The METRIC Study METRIC Study Key Eligibility Criteria

The pivotal METRIC Study is evaluating glembatumumab To qualify for the METRIC study, a patient must: vedotin in patients with gpNMB overexpressing • Be at least 18 years of age metastatic triple-negative breast cancer (TNBC). • Have been diagnosed with metastatic TNBC with: - Minimal or no expression of estrogen and • Approximately 300 gpNMB positive, metastatic progesterone receptors (ER/PR); <10% of cells TNBC patients will be enrolled in up to positive by immunohistochemistry approximately 160 sites within the United States, - HER2 staining 0 or 1+ by IHC or copy number Canada, Australia and Europe <4.0 signals/cell by ISH • This is an open label, 2-to-1 randomized • Have documented progression of disease based on comparison of glembatumumab vedotin versus an radiographic, clinical or pathologic assessment during active control, capecitabine (Xeloda®) or subsequent to the last anticancer regimen received Glembatumumab Vedotin (CDX-011) • Have received 0-2 prior chemotherapy treatments for in Patients with Metastatic, Treatment Design advanced (locally advanced/recurrent or metastatic) gpNMB Overexpressing, • Patients treated over 21-day cycles breast cancer Triple-Negative Breast Cancer • Randomized 2-to-1 to receive either: • Have prior chemotherapy treatment with a taxane - Glembatumumab vedotin: an intravenous and, if clinically indicated, an anthracycline infusion of medication (1.88 mg/kg) on day 1 • No prior capecitabine of each cycle, or • Have ECOG performance status of 0 - 1 - Capecitabine: oral medication (1250 mg/m2) • Have adequate bone marrow, liver and renal function HELP TAKE taken twice daily on days 1 through 14 of each • No progression/recurrence during or within 3 months TRIPLE-NEGATIVE cycle of completion of neoadjuvant or adjuvant therapy BREAST CANCER • Treatment cycles continue as long as the cancer • No ongoing neuropathy or other toxicities that are does not progress or until a study physician Grade 2 or worse in severity TREATMENT OPTIONS determines that the patient should stop receiving IN A NEW DIRECTION treatment in the study Breast cancer tumors must be confirmed to express gpNMB. • Tumor assessments conducted at 6-week intervals This will be determined by submitting a tissue sample from for 6 months and 9-week intervals thereafter, until the advanced (locally advanced/recurrent or metastatic) documented progression disease setting to a central laboratory for analysis prior to the study entry (~45% positivity rate). CONTACT A STUDY INVESTIGATOR Study Endpoints • The primary endpoint for this study is progression free survival (PFS) If you have patients who have been diagnosed with • Secondary endpoints include objective response metastatic triple-negative breast cancer, we hope rate, duration of response, overall survival, safety that you will consider the METRIC study. To learn and pharmacokinetics more about this study, please contact the study • Exploratory endpoints include quality of life and/or investigator listed on the front of this brochure. reduction in cancer-related pain, assessed through analgesic use

