Final Results of a Phase I Study of the Anti-CD22 Antibody-Drug Conjugate Pinatuzumab Vedotin (DCDT2980S) 4399 with or without in Patients with Relapsed or Refractory B-Cell Non-Hodgkin’s Lymphoma

Ranjana Advani,1 Andy Chen,2 Daniel Lebovic,3 Mark Brunvand,4 Andre Goy,5 Julie Chang,6 Ephraim Hochberg,7 Sreeni Yalamanchili,8 Robert Kahn,8 Dan Lu,8 Akiko Chai,8 Yu-Waye Chu,8 Bruce D. Cheson9 1Stanford University Medical Center, Stanford, CA; 2Oregon Health and Science University, Portland, OR; 3University of Michigan Medical School, Ann Arbor, MI; 4Colorado Blood Cancer Institute, Denver, CO; 5Hackensack University Medical Center, Hackensack, NJ; 6University of Wisconsin-Madison, Madison, WI; 7Massachusetts General Hospital, Boston, MA; 8Genentech, Inc., South San Francisco, CA; 9Georgetown University Hospital, Washington, DC BACKGROUND Table 1. Patient Baseline Characteristics. Figure 3. Time to First Onset of Peripheral Neuropathy. Figure 5. Pinatuzumab Vedotin Anti-Tumor Responses Observed by Lymphoma Subtypes ≥ 1.8 mg/kg. All Patients, n (%) Histology Patients, n (%) •• CD22 is a cell-surface antigen expressed on all mature B cells (except plasma cells). The antigen is expressed on nearly all B-cell hematologic malignancies. Age, median (range) 66 (30–89) Diffuse large B-cell lymphoma a 47 (57) •• The antibody drug conjugate pinatuzumab vedotin (DCDT2980S) consists of a potent microbubule disrupting Female (%) 31 (53) Follicular lymphoma 26 (32) agent, (MMAE), conjugated to a directed against CD22 via a ECOG performance status, n protease-cleavable peptide linker maleimidocaproylvaline-citrulline-p-aminobenzoyloxycarbonyl (MC-VC- Mantle cell lymphoma 3 (4) 0 23 (39) PABC) 1 32 (54) Small lymphocytic lymphoma 3 (4) 2 4 (7) •• We previously reported clinical activity and acceptable toxicity in patients with relapsed/refractory (R/R) Pharmacokinetics B-cell NHL treated at pinatuzumab vedotin doses of 1.8 and 2.4 mg/kg, with a maximum tolerated dose Prior systemic therapies, median (range) 3 (1–11) Marginal zone lymphoma 2 (2) • acMMAE PK: largely similar to total antibody with a trend of higher clearance (MTD) of 2.4 mg/kg either as a single-agent or in combination with rituximab (375 mg/m2) every 21 days 1 8 (13) • 2 11 (19) 1 Gray zone lymphoma 1 (1) •• Maximal concentrations of unconjugated MMAE were >100-fold lower than acMMAE (q21d) ≥3 40 (68) •• Small to moderate accumulation of acMMAE and total Ab on the q21d dosing schedule expected with no • Herein we report final results of the Phase 1 study Prior rituximab therapy 59 (100) • accumulation of free MMAE Rituximab refractory 38 (64) •• Concurrent rituximab administration did not dramatically impact pinatuzumab vedotin PK (Figure 4) Figure 1. Pinatuzumab Vedotin Mechanism of Action. Autologous stem cell transplant therapy 5 (8) a Includes 3 patients with transformed follicular lymphoma. Table 4. Cycle 1 Mean PK Parameters at 2.4 mg/kg. * No response on or within 6 months of last rituximab dose. Overall Safety PK Parameter acMMAE Total Antibody Free MMAE C (µg/mL) 0.834 (24.7%) 39.1 (30.3%) 5.55 (58.7%) Figure 6. PFS Kaplan-Meier Curves by Histology. •• The pinatuzumab vedotin + rituximab safety profile did not differ from pinatuzumab vedotin monotherapy (Figure 2) max AUCinf (day*µg/mL) 2.58 (37%) 254 (43.2%) 44.8 39.4%) DLBCL: Single-Agent Pinatuzumab Vedotin iNHL: Single-Agent Pinatuzumab Vedotin •• SAEs occurred in 21 (35%) of patients, including pyrexia (3), pneumonia (3) and dyspnea (3) in > 2 patients 1.0 1.0 CL (mL/day/kg) 21.3 (77.8%) 18.2 (136%) - Median days 115 Median days 232 95% CI 71-163 95% CI 75-NE •• Neutropenia and peripheral neuropathy accounted for the majority of pinatuzumab vedotin dose and schedule 0.8 0.8 Vss (mL/kg) 85.4 (45.2%) 128 (31.9%) - modifications (Table 2) Half-life (day) 7.36 (25.8%) 11.5 (48.9%) 3.46 (30.3%) 0.6 0.6

