Phase II HALO-202: nab-Paclitaxel and Gemcitabine ± PEGPH20 in Untreated Metastatic Pancreatic Ductal Adenocarcinoma CCO Independent Conference Highlights* of the 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, Illinois *Clinical Care Options (CCO) is an independent medical education organization that provides conference coverage and other unique educational programs for healthcare professionals This activity is supported by educational grants from AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co., Inc.

nab-Paclitaxel/Gemcitabine ± PEGPH20 in Untreated Pancreatic Cancer: Background Accumulation of hyaluronan associated with accelerated tumor growth, negative predictor of survival in pancreatic ductal adenocarcinoma Naturally occurring polysaccharide component of tumor stroma Increases interstitial pressure, restricts blood flow and potentially drug delivery PEGPH20 (pegvorhyaluronidase alfa): degrades hyaluronan, remodels stroma HALO-202: phase II trial evaluating efficacy, safety of adding PEGPH20 to nab-paclitaxel + gemcitabine in previously untreated metastatic pancreatic ductal adenocarcinoma Slide credit: clinicaloptions.com Hingorani SR, et al. ASCO 2017. Abstract 4008.

HALO-202: Phase II Study Design Stage 1 (n = 146) 1:1 randomization Clinical hold set due to increased TE events in PAG arm Training Set for HA assay PEGPH20 3 mg/kg IV 2/wk x 3 wks cycle 1 then 1/wk x 3 wks cycle 2+ + nab-Paclitaxel 125 mg/m2 Days 1, 8, 15 + Gemcitabine 1000 mg/m2 Days 1, 8, 15 (n = 166) Pts with previously untreated stage IV pancreatic ductal adenocarcinoma; KPS 70-100 (N = 279) nab-Paclitaxel 125 mg/m2 Days 1, 8, 15 + Gemcitabine 1000 mg/m2 Days 1, 8, 15 (n = 113) Stage 2 (n = 133) 2:1 randomization Protocol amendment to include TE screening and enoxaparin prophylaxis Validation Set to evaluate HA algorithm DCR, disease control rate; DoR, duration of response; HA, hyaluronan; ITT, intent to treat; KPS, Karnofsky performance status; PAG, PEGPH20 + nab-paclitaxel + gemcitabine; TE, thromboembolic event. Endpoints Primary: PFS, thromboembolic event rate Secondary: PFS by HA level, ORR, OS Exploratory: OS by HA level, DoR, DCR Analysis Populations ITT: baseline, efficacy Treated: safety Slide credit: clinicaloptions.com Hingorani SR, et al. ASCO 2017. Abstract 4008.

HALO-202: Pt Characteristics (Stages 1 + 2) All Pts HA High* PAG (n = 166) AG (n = 113) (n = 49) (n = 35) Mean age, yrs (SD) ≥ 65 yrs, % 64 (10) 53 65 (9) 55 66 (9) 67 67 (7) 63 Male, % 61 49 43 KPS 70-80/≥ 90, % 32/68 36/64 33/67 37/63 Primary tumor location, % Head Body Tail 38 19 35 51 12 25 47 29 57 11 Metastasis in liver/lung, % 92/26 86/27 90/33 74/31 Serum CA 19-9 ≥ 37 U/mL, % 84 82 80 86 AG, nab-paclitaxel + gemcitabine; CA, calcium; ECM, extracellular matrix; HA, hyaluronan; KPS, Karnofsky performance status; PAG, PEGPH20 + nab-paclitaxel + gemcitabine; SD, standard deviation *HA high defined as ≥ 50% of ECM stained for hyaluronan using HA RxDx assay Slide credit: clinicaloptions.com Hingorani SR, et al. ASCO 2017. Abstract 4008. Pu J, et al. ASCO 2017. Abstract e23196.

