1. Lymphoma & Myeloma 2014 October 24, 2014 Obinutuzumab: Analysis of it’s Pivotal Data Myron S. Czuczman, MD Chief, Lymphoma/Myeloma Section Head, Lymphoma Translational Research Lab Roswell Park Cancer Institute Buffalo, NY

2. Original Article Obinutuzumab plus Chlorambucil in Patients with CLL and Coexisting Conditions Valentin Goede, M.D., Kirsten Fischer, M.D., Raymonde Busch, M.S., Anja Engelke, M.D., Barbara Eichhorst, M.D., Clemens M. Wendtner, M.D., Tatiana Chagorova, M.D., Javier de la Serna, M.D., Marie-Sarah Dilhuydy, M.D., Thomas Illmer, M.D., Stephen Opat, M.D., Carolyn J. Owen, M.D., Olga Samoylova, M.D., Karl-Anton Kreuzer, M.D., Stephan Stilgenbauer, M.D., Hartmut Döhner, M.D., Anton W. Langerak, Ph.D., Matthias Ritgen, M.D., Michael Kneba, M.D., Elina Asikanius, M.Sc., Kathryn Humphrey, B.Sc., Michael Wenger, M.D., and Michael Hallek, M.D. N Engl J Med Volume 370(12):1101-1110 March 20, 2014

3. Background CLL-11 is a large randomized Phase III trial of first-line chemoimmunotherapy for patients with CLL and comorbidities Obinutuzumab is a third-generation type II anti-CD20 monoclonal antibody Preliminary analysis of the Stage 1 part of CLL-11 demonstrated that treatment with obinutuzumab and chlorambucil (G-Clb) significantly improved PFS compared to Clb alone (Proc ASCO 2013;Abstract 7004) Study objective: To determine the benefit of anti-CD20 antibody-based chemoimmunotherapy (with Clb as backbone) and compare the efficacy of O-Clb to that of rituximab-Clb (R-Clb) in patients with untreated CLL with comorbidities Goede V et al. N Engl J Med 2014;370(12):1101-1110

4. Type I mAbsType II mAbs Localize CD20 to lipid raftsDo not localize CD20 to lipid rafts High CDC Minimal CDC ADCC activity Full number of binding sites / B-cell Half number of binding sites / B-cell Weak homotypic aggregation Strong homotypic aggregation Limited direct apoptosis Strong direct apoptosis Rituximab Ofatumumab Ublituximab Veltuzumab Tositumumab (B1) GA101 (Obinutuzumab) CD20 Type I and Type II mAbs

5. Obinutuzumab (GA101): new Type II, glycoengineered anti-CD20 monoclonal antibody First type II, glycoengineered, humanized anti-CD20 monoclonal antibody In preclinical studies compared to rituximab, GA101 provides: Increased direct cell death induction Enhanced ADCC GA101 is being evaluated in several B cell malignancies Umana P, et al. Blood 2006: 108; Abst # 229 Umana P, et al, Ann Oncol. 2008; 19(Suppl.4): Abst #098

6. Phase III CLL11 Trial Design Eligibility (n = 781) Previously untreated CLL with comorbidities Total CIRS score >6 and/or CrCl <70 mL/min G=Obinutuzumab: IV, 1,000 mg on d1, 8, 15 (cycle 1); d1 (cycles 2-6), every 28 days Rituximab: IV, 375 mg/m 2 d1 (cycle 1); 500 mg/m 2 d1 (cycles 2-6), every 28 days Clb: PO, 0.5 mg/kg d1, 15 (cycles 1-6), every 28 days Stage 2 directly compares O-Clb to R-Clb Pts with POD in the Clb-alone arm were allowed to cross over to O-Clb Primary endpoint: PFS G-Clb (n = 333) 6 cycles CIRS = cumulative illness rating scale; CrCl = creatinine clearance Clb (n = 118) 6 cycles R-Clb (n = 330) 6 cycles 2:1:2 Stage 1a G-Clb vs Clb Stage 1b R-Clb vs Clb R Goede V et al. N Engl J Med 2014;370(12):1101-1110

7. Disease Assessment (DA) and F/U DA was performed at base-line, after 3 cycles, 1 months and 3 months after end-of-Rx; then q 3 m until 3 years from last Rx; then q 6 m for 5 years and then yearly for 8 years CT scan performed in pts who achieved a CR or PR 2-3 m after end-of-Rx Pts who had a CR (or cytopenic CR): BM asp/bx was to be obtained CT scan was performed when POD was detected by physical exam Goede V et al. N Engl J Med 2014;370(12):1101-1110