•• Three deaths due to disease progression occurred within 60 days of the last dose of pinatuzumab vedotin judged Numbers in the parentheses represent %CV. 0.4 0.4 Survival Rate Survival Rate

unrelated to study drug 0.2 0.2

Figure 4. Cycle 1 Mean PK Profiles after Pinatuzumab Vedotin Administration (2.4 mg/kg). 0.0 0.0 0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20 22 24 Figure 2. Treatment-Emergent AEs in ≥ 10% of Patients (1.8 and 2.4 mg/kg). Progression-Free Survival (Months) Progression-Free Survival (Months) acMMAE Free MMAE Number: 28 21 13 6 6 3 2 2 2 2 0 Number: 16 11 9 8 4 2 1 1 1 1 1 1 1 Single-Agent Pinatuzumab Vedotin (N=46) Pinatuzumab Vedotin + Rituximab (N=13) DLBCL: Pinatuzumab Vedotin + Rituximab iNHL: Pinatuzumab Vedotin + Rituximab 1.0 1.0 Median days 175 Median days NE 95% CI 31-NE 95% CI 18-NE 0.8 0.8

0.6 0.6

0.4 0.4 Survival Rate Survival Rate

0.2 0.2

0.0 0.0 0 2 4 6 8 10 12 14 16 18 0 2 4 6 8 10 12 14 16 18 Progression-Free Survival (Months) Progression-Free Survival (Months) METHODS Number: 7 5 4 3 2 2 2 2 1 Number: 5 4 3 2 1 1 1 1 1 Study Design •• This study evaluated safety, tolerability, pharmacokinetics (PK), and activity of pinatuzumab vedotin q21d CONCLUSIONS with or without rituximab (375 mg/m2) in patients with R/R B-cell NHL • •• Expanded cohorts of patients with R/R diffuse large cell lymphoma or indolent (i)NHL were evaluated at the • Pinatuzumab vedotin alone or combined with rituximab was generally well-tolerated. Rituximab had no impact on pinatuzumab vedotin PK single-agent MTD of 2.4 mg/kg q21d Table 2. Dose and Schedule Modifications. •• Peripheral neuropathy and neutropenia are the principal toxicities associated with pinatuzumab vedotin. Peripheral Single-Agent Pinatuzumab Vedotin Pinatuzumab Vedotin + Rituximab Pharmacokinetic and Pharmacodynamic Evaluations Dose Modification Clinical Activity/Efficacy neuropathy was generally manageable with dose delays and reductions. Clinical sequelae of neutropenia, e.g. (N=46) (N=13) •• PK analysis was performed for total antibody, antibody-conjugated MMAE (acMMAE), and unconjugated •• Overall objective responses were observed in 19/44 (43%) pinatuzumab vedotin and 4/12 (33%) pinatuzumab febrile neutropenia and infection were infrequent. Dose discontinuation, n (%) 12 (26) a 3 (23) b MMAE vedotin + rituximab patients •• Encouraging antitumor activity was observed in heavily pre-treated patients with R/R NHL including patients who Dose delay, n (%) 16 (35) c 6 (46) d •• Rituximab refractory DLBCL patients: responses seen in 6/22 and 1/5 patients treated with pinatuzumab vedotin were rituximab refractory Clinical Evaluations e f Dose reduction, n (%) 9 (20) 3 (23) and pinatuzumab vedotin + rituximab, respectively •• Based on limited data from small numbers of patients, the addition of rituximab to pinatuzumab vedotin did not 2 •• Anti-tumor activity evaluated per revised IWG criteria every three months; PET scans were performed at the Note: one