clinicaltrials.gov/ct2/show/NCT01997333 Glembatumumab Vedotin, an ADC The EMERGE Study, a randomized Phase 2 Efficacy Measures for Patients with TNBC targeting gpNMB in multiple cancers study in patients with locally advanced or and High gpNMB Expression metastatic, gpNMB-positive breast cancer Glembatumumab Investigator’s Glembatumumab vedotin (CDX-011) is an investigational, Vedotin Choice Chemo Study Design fully human monoclonal antibody-drug conjugate (ADC) Patients n=10 n=6 • Examined whether the anti-cancer activity of designed to release monomethylauristatin E (MMAE) 10.0 5.5 glembatumumab vedotin is dependent upon gpNMB Overall Survival months HR=0.14, p=0.003 upon internalization into gpNMB-expressing tumor cells. expression 3.5 1.5 MMAE binds to tubulin, inhibiting mitosis and leading • Randomized 124 patients (2-to-1) to Progression Free Survival months HR=0.11, p=0.0017 to cell cycle arrest and apoptosis. The compound and its glembatumumab vedotin (n=83) or to chemotherapy of the investigator’s choice (IC) (n=41) Objective Response Rate (ORR) n (%) 4 (40%) 0 metabolites do not accumulate over time. • Stratified by gpNMB expression pattern: high- Confirmed PR n (%) 1 (10%) 0 expressing gpNMB in 40% of TNBC samples vs. 21% Stable Disease or Better n (%) 9 (90%) 1 (17%) gpNMB as a TNBC Therapy Target of all others ORR per RECIST 1.1, inclusive of response observed at a single time point Triple-negative breast cancer (TNBC) represents a Glembatumumab vedotin (1.88 mg/kg) was administered Safety disease with substantial molecular heterogeneity.¹ by IV infusion over 90 minutes once every three weeks. Up • Adverse events were manageable and consistent Treatment with standard-of-care is associated with to two dose reductions (to 1.34 or 1.0 mg/kg) were with prior studies progressive resistance and short survival.² There is great allowed for toxicity. Investigator’s choice (IC) consisted of • Rash, neutropenia, fatigue, nausea, vomiting, single-agent chemotherapy, and dosing and supportive interest in identifying molecular markers that can be peripheral neuropathy and alopecia were more care were managed per standard practice. Study treatment frequent in the glembatumumab vedotin arm targeted for therapeutic intervention.³ The continued until disease progression or intolerance, and • Hematologic toxicity was less frequent than IC transmembrane protein gpNMB is aberrantly expressed after documented progression, IC-treated patients were • PFS and OS (but not ORR) were prolonged for at high levels in a range of cancers including breast permitted to receive glembatumumab vedotin in a cross- patients who developed a rash in cycle 1 compared over treatment phase. cancer. to those who did not; a similar association was • High tumor expression of gpNMB is: observed in a Phase 1/2 melanoma study5 Efficacy 4 Summary - Associated with invasion and metastasis The primary efficacy endpoint, objective response rate • Patients with TNBC and tumor gpNMB - Correlated with reduced time to progression and (ORR) of more than 10% for all patients, was not met; overexpression may potentially derive the greatest survival in breast cancer3,4 however, improvements in progression free (PFS) and benefit from glembatumumab vedotin - Implicated as a negative regulator of anti-tumor overall survival (OS) were observed in TNBC patients with high gpNMB expression. Strong trends towards benefits • The identified threshold for high gpNMB immune response were seen in all patients with high gpNMB expression, and expression, ≥ 25% of malignant epithelial cells, in some cases were statistically significant. includes 41% of the screened patients Three Completed Clinical Studies with TNBC (including archived samples) • Patients receiving IC alone who crossed over to • Studied in more than 250 patients with heavily • The ongoing pivotal METRIC study is enrolling receive glembatumumab vedotin upon disease patients in order to confirm these findings pre-treated breast cancer and melanoma progression appeared to represent the better References • Patients with TNBC derived greater clinical benefit outcomes in the control arm, with a median survival of 12.5 months, as compared to those who did not 1. Cancer Genome Atlas Network. Nature. 2012; 490:61-70. from glembatumumab vedotin than from standard 2. Crown, et al. Ann Oncol. 2012; 23:vi56-vi65. cross over, with a median of 5.4 months. of care 3. Yardley, et al. J Clin Oncol. 2015; 33(14): 1609-19. • Similar outcomes observed for all patients on • Phase 2 EMERGE study results published 4. Rose, et al. Clin Cancer Res. 2010; 16(7):2147-56. glembatumumab vedotin and IC, without selecting 5. Ott, et al. J Clin Oncol. 2014; 32(32):3659-66. (Yardley, et al. J Clin Oncol. 2015) for gpNMB expression Xeloda® is a registered trademark of Hoffmann-La Roche, Inc. KEY KEY INCLUSION EXCLUSION CRITERIA CRITERIA

