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

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

3. Major aberrant pathways susceptible to targeted therapies. Humala, Younes. Leuk Lymphoma. 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 Fisher R I et al. JCO 2006;24:4867-4874 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.

7. What are we comparing new agents to? Bendamustine in Relapsed Mantle Cell Lymphoma García-Noblejas A et al. Ann Hematol. 2014;93(9):1551-8 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.

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

9. Goy A et al. JCO 2013;31:3688-3695 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. Efficacy of Lenalidomide in Relapsed Mantle Cell Lymphoma

10. Wang et al. Br J Haematol. 2014; 165(4):510-8. 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

11. Leonard J P et al. Blood 2012;119:4597-4607 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

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. 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. Efficacy of BTK inhibition – Ibrutinib - in Relapsed Mantle Cell Lymphoma

14. Novel Agents for Follicular Lymphoma

15.  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. Cancer Sci. 2011 Sep;102(9):1698-705. What are we comparing new agents to? Rituximab retreatment in Relapsed Follicular Lymphoma

16.  Multicenter study - bendamustine 120 mg/m 2 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. What are we comparing new agents to? Bendamustine in Relapsed Follicular Lymphoma

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 Witzig et al. J Clin Onc 2009;27:5404. Response*% of PatientsAE* (Grade 3/4)% of Patients ORR23Neutropenia46 CR7 Thrombocytopenia 19 PR16Febrile Neutropenia2 SD37Anemia9 PD40Asthenia5 Median PFS 4.4 months Median DOR > 16.5 months 7/10 responses ongoing at 15-28 months 43 patients – follicular and other indolent lymphomas

19. Ibrutinib in 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 Waldenstrom macroglobulinemia) – 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 Clin Oncol. 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. 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 Phase I/II study of Inotuzumab Ozogamicin With Rituximab (R-INO) in patients with lymphoma

23. Pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma Westin et al. Lancet Oncol. 2014;15(1):69-77. 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

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.