patient may experience multiple AEs. PN, peripheral neuropathy; PMN, peripheral motor neuropathy; N, neutropenia. substantially increase the response rates compare to single agent pinatuzumab vedotin a b c d e f •• Rituximab refractory iNHL patients: responses seen in 2/6 and 0/2 patients treated with pinatuzumab vedotin and discretion of the investigator PN (9), PMN (1). PN (2). PN (3), PMN (2), N (5). PN (1). PN (6), N (2). PN (2). pinatuzumab vedotin + rituximab, respectively •• Combination pinatuzumab vedotin with rituximab continues to be evaluated in an ongoing randomized Phase II study (ROMULUS; ClinicalTrials.gov Identifier NCT01691898) in patients with R/R DLBCL and FL of pinatuzumab •• Treatment-emergent adverse events graded per NCI CTCAE v4.0 a Table 3. Peripheral Neuropathy Per Standard MedDRA Query. Table 5. Investigator-Assessed Best Responses in Efficacy Evaluable Patients by Histology. vedotin + rituximab versus a CD79b-directed ADC () with the same linker-cytotoxic agent + Single-Agent Pinatuzumab Vedotin Pinatuzumab Vedotin b Single-Agent Pinatuzumab Vedotin Pinatuzumab Vedotin rituximab Dose Modification DLBCL RESULTS (N=46) + Rituximab (N=13) (N=28) + Rituximab (N=7) Objective Response, n (%) 11 (39) 3 (43) Patient Characteristics, Patient Status Patients with PN AE, n (%) 26 (56) 5 (38) Complete Response (CR) 5 (18) 2 (29) REFERENCES Grade 1-2 21 (46) 3 (23) Partial Response (PR) 6 (21) 1 (14) •• Data cut off : September 2013; median time of follow up 286 days (range: 4-730) Grade 3-4 5 (11) 2 (15) Single-Agent Pinatuzumab Vedotin Pinatuzumab Vedotin 1. Advani et al. ICML 2013. Indolent NHL •• Forty-six patients were treated with single-agent pinatuzumab vedotin ≥ 1.8 mg/kg (7 at 1.8 mg/kg, 39 at 2.4 Patients reported PN completely reversed, n (% with PN AE) a 5 (19) 1 (20) (N=16) + Rituximab (N=5) 2. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579–86. Objective Response, n (%) 8 (50) 1 (20) mg/kg) and 13 with pinatuzumab vedotin + rituximab cohort (5 at 1.8 mg/kg, 8 at 2.4 mg/kg) a Onset of initial and/or subsequent PN events resolved and no new events are noted. Complete Response (CR) 3 (19) 1 (20) •• Patients received a median of 5 cycles (range 1-24) of pinatuzumab vedotin and 4 cycles (range 1-15) of •• Twenty (34%) patients had a prior history of peripheral neuropathy Partial Response (PR) 5 (31) 0 (0) ACKNOWLEDGMENTS pinatuzumab vedotin + rituximab a Patients who received ≥ 1 dose of study treatment and had ≥1 on-treatment tumor assessment. Disease measured by revised IWG •• Eighteen (31%) patients had ongoing peripheral neuropathy at study entry 2 b •• We thank the patients who participated in the study and their families •• Six patients continue to receive study treatment criteria. Includes three patients with transformed follicular lymphoma. •• Peripheral neuropathy was managed with dose delays and dose reductions •• provided support for this poster

ASH Annual Meeting, New Orleans, LA, December 7-10, 2013