Novel Agents for Indolent Lymphoma and Mantle Cell Lymphoma

Stephen Ansell, MD, PhDMayo Clinic

Tiacci et al, Nature Reviews Cancer 6, 437-448, 2006.

Would we expect mantle cell lymphoma and follicular lymphoma to respond to similar agents?

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

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.

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.

Humala, Younes. Leuk Lymphoma. 2013 May;54(5):912-21.

Treatment options for Relapsed Mantle Cell Lymphoma

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

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

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

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.

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

Novel Agents for 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? Rituximab retreatment 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.

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

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

Lenalidomide in Relapsed/Refractory Indolent NHL: Phase II Results

Witzig et al. J Clin Onc 2009;27:5404.

Response* % of Patients AE* (Grade 3/4) % of PatientsORR 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

43 patients – follicular and other indolent lymphomas

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 toleratedAdvani et al, J Clin Oncol. 2013;31(1):88-94.

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

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

• 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

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

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.