 Patients aged >18 years with mBC  Progression/recurrence within 3 months of  TNBC status (ER and PR < 10%; minimal or no completion of neoadjuvant or adjuvant expression of HER2) confirmed in advanced chemotherapy setting  Baseline neuropathy > Grade 1  Documented PD during or subsequent to the last  Known brain metastases, unless previously treated anticancer regimen and asymptomatic for 2 months and not  Overexpression of gpNMB (≥ 25% of malignant progressive in size or number for 2 months prior to epithelial cells expressing gpNMB, as determined randomization by a central laboratory in at least one tumor  Previously received capecitabine and discontinued obtained in the advanced setting) due to progressive disease or intolerance  0 to 2 prior chemotherapy‐containing regimens  Active systemic infection requiring treatment; for advanced breast cancer Infection controlled by oral therapy will not be  Prior receipt of anthracycline‐containing exclusionary chemotherapy in any setting, unless anthracycline  Chronic use of systemic corticosteroids above the therapy is not clinically indicated physiologic dose within 7 days of enrollment,  Prior receipt of taxane‐containing chemotherapy, except for premedication in any setting  Significant cardiovascular disease  ECOG Performance Status 0 to 1  Any underlying medical condition that, in the  Life expectancy of ≥ 3 months investigator’s opinion, will make the trial  Measurable (target) disease by RECIST 1.1 criteria inappropriate  Resolution of all chemotherapy or radiation‐  Other malignancy except for treated basal or related toxicities to ≤ Grade 1 severity, except squamous skin cancer, curatively treated in situ for alopecia disease, or any other cancers free of disease  Adequate bone marrow, liver and renal function for ≥ 5 years

See Protocol for Full List of Eligibility Criteria See Protocol for Full List of Eligibility Criteria

Glembatumumab Vedotin

1 Glembatumumab Vedotin: gpNMB is an Attractive Target

gpNMB is aberrantly expressed at high levels in a range of cancers • Predominantly intracellular in normal cells • May become localized to the cell surface in cancer • Associated with the ability of the cancer cell to invade and metastasize • Correlated with reduced time to progression and survival in breast cancer

2016 Projected Est. % Patients Est. # Patients TARGET POPULATION Incidence* gpNMB Positive gpNMB Positive All Breast Cancers (invasive) 249,000 ~20% (≥25% expression) 50,000 Metastatic Triple Negative 20,000 ~40% (≥25% expression) 8,000 Breast Cancer

Metastatic Melanoma 20,600 >80% 16,500 (Stage III/IV unresectable)

Squamous Cell Lung Cancer 54,000 >85% 45,900

Osteosarcoma 800 >60% 500

Head and Neck Cancer 62,000 >40% 25,000

Pancreatic Cancer 53,000 >55% 29,000

Glioblastoma 12,000 >66% 7,900

*Estimated patient numbers are calculated based on American Cancer Confidential (Do Not Reproduce without Celldex Permission Society incidence projections for 2016 2 Glembatumumab Vedotin: ADC Targeting gpNMB in Multiple Indications

• Antibody drug conjugate designed to release the potent cytotoxin MMAE upon internalization into gpNMB- expressing tumor cells – Celldex proprietary target and antibody – Fully human IgG2 anti-gpNMB monoclonal antibody – Toxin and linker licensed from Seattle Genetics; same technology as Adcetris® (brentuximab vedotin) – MMAE binds to tubulin, inhibiting mitosis and leading to cell cycle arrest and apoptosis

• Companion diagnostic to detect gpNMB in development

Confidential (Do Not Reproduce without Celldex Permission 3 Adcetris is a registered trademark of Seattle Genetics, Inc.

Glembatumumab Vedotin: Summary of Clinical Experience (completed trials)

• Three completed clinical studies (n=283, including control; patients treated with glembatumumab vedotin=255) – Phase 1/2 unresectable stage III or stage IV melanoma (n=117)1 – Phase 1/2 advanced, heavily pre-treated breast cancers (n=42)2 – Phase 2 EMERGE study in advanced, heavily pre-treated breast cancers (n=124)3

• MTD (Phase 2 dose) was established as 1.88 mg/kg q3w in melanoma study; more frequent dosing regimens (q2/3w and qw) were associated with increased toxicity

