Mg/Kg; These Values Were Care Across Multiple Cancers (Figure 1A)

Abstract Number: 2524 Evaluation of fixed-dose regimens of seribantumab in patients with solid tumors Bambang Adiwijaya1, Walid Kamoun1, Sara Ghassemifar1, Sergio Santillana1, Lecia V. Sequist2, Peter Kaufmann3, Johannes Ettl4, Joyce F. Liu5, Michaela J. Higgins6, J. Marc Pipas1 1Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts, USA; 2Massachusetts General Hospital, Boston, Massachusetts, USA; 3Norris Cotton Cancer Center, Lebanon, New Hampshire, USA ; 4Frauenklinik der Technischen Universität München, Munich, Germany ; 5Dana Farber Cancer Institute, Boston, MA; 6Mater Misericordiae University Hospital, Dublin, Ireland

Background Study information and baseline demographics Pharmacokinetics of fixed dose vs. weight-based dose Effects of pharmacokinetics on Safety

• Heregulin (HRG)-induced HER3 (ErbB3) signaling contributes to tumor cell Statistics • Fixed and weight-based doses showed similar variability (Figure 3 and Table 3). • From the association between concentration and safety, AE with significant proliferation and survival and is associated with a poor response to standard-of- association (p<0.05) are grade 1+ (G1+) diarrhea, fatigue, nausea, rash, and Baseline factors Subgroups N (%), or median • Steady-state Cmax were higher with 3 g than with 20 mg/kg; these values were care across multiple cancers (Figure 1A). stomatitis (Figure 5) (range) comparable to Cmax with 40 mg/kg. Study MM-121-01-100 43 (9%) • Seribantumab (MM-121) is a human monoclonal antibody that targets and • Steady-state Cavg were equal to or higher for fixed dose than comparable • None of the grade 3+ AEs were significantly associated with PK (Figure 5A). downregulates HER3 and blocks HRG from binding to HER3 (Figure1B). MM-121-01-101 182 (36%) weight-based dose. MM-121-02-02-03 18 (4%) • All doses tested had minimum concentrations (Cmin) higher than the nonclinical • Seribantumab has been previously investigated in Phase 1 and Phase 2 clinical MM-121-02-02-07 131 (26%) target concentration of 100 mg/L. studies (9 studies altogether) across multiple indications. MM-121-04-02-08 34 (7%) • With higher weight, weight-based dose resulted in higher exposure (average MM-121-05-01-05 48 (10%) concentration [C ] and maximum concentration [C ]), and fixed dose resulted • Seribantumab is currently in clinical trials for treatment of patients with high MM-121-06-01-06 43 (9%) avg max in lower exposure (Figure 4). expression of heregulin mRNA in non-small cell lung cancer (NSCLC) Treatment combination MM121 alone 43 (9%) (SHERLOC study, 3 g every 3 weeks [Q3W]+docetaxel) and in HR+/ HER2- MM121+cabazitaxel 11 (2%) metastatic breast cancer (mBC) (SHERBOC study, 3 g every 2 weeks MM121+carboplatin 11 (2%) [Q2W]+fulvestrant). MM121+cetuximab 34 (7%)

MM121+cetuximab+irinotecan 14 (3%) population patient Total (A) • Here, we aimed to evaluate seribantumab dose regimens based on PK and MM121+erlotinib 182 (36%) safety and compared various weight-based versus fixed dosing regimens (in NSCLC, 3 g Q3W vs. 20 mg/kg Q2W; in mBC, 3 g Q2W vs. 40 mg/kg loading MM121+exemestane 18 (4%) dose, followed by 20 mg/kg QW) MM121+gemcitabine 11 (2%) MM121+paclitaxel 34 (7%) BTC HRG MM121+paclitaxel+ 131 (26%) HER1 HER2 (EGFR) HER3 A HER3 B doxorubicin+cyclophosphamide MM121+pemetrexed 10 (2%) HRG Seribantumab Dose (mg/kg) 3.2 6 (1%) 6 7 (1%) HER3 10 4 (1%) 12 20 (4%) 15 3 (1%) 20 210 (42%) Tumor Cell Proliferation, Survival 40 249 (50%) and Drug Resistance Sex Female 350 (70%) Figure 3: Predicted pharmacokinetics by seribantumab dose regimens Figure 1: (A) HER3 molecular signaling (B) Seribantumab mechanism of action Male 149 (30%) Race Asian 19 (4%) GLS mean ratio Methods Geometric Means