HALO-202: PFS (Stages 1 + 2) All Pts HA-High Subset 100 100 PAG AG PAG (n = 166) 102 6.0 AG (n = 113) 67 5.3 100 100 Events Median PFS, mo HR (95% CI) P value PAG (n = 49) 24 9.2 AG (n = 35) 19 5.2 0.51 (0.26-1.00) .048 PAG AG PAG AG Events Median PFS, mo HR (95% CI) P value 80 80 0.73 (0.53-0.99) .045 60 60 PFS (%) PFS (%) 40 40 20 20 AG, nab-paclitaxel + gemcitabine; HA, hyaluronan; PAG, PEGPH20 + nab-paclitaxel + gemcitabine 2 4 6 8 10 12 14 16 18 2 4 6 8 10 12 14 16 18 Pts at Risk, n PAG AG Mos Pts at Risk, n PAG AG Mos 166 113 101 62 79 42 55 26 36 9 22 4 9 2 7 1 166 113 101 62 79 42 55 26 36 9 22 4 9 2 7 1 Slide credit: clinicaloptions.com Hingorani SR, et al. ASCO 2017. Abstract 4008. Reproduced with permission.

HALO-202: Other Efficacy Outcomes All Pts HA-High PAG (n = 166) AG (n = 113) (n = 49) (n = 35) Stages 1 + 2 ORR, % 40 33 45 31 Median OS, mos NR 11.5 8.5 HR (95% CI) 0.96 (0.57-1.61) Stage 2 only Median PFS, mos 8.6 4.5 0.63 (0.21-1.93) 11.7 7.8 0.52 (0.22-1.23) AG, nab-paclitaxel + gemcitabine; HA, hyaluronan; NR, not reported; PAG, PEGPH20 + nab-paclitaxel + gemcitabine. Slide credit: clinicaloptions.com Hingorani SR, et al. ASCO 2017. Abstract 4008.

HALO-202: Thromboembolic Events No difference in TE rate by treatment arm or tumor HA level TE Rate, % (n/N) All Pts PAG (n = 166) AG (n = 113) Stage 1 43 (32/74) 25 (15/61) Stage 2 40 mg/day enoxaparin* 1 mg/kg/day enoxaparin* 14 (12/86) 28 (5/18) 10 (7/68) 10 (4/39) 29 (2/7) 6 (2/32) *Prophylaxis. AG, nab-paclitaxel + gemcitabine; HA, hyaluronan; PAG, PEGPH20 + nab-paclitaxel + gemcitabine; TE, thromboembolic event. Slide credit: clinicaloptions.com Hingorani SR, et al. ASCO 2017. Abstract 4008.

HALO-202: Treatment-Related Adverse Events Selected Adverse Event in ≥ 25% of Pts, % PAG (n = 160) AG (n = 100) Any Grade Grade ≥ 3 Fatigue 72 21 66 16 Peripheral edema 63 5 26 4 Muscle spasms 56 13 3 1 Diarrhea 40 7 39 Anemia 17 38 20 Neutropenia 34 29 19 18 Peripheral neuropathy 6 31 8 Myalgia Thrombocytopenia 9 AG, nab-paclitaxel + gemcitabine; PAG, PEGPH20 + nab-paclitaxel + gemcitabine. Slide credit: clinicaloptions.com Hingorani SR, et al. ASCO 2017. Abstract 4008.

HALO-202: Conclusions Addition of PEGPH20 to nab-paclitaxel + gemcitabine improved PFS in both full study population and subgroup with high tumor HA Trend toward improved OS in Stage 2 HA-high pts Protocol amendments including TE screening and use of LMWH prophylaxis reduced TE events Safety profile of combination regimen manageable Investigators conclude data support ongoing randomized phase III multicenter HALO-301 study of PEGPH20 + nab-paclitaxel + gemcitabine in pts with stage IV pancreatic ductal adenocarcinoma and high HA levels HA, hyaluronan; LMWH, low-molecular-weight heparin; TE, thromboembolic event. Slide credit: clinicaloptions.com Hingorani SR, et al. ASCO 2017. Abstract 4008.

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