in four (14%). • Median PFS for all patients was 18·8 months Westin et al. Lancet Oncol. 2014;15(1):69-77.

  24. Conclusions • Similar classes of agents have promising activity in relapsed and refractory mantle cell lymphoma as well as indolent lymphomas. • Many current trials are combining these agents to improve results. • Future studies may need a rational approach to decide which drugs to combine. • A standard regimen and patient population will be needed to allow for comparisons between studies.

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