1. Should Chlorambucil Be Used with Obinutuzumab in Untreated CLL? Answer: YES! 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. 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

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. 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 G-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

6. Select Adverse Events: Stage 2 (≥3% Incidence) Grade ≥3 G-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

7. CLL11: Responses

8. Investigator-Assessed PFS G-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 G-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

9. CLL11: Overall Survival

10. CLL 11: 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(s) (e.g. bendamustine, FC, etc) 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

11. What data is available with respect to combining Obinutuzumab with drugs other than chlorambucil in patients with untreated CLL?

12. Safety and Efficacy of Obinutuzumab (GA101) with Fludarabine+Cyclophosphamide (G-FC) or Bendamustine (G-B) in the Initial Therapy of Patients with Chronic Lymphocytic Leukemia (CLL): Results from the Phase 1b GALTON Trial (GAO4779g) Brown JR et al. ASH 2013;Abstract 523

13. GALTON Trial Primary study endpoint: To evaluate the safety and tolerability of obinutuzumab in combination with common standard regimens for patients with treatment- naïve CLL (e.g. bendamustine; FC) Secondary Study endpoint: Response rates as per iwCLL criteria (including CT scans to confirm response) Brown JR et al. ASH 2013;Abstract 523

14. Phase Ib GALTON Trial Design Eligibility (n = 41) Previously untreated CLL CD20-positive G: IV, d1 (100 mg), d2 (900 mg), d8, 15 (1,000 mg) for cycle 1 and d1 (1,000 mg) for cycles 2-6 F: IV, 25 mg/m 2 on d2, 3, 4 for cycle 1 and d1, 2, 3 for cycles 2-6 C: IV, 250 mg/m 2 on d2, 3, 4 for cycle 1 and d1, 2, 3 for cycles 2-6 Benda: IV, 90 mg/m 2 on d2, 3 for cycle 1 and d1, 2 for cycles 2-6 G + FC 6 cycles (n = 21) G + bendamustine 6 cycles (n = 20) G=GA101=obinutuzumab; F=fludarabine; C=cyclophosphamide Brown JR et al. ASH 2013;Abstract 523

15. Adverse Events (AEs) Grade 3/4 AE G + FC (n = 21) G + Benda (n = 20) G + CLB (CLL 11) (n = 336) Any86%85%70% Neutropenia29%50%33% Febrile neutropenia19%10%2% Thrombocytopenia5%10% Anemia14%5%4% Infections19%5%12% Increased ALT/AST19%/10%5%/5%0 Tumor lysis syndrome (TLS)0%5%0 Ga101 IRR29%10%21% Brown JR et al. ASH 2013;Abstract 523

16. Response Rates Response RateG + FC (n=21)G + Benda (n=20) G + CLB (CLL II) (n=33) ORR62%90%78% Complete Response (CR)10%20%21% CRi14%25% Partial Response38%45%58% Stable Disease19%0%5% Progressive Disease (PD)0% 4% Not Evaluable5% 13% CRi = CR with incomplete blood count recovery Brown JR et al. ASH 2013;Abstract 523

17. Patient Disposition G-FC patients enrolled (n=21) –G-FC patients completing Rx = 14 –33% (n=7) discontinued Rx Cytopenias (n=6) LFT’s elevated (n=1) G-Benda patients enrolled (n=20) –G-Benda patients completing Rx = 17 –15% (n=3) discontinued Rx Cytopenia (i.e.neutropenia): n=2 M.D. decision (n=1) Overall, short median observation times = ~ 1 year –Need longer F/U for PFS data and assess long-term toxicity

18. Conclusions 1. CLL 11 is the largest clinical trial combining obinutuzumab with chlorambucil in untreated CLL FDA approval of the combo of G-CLB for upfront CLL was granted because of an OS advantage over CLB alone + better outcomes c/w R-CLB 2. GALTON trial is a small Phase Ib trial evaluating the safety and tolerability of combining obinutuzumab with FC or Benda in untreated CLL Concern: More toxicity in GALTON c/w CLL 11! 33% of GFC and 15% of G-Benda pts discontinued Rx Primarily secondary to cytopenias 3. Not clear that GFC is better than RFC or GB better than RB in upfront CLL; need more data and longer F/U 4. For now: CBL should be the ONLY chemo agent combined with Obinutuzumab to treat upfront CLL (outside of clinical trial participation)!!!