THE ROLE OF 90Y-IBRITUMOMAB TIUXETAN ZEVALIN IN THE TREATMENT OF FOLLICULAR LYMPHOMA Chasing a Moving Target

1. THE ROLE OF 90Y-IBRITUMOMAB TIUXETAN (ZEVALIN®) IN THE TREATMENT OF FOLLICULAR LYMPHOMAChasing a Moving Target Sagun D. Goyal Hematology/Oncology Grand Rounds September 16, 2011 Use generic nameUse generic name

2. No disclosures

3. Case #1 54 y/o M presents with massive ascites requiring 30 L LVP CT shows bulky mesenteric and RP LAD Biopsy shows “grade 1 follicular lymphoma” Treated with 6 cycles of R-CVP from 3/09 -10/09 with PR Relapsed with massive ascites in 2/2010 Treated with 6 cycles of BR from 2/10 – 8/10 with PR vs CR?? Progressed after 2 cycles of maintenance Rituxan Treated with 6 cycles of BR from 2/11 – 7/11 with PR Reason for referral – “evaluate for Zevalin” Progressed on RituxanProgressed on Rituxan

4. Case #2 53 y/o F presents with stage I follicular lymphoma involving R inguinal lymph node R-CHOP x 3 + XRT ending 8/2007 Recurrent systemic disease noted 5/2008 4 weekly rituxan + lenalidomide x 12 ending 10/2009 ? SD Progressive disease in RP ? hydronephrosis Bendamustine/rituxan x 6 ending 12/2010 ? PR Rituxan maintenance q3 months x 2 Incidentally noted bulky RP/inguinal LAD in 8/2011 What next?? Comment that both patients had very aggressive disease and that maybe they’re on the lower end of benefit from these therapiesComment that both patients had very aggressive disease and that maybe they’re on the lower end of benefit from these therapies

5. Outline Background Efficacy Safety Special circumstances Rituximab refractory Sequencing 1st-line vs 2nd-line+ Consolidation

6. Follicular lymphoma Most common indolent NHL 20-30% of all NHLs Median age at diagnosis: 60 Typically presents in advanced stage Management options Observation Single-agent immunotherapy Chemoimmunotherapy Radiation Radio-immunotherapy Not considered “curable” Solal-Céligny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood. 2004;104:1258-1265.Solal-Céligny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood. 2004;104:1258-1265.

7. Radioimmunotherapy XRT is highly effective treatment modality for FL Advanced stage of disease makes localized XRT an inappropriate treatment for FL CD20 makes a good target as it is expressed on >90% of B-NHL

8. Something better than rituximab? Single-agent rituximab (4 weekly doses) Response rates of ~50% (44% PR) in relapsed/refractory low-grade or follicular NHL Median time to progression (TTP) is 13.2 months

9. Unlabeled rituxan improves biodistributionUnlabeled rituxan improves biodistribution

10. Comparing yttrium-90 to iodine-131 Pure beta-emitter Produces higher energy radiation at longer path length Advantageous for bulky, poorly vascularized tumors May increase normal tissue toxicity Half life is 2.6 days vs 8.0 days Enables outpatient delivery Yttrium is retained within cell after internalization Iodine can undergo dehalogenation and can be transported out of cell

11. Treatment schema

14. Design 51 patients CD20+ relapsed/refractory B-cell NHL Low-grade (66%), Intermediate-grade (28%), Mantle cell (6%) Baseline characteristics (n = 51) Median age 60 Median 2 prior treatments 92% with prior anthracycline exposure 43% had BMI at study entry 37% had received EB XRT Disease No limit on bulky disease 59% has at least one mass = 5 cm BMI < 25% Counts – ANC > 1500, Hb > 8.0, plt > 100K Prior anti-CD20 therapy excluded* MTD 0.4 mCi/kg (received by 30 patients) 0.3 mCi/kg for pts with platelet 100-149K Definition of relapsed/refractoryDefinition of relapsed/refractory

