1. May 29 - June 2, 2015 CR Rate at 30 Mos Is a Feasible Surrogate Endpoint for PFS in First-line Follicular Lymphoma Trials CCO Independent Conference Highlights of the 2015 ASCO Annual Meeting* *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This program is supported by educational grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene Corporation, Genentech, Incyte, and Novartis.

2. clinicaloptions.com/oncology CR at 30 Mos as a Surrogate Endpoint for PFS in First-line FL Survival in Follicular Lymphoma: Background  Current FL treatments delay disease progression but are marked by frequent relapse [1]  Timelines for first-line FL clinical trials are long –Median PFS ~ 7 yrs; thus, phase III trials with PFS as endpoint would require 8-10 yrs –Surrogate endpoints with earlier readouts needed to complete clinical trials in a timely manner  Current study evaluated CR rate at 30 mos as potential surrogate endpoint for PFS in first-line FL using individual pt data from previously conducted randomized trials [2] 1. Hiddemann W, et al. Leukemia. 2014;28:1388-1395. 2. Sargent DJ, et al. ASCO 2015. Abstract 8504.

3. clinicaloptions.com/oncology CR at 30 Mos as a Surrogate Endpoint for PFS in First-line FL CR30 for PFS in FL: Study Design  Prospective meta-analysis of surrogacy evaluation –Previously untreated FL pts in randomized, multicenter studies published after 1990  FLASH (Follicular Lymphoma Analysis of Surrogate Hypotheses): collaboration of clinicians and statisticians created to analyze data  Prespecified principal surrogacy candidate: CR at 30 mos after enrollment –CRu not included; PET not used  Primary evaluation: trial-level surrogacy analysis with R2 linear regression models to determine how well treatment effect on CR30 predicts treatment effect on PFS –Additional surrogacy analysis at individual pt level Sargent DJ, et al. ASCO 2015. Abstract 8504.

4. clinicaloptions.com/oncology CR at 30 Mos as a Surrogate Endpoint for PFS in First-line FL CR30 for PFS in FL: Study Design  13 studies out of 348 screened used in final analysis –26 treatment arms including induction and maintenance –9 studies included rituximab in at least 1 treatment arm –8 studies with induction therapy; 5 with maintenance therapy –N = 3837  Primary qualification criteria –R 2 WLS or R 2 Copula ≥ 0.80 with lower bound of 95% CI > 0.6 and neither R 2 WLS or R 2 Copula < 0.7 Sargent DJ, et al. ASCO 2015. Abstract 8504.

5. clinicaloptions.com/oncology CR at 30 Mos as a Surrogate Endpoint for PFS in First-line FL CR30 for PFS in FL: Pt Population Characteristic Control (n = 1988) Experimental (n = 1849) P Value Median age, yrs 55.756.6.031 Male, % 5150.56 ECOG PS, %  0  1 56 40 59 36.097 FLIPI, %  Low  Intermediate  High (n = 1759) 18 39 44 (n = 1599) 18 38 44.93 Ann Arbor stage IV, % 6867.5 Sargent DJ, et al. ASCO 2015. Abstract 8504. Reprinted with permission.

6. clinicaloptions.com/oncology CR at 30 Mos as a Surrogate Endpoint for PFS in First-line FL CR30 for PFS in FL: Results  30-mo CR rate met prespecified surrogacy qualification criteria for PFS –R 2 WLS : 0.88 (95% CI: 0.77-0.96) –R 2 Copula : 0.86 (95% CI: 0.72-1.00)  Correlation similar for induction vs maintenance trials and rituximab vs non-rituximab trials  Surrogate threshold suggests that observed OR ≥ 1.56 in an ongoing trial will predict non-zero PFS treatment effect –Nearly 10% improvement in CR30 of experimental arm vs control arm would reliably predict non-zero PFS treatment effect  At individual pt level, overall global OR 11.84 shows CR30 associated with greatly reduced odds of progression Sargent DJ, et al. ASCO 2015. Abstract 8504. Reprinted with permission. Log(OR) on 30mCR Log(HR) on PFS -0.50.00.51.01.52.0 0.5 0.0 -0.5 -1.5 Log(HR PFS ) = -0.093 – 0.636 x log(OR 30mCR ) Object size is proportional to sample size

7. clinicaloptions.com/oncology CR at 30 Mos as a Surrogate Endpoint for PFS in First-line FL CR30 for PFS in FL: Individual Level Surrogacy Group Number of TrialsGlobal Odds Ratio (95% CI) Overall 1311.84 (10.03-13.65)  Rituximab trials 911.08 (9.13-13.03)  Non-rituximab trials 414.40 (9.96-18.84)  Induction trials 810.34 (8.27-12.41)  Maintenance trials 514.14 (10.82-17.46)  Global odds ratio: OR for PFS in pts with CR30 vs those without CR30 Sargent DJ, et al. ASCO 2015. Abstract 8504. Reprinted with permission.

8. clinicaloptions.com/oncology CR at 30 Mos as a Surrogate Endpoint for PFS in First-line FL CR30 for PFS in FL: Conclusions  CR rate at 30 mos met criteria as surrogate endpoint for PFS –Surrogacy conclusions limited to pt population evaluated (untreated FL pts receiving rituximab or non-rituximab therapy) –Surrogacy threshold effect: OR of 1.56 or improvement in CR30 rate from a control rate of 50% to experimental rate of 61% would predict a non-zero treatment effect on PFS in clinical trials  CR30 may be appropriate primary endpoint in future studies of first-line FL treatment  FLASH database offers rich resource for future FL studies Sargent DJ, et al. ASCO 2015. Abstract 8504.

9. Go Online for More CCO Coverage of ASCO 2015! clinicaloptions.com/oncology Short slidesets of all the key data Additional CME-certified analyses with expert faculty commentary on all the key studies in:  Gastrointestinal cancers  Genitourinary cancer  Hematologic malignancies  Immunotherapy  Lung cancer