STN 125011 Tositumomab Therapeutic Regimen (TTR) [tositumomab plus I-131 tositumomab]

1. STN 125011 Tositumomab Therapeutic Regimen (TTR)[tositumomab plus I-131 tositumomab] Oncologic Drugs Advisory Committee December 17, 2002

2. Proposed Indication Treatment of Patients with Relapsed or Refractory, Low-Grade, Follicular, or Transformed Low-Grade Non-Hodgkin’s Lymphoma (NHL) including Patients with Rituximab-Refractory Follicular NHL

3. OVERVIEW OF CLINICAL STUDIESEfficacy • Study RIT-II-004 - The primary efficacy trial supporting the request for accelerated approval for the treatment of chemotherapy-refractory patients with low grade and follicular NHL, with or without transformation.

4. OVERVIEW OF CLINICAL STUDIES Efficacy • Study CP97-012 : The primary efficacy trial supporting standard approval for the treatment of Rituximab-refractory patients with follicular NHL.

5. OVERVIEW OF CLINICAL STUDIES Efficacy • Three additional studies provide supportive anti-tumor activity data for the proposed indications. • RIT-II-002 - controlled Phase 2 study • RIT-II-000 & 001 are single-arm trials

6. Study RIT-II-004Trial Design • multicenter • historically-controlled • single-arm • patients w/ chemotherapy-refractory low grade or follicular NHL • with or without transformation

7. Study RIT-II-004Analytic Plan (Final) • Primary Efficacy Endpoint – • proportion of patients with longer duration of response after TTR vs. proportion with longer duration of response after Last Qualifying Chemotherapy (LQC) regimen • based on MIRROR Panel assessment

8. Study RIT-II-004 Analytic Plan (Final) • Secondary Efficacy Endpoints • overall response rate • complete response rate • duration of response • time to progression • survival

9. Study RIT-II-004 • Study population consisted of 61 patients enrolled at 8 centers • FDA analyses include 1 patient who withdrew consent and did not receive either dosimetric or therapeutic dose

10. RIT-II-004 Among the 61 patients registered: • 7 (11%) responded to LQC • 1 (2%) achieved CR/CCR to LQC • Median duration of response - 4.1 months (range 3.0-5.4 months)

11. Study RIT-II-004 MIRROR-Assessed Response

12. Study RIT-II-004Primary Endpoint Analysis • Equivalent duration • Longer duration of response after TTR (>30 days longer) than after LQC • Longer duration of response after LQC than after TTR

13. Study RIT-II-004Primary Endpoint Analysis

14. Study RIT-II-004Primary Endpoint Analysis Response Frequency % of 61 ---------------------------------------------------------------------- Equivalent duration 29 48% Longer response w/ TTR 27 44% Longer response w/ LQC 5 8% Significant by McNemar’s and by sign-rank test

15. Study RIT-II-004

16. Study CP97-012Design • Single‑arm, multicenter • Conducted in patients who had relapsed after  1 course(s) of Rituximab • Endpoints: ORR, CR+CCR, response duration, time to progression, time to treatment failure, and survival.

17. Study CP97-012 Population/Subpopulations • Registered n = 43 • Treated n = 40 • “Indicated” Population • follicular NHL • Rituximab response duration of < 6 mosn = 30

18. Study CP97-012 Registered (n=43)

19. Study CP97-012 “Indicated” subpopulation (n=30)

20. Study CP97-012Exploratory Analysis of efficacy by responsiveness to Rituximab

21. Supportive studies • RIT-II-002 • RIT-II-001 • RIT-II-000

22. Study RIT-II-002Design • Two-arm • Open-label • Multi-center • Randomized (not stratified) • Chemotherapy-relapsed or refractory • Low-grade, follicular, or transformed low-grade NHL

23. Study RIT-II-002Design • Treatment Arms • Arm A –TTR (hot arm) • Arm B – unlabeled Tositumomab antibody (cold arm) • Endpoints: • 1 CR/CCR • 2° ORR, response duration, TTP, and toxicity profile

24. Study RIT-II-002 • 78 patients enrolled • 42 in arm A • 36 in arm B • Prognostic variables similar except for • 7% intermed. histology in A vs. 17% B • 10% high IPI in Arm A vs. 3% in Arm B • 52%  5 cm lesions Arm A vs. 34% Arm B

25. Study RIT-II-002

28. Survival in Years RIT-II-002

29. Study RIT-I-000 • Single-center, dose escalation study • to determine • the optimal biologic dose of cold antibody • MTD for TTR in patients with and without prior BMT • 59 patients were enrolled • 22 patients without prior BMT were treated at the MTD

30. Study RIT-II-001 • Multicenter, single arm study to assess reproducibility of dosimetry methods across clinical sites • 47 patients enrolled

31. Overview of Study Results

32. Pooled Subset Analyses • Long-term responders • Submitted by sponsor to show that TTR provides “a meaningful therapeutic benefit over existing treatments” in support of accelerated approval • Low-Grade Transformed NHL • Analyses requested by FDA to assess for differences in activity in transformed vs. non-transformed since results include both types of patients

33. Long-Term Responders • Defined as responding patients with TTP  1 year per MIRROR review • 76/271 (28%) patients identified by MIRROR • 68/271 who rec’d a single dosimetric and any therapeutic dose • Patients retrospectively identified across 5 efficacy/activity studies (n=271)

34. Long-term responders (n=68) • CR/CCR - 54 of 68 (79%) • PR - 14 of 68 (21%) • Median response duration 4.9 years (range from 0.9 to 7.8+ years)

36. Low Grade NHL w/Transformation • 71 of 271 (26%) patients across 5 efficacy studies with evidence of transformed histology • FDA reviewed and confirmed sufficient info to document transformation in 40 of the 59 (remaining 12 under review)

37. Low Grade NHL w/Transformation • ORR 40% (16/40) • CR/CCR 26% (11/40) • Median response duration 1.6 years (range 0.1+ to 4.9 years)

38. Safety Summary • Hematologic-acute • Neutropenia/lymphopenia: Infections • Thrombocytopenia: Hemorrhagic events • Infusional reactions • Gastrointestinal toxicity • Immune responses to murine protein • Delayed toxicity due to irradiation • Hypothyroidism • Secondary leukemias, myelodysplasia, other cancers

39. Safety Database • Safety data provided for 620 patients • 229 patients enrolled in 5 efficacy/activity studies (RIT‑I‑000, RIT-II-001, RIT‑II‑002, RIT‑II‑004 and CP‑97‑012) • 391 patients treated under expanded access experience in Protocol CP-98-020 and 4 sponsor-investigator INDs

40. Safety Database

41. Safety Database • Safety profile in 5 efficacy/activity studies (n=229, ISS-A) showed a higher incidence for adverse events in the first 13 weeks vs. expanded access (n=391, ISS-B) • Less comprehensive collection of data in expanded access and no monitoring • Underreporting of AEs in expanded access confirmed during inspection

42. Incidence of AEs

43. Incidence of AEs

44. Incidence of SAE

45. Acute Hematologic Toxicity • Complete blood counts were to be collected at least weekly beginning at week 3 until • recovery from nadir • removal from study • Patients with missing data during the period of expected nadir (weeks 5-9) or at recovery (week 13) were assigned worst toxicity in “Worst case scenario” analyses

46. Acute Hematologic Toxicity

47. Acute Hematologic Toxicity

48. Lymphopenia in RIT-001 & 003

49. Infections/Fever Fever • 37% (84 patients) • 19% (43 pts)  study day 14 • 7-8% (15 pts/3 missing) fever associated with neutropenia

50. Infectious Events