15. Response

16. Response ? Plateau of curves, specify (A) all responders and (B) DLBCL? Plateau of curves, specify (A) all responders and (B) DLBCL

17. Correlation with prognostic factors Note higher RR in low-grade vs int-grade lymphomas; probably keep Table 2 but put in updates response slides hereNote higher RR in low-grade vs int-grade lymphomas; probably keep Table 2 but put in updates response slides here

18. Questions/Conclusions 90Y-ibritumomab tiuxetan is effective for the treatment of CD20+ B-cell NHL Seems better for low-grade, “low burden” disease ORR higher than single-agent rituximab?? But median TTP?? Are there long-term responders?

19. Address PERIOD OF F/UAddress PERIOD OF F/U

21. Method A – more conservative, duration was measure from date of last lab value before grade III/IV to date of first value in grade 2 Method B – duration was measured from date of first lab values in grade III/IV to last value in grade III/IV Blood counts measured weekly – therefore values differ by about 14 daysMethod A – more conservative, duration was measure from date of last lab value before grade III/IV to date of first value in grade 2 Method B – duration was measured from date of first lab values in grade III/IV to last value in grade III/IV Blood counts measured weekly – therefore values differ by about 14 days

22. Ongoing studies addressing whether use of growth factors can reduce duration of neutropenia; in FIT trial – 67% had grade III/IV neutropenia but only 8% had grade III/IV infectionsOngoing studies addressing whether use of growth factors can reduce duration of neutropenia; in FIT trial – 67% had grade III/IV neutropenia but only 8% had grade III/IV infections

23. Secondary malignancies 1% (n = 5) patients All had prior alkylator MDS in 2, AML in 2, MDS ? AML in 1 8 – 34 months after RIT 4 – 14 years after diagnosis of NHL

25. Results note how frequently patients were IMAGED or assessed for response; consider omitting variables partnote how frequently patients were IMAGED or assessed for response; consider omitting variables part

26. Results Superior ORR did not translate to longer TTP Not powered to assess differences in TTP RIT group had greater absolute shrinkage of tumor and small change in size from nadir SPD would constitute progression Mention censoringMention censoring

27. Conclusions What is meaningful endpoint? Superior ORR of RIT over rituximab did not translate to longer TTP, but did prolong time to next treatment Will there be survival benefit? Good response rates in chemo-resistant group

29. Study design 57 patients with follicular lymphoma Prior treatment with 4 weekly doses of rituximab No response TTP < 6 months Endpoints Primary ? ORR Secondary ? TTP, DOR, comparison to efficacy of prior rituximab

30. Response ORR – 74% CR – 15% PR – 59% Responses in: 50% of patients with bulky disease > 10cm 68% with 4+ prior therapies Discuss/look into biology of response according to rituxan concentration and b/l B cell count; question how effective this is going to be in someone who progresses 1 month after therapy; also look at timing of consolidation trial in terms of when the treatment was givenDiscuss/look into biology of response according to rituxan concentration and b/l B cell count; question how effective this is going to be in someone who progresses 1 month after therapy; also look at timing of consolidation trial in terms of when the treatment was given

31. Time to progression

32. Comparison to rituximab & prior chemotherapy

33. Questions How effective is this is going to be in someone who progresses 1 month after therapy. or now – while on maintenance rituximab?? High likelihood of “more” exposure to rituximab with modern treatment If outcomes are similar to prior chemotherapy outcomes, is the toxicity that comes with the prolonged cytopenias worth it?

