Novel Agents for Indolent Lymphoma and Mantle Cell

Novel Agents for Indolent Lymphoma and Mantle Cell Lymphoma Stephen Ansell, MD, Ph. D 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.

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

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

Novel Agents for Mantle Cell Lymphoma

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 followup of 13. 4 months. Fisher R I et al. JCO 2006; 24: 4867 -4874

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 (12 m for prior). • Median PFS for patients with CR after bendamustine was 33 months • Median OS was 32. 4 months. García-Noblejas A et al. Ann Hematol. 2014; 93(9): 1551 -8

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

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

Efficacy of m. TOR 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.

Efficacy of CDK 4/6 inhibition – PD 0332991 - 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 Ki 67 Leonard J P et al. Blood 2012; 119: 4597 -4607

Efficacy of PI 3 kinase 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.

Efficacy of BTK inhibition – Ibrutinib - in Relapsed Mantle Cell Lymphoma • 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. Wang ML et al. N Engl J Med 2013; 369: 507 -516.

Novel Agents for Follicular Lymphoma

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. Cancer Sci. 2011 Sep; 102(9): 1698 -705.

What are we comparing new agents to? Bendamustine in Relapsed Follicular Lymphoma § 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.

GA 101 (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

Lenalidomide in Relapsed/Refractory Indolent NHL: Phase II Results 43 patients – follicular and other indolent lymphomas Response* % of Patients AE* (Grade 3/4) % of Patients ORR 23 Neutropenia 46 CR 7 Thrombocytopenia 19 PR 16 Febrile Neutropenia 2 SD 37 Anemia 9 PD 40 Asthenia 5 • Median PFS 4. 4 months • Median DOR > 16. 5 months • 7/10 responses ongoing at 15 -28 months Witzig et al. J Clin Onc 2009; 27: 5404.

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.

Efficacy of PI 3 kinase 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

Idelalisib – Phase II study in Relapsed Indolent Lymphoma • 125 patients with relapsed indolent NHL • Idelalisib 150 mg 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

Phase I/II study of Inotuzumab Ozogamicin With Rituximab (R-INO) in patients with lymphoma • Targets CD 22. 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

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.

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.