PK combination treatment By (B) Black 35 (7%) Cycle Dose Regimen (ref:40+20mg/kg QW) • Pharmacokinetic data were available from a total of 499 adult patients with solid Other 20 (4%) Parameter Point Point tumors across multiple indications in 7 clinical trials treated with seribantumab White 425 (85%) 95%CI 95%CI Est Est alone or in combination with other treatments (Table1) Age (years) 59 (23-90.5) Initial Weight (kg) 72.5 (38.9-180) Clearance NA NA 2.90 2.80 3.00 NA NA NA • Available plasma concentrations obtained from patients were analyzed by Albumin (g/L) 39 (19-51) (L/week) population PK using a non-linear mixed effects modeling approach in Nonmem Volume (L) NA NA 3.18 3.11 3.25 NA NA NA Alkaline phosphatase (IU/L) 87 (31-879) Figure 5: Association between weight-based dosing PK and adverse events of software. Initial half- ALT (IU/L) 20 (4-123) NA NA 0.27 0.27 0.28 NA NA NA interest for grade 1+ and grade 3+ with logistic regression life (weeks) AST (IU/L) 23 (1.2-246) • PK was quantified with the following covariates: sex, race, age, weight, dose, Terminal Bilirubin (umol/L) 8.6 (1.7-300) study, and hepatic functions. half-life NA NA 1.65 1.62 1.69 NA NA NA AE rates of fixed dose vs. weight-based dose (weeks) Creatinine (umol/L) 70.7 (26.5-173) • Compared to weight-based dosing, fixed dosing tends to increase AE rates in • Association between weight-based dosing PK and safety were modeled for Lactate dehydrogenase 242.7 (108-6077) Average Cycle 1 40+20mg/kg QW 907.2 885.3 929.6 reference patients with lower weight and reduce AE rates in patients with higher weight conc [C ] (IU/L) avg grade 1+ and 3+ adverse events (AE) of interest for logistic regression. (mg/L) Cycle 1 3000mg Q2W 378.4 371.3 385.7 0.42 0.40 0.43 (Figure 6). Cycle 1 20mg/kg Q2W 173.0 168.6 177.5 0.19 0.18 0.20 • Using the logistic regression model obtained from the weight-based safety data Table 2: Distribution of baseline factors in the population PK dataset • In most instances (all except fatigue G1+), the predicted AE rates in lower- and simulated fixed dosing PK, fixed dosing AE rates of seribantumab were Cycle 1 3000mg Q3W 279.7 274.0 285.5 0.31 0.30 0.32 weight patients (<=70kg) treated with fixed dosing are still lower than the estimated. Steady-state 40+20mg/kg QW 636.9 620.3 654.0 reference predicted AE rates in higher-weight patients (>70kg) treated with weight-based Effects of baseline factors on clearance Steady-state 3000mg Q2W 645.7 630.9 660.8 1.01 0.98 1.05 dosing. Study ID / N Doses (IV PK sample collections Steady-state 20mg/kg Q2W 299.9 292.1 307.9 0.47 0.45 0.49 Indication / N patients PK • Population PK analysis identified a few statistically significant covariates mg/kg) Cycle.Week: Timepoint Phase samples including weight, sex, race, and albumin levels (Figure 2). Steady-state 3000mg Q3W 442.6 432.4 453.1 0.69 0.67 0.72 Maximum MM-121-01-100 121:44 43 3.2, 6, 10, 1.1, 1.3: Pre-infusion, end of Cycle 1 40+20mg/kg QW 1083.8 1057.0 1111.1 reference conc [C ] Advanced