35. Study design International, randomized, phase III trial CD20+ stage III/IV follicular lymphoma 414 patients enrolled Primary endpoint ? PFS

36. Not Median f/u for this study so it can be compared to updated f/u; now we follow with maintenance rituxan so how does this compare???; also compare to BR dataNot Median f/u for this study so it can be compared to updated f/u; now we follow with maintenance rituxan so how does this compare???; also compare to BR data

37. Comment that effective rescue with rituxan-containing regimens, to which most were rituxan-naïve may explain lack of diff in OS. Since trial was initiated prior to common use of rituximab/chemo combinations, only 14% had rituxan with induction; interesting that median PFS not reached with R-induction, therefore rituxan may overcome beneficial effects of RIT, but this trial was not designed or powered to detect differences based on front-line inductionComment that effective rescue with rituxan-containing regimens, to which most were rituxan-naïve may explain lack of diff in OS. Since trial was initiated prior to common use of rituximab/chemo combinations, only 14% had rituxan with induction; interesting that median PFS not reached with R-induction, therefore rituxan may overcome beneficial effects of RIT, but this trial was not designed or powered to detect differences based on front-line induction

38. Consolidation of 1st remission with 90Y-ibritumomab tiuxetan Highly effective in advanced stage follicular lymphoma Prolongs median PFS by ~3 years regardless of response High PR ? CR conversion rates Achieving a CR to first-line therapy ~ OS No unexpected toxicities

39. Questions What is role of consolidation now that common practice (based on PRIMA study) involves maintenance rituximab Use 6-8 cycles of immunochemotherapy followed by RIT consolidation (in patients who fail to achieve better than PR) and follow with maintenance rituximab Median PFS not reached at 90 months in CR/CRu groups Should consolidation be considered in that group?? Patients in this study did not get rituximab with induction chemotherapy How does this compare with newer 1st-line chemoimmunotherapy regimens

40. Front-line therapy Untreated stage III/IV follicular lymphoma > 50 y/o Started recruitment in June 2007 Endpoint Primary ? clinical/molecular remission rate at 6 months Secondary ? TTP, safety 59 patients recruited 6 month f/u 45% (CR), 40% (PR) ? ORR 85% >18 month f/u (33 pts) 52% (CR), 9% (PR), 36% (progressed or off study) “Duration of remission will be crucial issue for final comparison” Bone marrow involvement may preclude use in front-line setting

41. Frontline + maintenance 90Y-ibritumomab tiuxetan with maintenance rituximab as initial therapy for high tumor burden follicular lymphoma: A Wisconsin Oncology Network study Treatment Single-dose 90Y-ibritumomab tiuxetan 4 weekly doses of rituximab at 6 months Maintenance rituximab every 3 months for 5 years 16 patients enrolled (closed early due to slow accrual) ORR to 90Y-IT was 69% (lower than modern chemo-immunotherapy) Masses > 9cm ? early PD; < 9cm ? remission from 39-71 mos “FL patients with large nodal masses (>9 cm) should be considered for alternative therapies while patients with intermediate size masses (3-9 cm) have the potential for durable responses”

42. Conclusions RIT is effective for the treatment of follicular lymphoma Primary toxicity is reversible myelosuppression May be appropriate for certain patients Elderly Suboptimal PS Ineligible for transplant or chemotherapy Non-bulky disease Does not affect ability to receive subsequent Tranplant Chemotherapy?? cytopenias may be limiting factor in setting of unresponsive disease

43. NCCN Guidelines

44. Expert recommendations RIT may be used as initial monotherapy in selected patients who have stages II-IV low-bulk disease that does not require immediate chemotherapy and who choose NOT to be observed For relapsed/refractory patients…plethora of new agents being tested in clinical trials for follicular lymphoma…patients should always be considered for novel agents…

45. Considerations Clinical studies have been designed during a time when much has changed in the treatment of FL Introduction of rituximab as standard upfront treatment Use of bendamustine-based induction regimen Use of maintenance rituximab for 2 years Emergence of investigational targeted agents Duration of cytopenia nadir can limit continuation of successive therapies in setting of progressive disease ? Meaningful endpoint for indolent disease