8. CLL11: Baseline Patient Characteristics

9. CLL11: Baseline Disease Characteristics

10. Select Adverse Events: Stage 1 (≥3% Incidence) Grade ≥3 O-Clb (n = 241) Clb (n = 116) R-Clb (n = 225) Any73%50%56% Infusion-related reaction 21%—4% Neutropenia35%16%27% Anemia5%4% Thrombocytopenia11%4% Infection11%14%13% Pneumonia3% 5% Neutropenic Fever2%4%2% Goede V et al. N Engl J Med 2014;370(12):1101-1110

11. Select Adverse Events: Stage 2 (≥3% Incidence) Grade ≥3 O-Clb (n = 336) R-Clb (n = 321) Any70%55% Infusion-related reaction20%4% Neutropenia33%28% Anemia4% Thrombocytopenia10%3% Infection12%14% Pneumonia4%5% Neutropenic Fever2%1% Goede V et al. N Engl J Med 2014;370(12):1101-1110

12. Impact of Infusion-Related Reactions on Clinical Course Goede V et al. N Engl J Med 2014;370(12):1101-1110

13. Treatment Exposure Goede V et al. N Engl J Med 2014;370(12):1101-1110

14. Response Rates Response G-Clb (n = 238) Clb (n = 118) R-Clb (n = 233) ORR77.3%31.4%65.7% CR22.3%0%7.3% PR55.0%31.4%58.4% Response G-Clb (n = 333) R-Clb (n = 329) ORR78.4%65.1% CR20.7%7.0% PR57.7%58.1% Stage 2 Stage 1 ORR: G-Clb vs Clb, p < 0.001; R-Clb vs Clb, p < 0.001; G-Clb vs R-Clb, p < 0.001 Goede V et al. N Engl J Med 2014;370(12):1101-1110

15. Investigator-Assessed PFS O-Clb (n = 238) Clb (n = 118) R-Clb (n = 233) Median PFS 26.7 mo 11.1 mo 16.3 mo O-Clb vs Clb: HR = 0.18, p < 0.001 R-Clb vs Clb: HR = 0.44, p < 0.001 O-Clb (n = 333) R-Clb (n = 330) Median PFS 26.7 mo15.2 mo O-Clb vs R-Clb: HR = 0.39, p < 0.001 Stage 1 Stage 2 Goede V et al. N Engl J Med 2014;370(12):1101-1110

16. CLL11: Progression-Free Survival

17. Progression-free Survival with Obinutuzumab– Chlorambucil versus Chlorambucil Alone Goede V et al. N Engl J Med 2014;370(12):1101-1110

18. ORR After Cross-over to G-Clb Pts assigned to Clb-alone group (n=118) in whom POD developed during Rx or within 6m after end-of-Rx were allowed to cross-over to G-Clb Why “within 6 months”? –@ 6 m it appears that ~70-75% pts had not progressed in Clb-alone arm; med PFS = 11.1 m –Of those pts who did cross-over: ORR = 84%! –Majority of Clb-alone pts seemed to progress at a higher rate after 6 months –Could these pts have been salvaged with G-Chl? –Any other salvage Rx’s permitted / given? –Influence this had on OS curve? Goede V et al. N Engl J Med 2014;370(12):1101-1110

19. CLL11: Overall Survival

20. Blood MRD Sampling of Patients MRD: analyzed by allele-specific oligo PCR assay at base-line and 3 m after completion of Rx Only blood samples for MRD were required Approximately 1/3 of pts randomized to mAb + Clb did not have end-of-Rx MRD blood results available (secondary to technical reasons or sample not taken) Note: –Significant amount of missing data –~1/3 of PR pts achieved MRD-negativity in blood –Why was MRD only assessed at 3 m after Rx end? –“late” converters? –Duration of MRD in blood? Goede V et al. N Engl J Med 2014;370(12):1101-1110

21. Conclusions The combination of an anti-CD20 antibody (obinutuzumab or rituximab) with Clb improves outcomes for patients with previously untreated CLL and coexisting comorbidities G-Clb provided an overall survival advantage over Clb alone and induced deeper and longer remissions than did R-Clb Should use caution in extrapolating current data to previously treated CLL patients and/or other B-cell neoplasms The use of a more active chemo agent (e.g. bendamustine) combined with rituximab versus obinutuzumab may not give similar results US FDA approved obinutuzumab for use in combo with chlorambucil for previously untreated CLL on 11-1-13 Goede V et al. N Engl J Med 2014;370(12):1101-1110