solid 15, 20, 40 infusion, 2h, 4h, 8h, 24h, 48h, • In this study, we evaluated the impact of weight on seribantumab PK. max (mg/L) Cycle 1 3000mg Q2W 937.5 917.2 958.2 0.87 0.84 0.89 tumors 72h Cycle 1 20mg/kg Q2W 459.1 447.3 471.3 0.42 0.41 0.44 Phase 1 1.2, 1.4, >=2.1: Pre-infusion, 30 day follow-up, 60 day follow-up Cycle 1 3000mg Q3W 937.5 917.2 958.2 0.87 0.84 0.89 MM-121-01-101 121+erlotinib: 200 182 Ph 1: 6, 1.1, 1.3, 2.1: pre-infusion, end of NSCLC Erlotinib: 59 12, 20 infusion, 2 h, 4 h, 6 h Steady-state 40+20mg/kg QW 880.3 858.8 902.4 reference Phase 1/2 Ph 2: 20 1.2, 1.4, 2.2, 2.3, >=3.1: Pre- Steady-state 3000mg Q2W 1242.5 1216.5 1269.0 1.41 1.37 1.46 Q2W infusion Steady-state 20mg/kg Q2W 588.9 574.0 604.3 0.67 0.65 0.69 30 day follow-up, 60 day follow- up Steady-state 3000mg Q3W 1102.2 1078.9 1125.9 1.25 1.21 1.29 MM-121-02-02-03 121+exemestane:59 18 40 (loading 1.1, 2.1: Pre-infusion, end of HER2- HR+ exmestane: 59 dose), 20 infusion, 2 h, 4 h, 6 h, 24 h metastatic breast Q1W 1.2, 1.4, 2.2, >=3.1:Pre-Infusion Table 3: Predicted PK parameters by seribantumab dose regimens cancer 1.3: Pre-infusion, end of infusion, Phase 2 2.5 h 30 day follow-up, 60 day follow- up MM-121-02-02-07 121+pacliatxel:133 131 40 (loading 1.1,2.1,4.1,5.1: Pre-infusion HER2- breast paclitaxel: 67 dose), 20 Figure 6: Predicted seribantumab adverse event rates by weight and dose cancer (neoadj.) Q1W regimens Phase 2 MM-121-04-02-08 121+paclitaxel:140 34 40 (loading 1.1, 1.2, 1.3, 1.4: Pre-infusion, Platinum resistant paclitaxel:83 dose), 20 end of infusion Conclusion ovarian cancer Q1W 2.1, 2.2: Pre-infusion ❖ The recommended fixed dose of seribantumab is 3 g Q3W+docetaxel in Phase 2 NSCLC and 3 g Q2W+fulvestrant in mBC. MM-121-05-01-05 121+cetuximab: 36 48 12, 20, 40 1.1, 1.3, 2.1: Pre-infusion, end of Solid tumors 121+cetuximab+ infusion, 2.5 h, 4 h, 6 h, 24 h ❖ The comparison of PK and safety of fixed vs. weigh-based dose suggests Phase 1 irinotecan:15 1.2, 1.4, 2.2, >=3.1: Pre-infusion comparable PK and safety results for both regimens. 30 day follow-up, 60 day follow- up ❖ The fixed dose of seribantumab allows acceptable concentrations and safety MM-121-06-01-06 121+gemcitabine:11 43 20, 40 1.1: Pre-infusion, end of Infusion, profiles. Solid tumors 121+carboplatin:11 2.5 h, 4 h, 6 h, 24 h, 48 h Phase 1 121+pemetrexed: 10 1.2, 1.3, 2.1, 2.2, 2.3, >=3.1: Pre- 121+cabazitaxel:11 infusion ❖ The findings of this study justify more convenient fixed dose regimens which 30 day follow-up, 60 day follow- potentially reduce drug waste and dosing errors. up Figure 4: Relationship between average seribantumab concentrations Figure 2: Impact of baseline factors on seribantumab clearance Table 1: Seribantumab clinical studies from which data for PK analysis was obtained and weight for alternative dose regimens Please contact Sara Ghassemifar at [email protected] for any A PASSION FOR OUTTHINKING CANCER questions or comments. © 2018 Merrimack Pharmaceuticals, Inc. All rights reserved.