46. Future directions Peri-transplant 90Y-ibritumomab tiuxetan incorporation in conditioning for autologous or allogeneic stem cell transplant 90Y-ibritumomab tiuxetan in post-transplant setting Front-line Randomized comparison between modern-day chemoimmunotherapy induction and RIT

47. Case #1 54 y/o M presents with massive ascites requiring 30 L LVP CT shows bulky mesenteric and RP LAD Biopsy shows “grade 1 follicular lymphoma” Treated with 6 cycles of R-CVP from 3/09 -10/09 with PR Relapsed with massive ascites in 2/2010 Treated with 6 cycles of BR from 2/10 – 8/10 with PR vs CR?? Progressed after 2 cycles of maintenance Rituxan Treated with 6 cycles of BR from 2/11 – 7/11 with PR Reason for referral – “evaluate for Zevalin” Progressed on RituxanProgressed on Rituxan

48. Case #2 53 y/o F presents with stage I follicular lymphoma involving R inguinal lymph node R-CHOP x 3 + XRT ending 8/2007 Recurrent systemic disease noted 5/2008 4 weekly rituxan + lenalidomide x 12 ending 10/2009 ? SD Progressive disease in RP ? hydronephrosis Bendamustine/rituxan x 6 ending 12/2010 ? PR Rituxan maintenance q3 months x 2 Incidentally noted bulky RP/inguinal LAD in 8/2011 What next?? Comment that both patients had very aggressive disease and that maybe they’re on the lower end of benefit from these therapiesComment that both patients had very aggressive disease and that maybe they’re on the lower end of benefit from these therapies

49. References Gordon LI et al. Durable responses after ibritumomab tiuxetan radioimmunotherapy for CD20+ B-cell lymphoma: long-term follow-up of a phase 1/2 study. Blood. 2004 Jun 15;103(12):4429-31. Epub 2004 Mar 11. Hagenbaeek A et al. 90Y-ibritumomab tiuxetan consolidation of first remission in advanced-stage follicular non-Hodgkin’s lymphoma: updated results after a median follow-up of 66.2 months from the international, randomized, phase III First-Line Indolent Trial (FIT) in 414 patients. Blood. 2010. ASH annual meeting abstracts. Illidge T and Morschhauser F. Radioimmunotherapy in follicular lymphoma. Best Pract Res Clin Haematol. 2011 Jun;24(2):279-93. Epub 2011 May 12. McLaughlin P et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998 Aug;16(8):2825-33. Morschhauser et al. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol. 2008 Nov 10;26(32):5156-64. Epub 2008 Oct 14. Solal-Céligny P et al. Follicular lymphoma international prognostic index. Blood. 2004 Sep 1;104(5):1258-65. Epub 2004 May 4. Scholz CW et al. 90Y-ibritumomab as first line treatment for follicular lymphoma. First results from an international phase II clinical trial. Blood. 2010. ASH annual meeting abstracts. Thorhildur K et al. 90Y-ibritumomab tiuxetan with maintenance rituximab as initial therapy for high tumor burden follicular lymphoma: A Wisconsin Oncology Network study. J Clin Oncol. 2011. ASCO annual meeting abstracts. Witzig TE et al. Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20(+) B-cell non-Hodgkin's lymphoma. J Clin Oncol. 1999 Dec;17(12):3793-803. Witzig TE et al . Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol. 2002 May 15;20(10):2453-63. Witzig TE et al. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's lymphoma. J Clin Oncol. 2002 Aug 1;20(15):3262-9. Witzig TE et al. Safety of yttrium-90 ibritumomab tiuxetan radioimmunotherapy for relapsed low-grade, follicular, or transformed non-hodgkin's lymphoma. J Clin Oncol. 2003 Apr 1;21(7):1263-70. Witzig TE et al. Treatment recommendations for radioimmunotherapy in follicular lymphoma: a consensus conference report. Leuk Lymphoma. 2011 Jul;52(7):1188-99. Epub 2011 May 23. www.nccn.org