• In these early studies, ORR and PFS at the Phase 2 dose have been favorable for the heavily-pretreated populations studied (advanced melanoma and breast cancer) – Although sample sizes are small, patients with tumors expressing higher levels of gpNMB consistently appear to derive greater clinical benefit from glembatumumab vedotin as compared to the entire population of treated patients – In both breast cancer studies, the subset of patient with triple negative breast cancer, where treatment options are limited, also appeared to derive greater clinical benefit from glembatumumab vedotin

1. Ott, et al. J Clin Oncol. 2014; (32)32: 3659-66. 2. Bendell, et al. J Clin Oncol. 2014; 32(32):3619- Confidential (Do Not Reproduce without Celldex Permission 3.25. Yardley, et al. J Clin Oncol. 2015; 33(14): 1609-19. 4 Phase 2 EMERGE Study in Metastatic Breast Cancer: Efficacy Measures (ITT)

Triple Negative and High gpNMB All Patients Triple Negative High gpNMB Expression Expression

Glemba IC Glemba IC Glemba IC Glemba IC (n=83) (n=41) (n=28) (n=11) (n=23) (n=11) (n=10) (n=6)

7.5 7.4 6.9 6.5 10.0 5.7 10.0 5.5 Overall Survival HR=1.37, p=0.20 HR=0.65, p=0.30 HR=0.67, p=0.31 HR=0.14, p=0.003

2.3 2.0 2.8 1.6 2.8 1.5 3.5 1.5 Progression Free Survival HR=1.19, p=0.42 HR=0.69, p=0.38 HR=0.63, p=0.18 HR=0.11, p=0.0017

Partial Response (PR) 10 (12%) 5 (12%) 5 (18%) 0 7 (30%) 1 (9%) 4 (40%) 0 [n (%)]

Confirmed PR 5 (6%) 3 (7%) 2 (7%) 0 3 (13%) 1 (9%) 1 (10%) 0 [n (%)]

Stable Disease or Better 41 (49%) 19 (46%) 17 (61%) 3 (27%) 15 (65%) 3 (27%) 9 (90%) 1 (17%) [n (%)]

On target effect clearly demonstrated in targeted patient populations

Responses per RECIST Confidential (Do Not Reproduce without Celldex Permission 1Yardley,.1 et al. J Clin Oncol. 2015; 33(14): 1609-19. 5 EMERGE: High Tumor gpNMB Expression Correlates with Response

Glembatumumab Vedotin Investigator Choice Treated Patients Treated Patients

• Thresholds of ≥10% and ≥25% gpNMB-positive tumor epithelial cells both show significant enrichment of responders – The more conservative choice of ≥25% gpNMB expression was chosen for entry into METRIC

Confidential (Do Not Reproduce without Celldex Permission Yardley, et al. J Clin Oncol. 2015; 33(14): 1609-19. 6 Glembatumumab Vedotin Safety Profile

• In breast cancer and melanoma patients, the most frequent (≥20% of patients) treatment-related toxicities were: – Rash/alopecia • Skin-related AEs were more common/severe in melanoma • Rash associated with greater PFS and ORR in melanoma and prolonged PFS/OS in EMERGE breast cancer study – Neutropenia – Fatigue/anorexia – Nausea/vomiting – Diarrhea – Peripheral neuropathy

• Glembatumumab vedotin safety profile is consistent with the class of drugs using the same linker and MMAE, including the approved drug Adcetris® – Glembatumumab vedotin hematologic toxicity may be less frequent/severe – Glembatumumab vedotin rash (mild to moderate severity) may be more frequent (compared with agents recently approved for refractory breast cancer2,3)

1. Younes, et al. N Engl J Med. 2010; 363(19): 1812-21. Adcetris® is a registered trademark of Seattle Genetics. 2. Perez, et al. J Clin Oncol. 25(23):3407- Confidential (Do Not Reproduce without Celldex Permission 3.14 .Cortes, et al. Lancet. 2011; 377(9769):914-23. 7 Registration Study Design in gpNMB Over-expressing TNBC (METRIC)

glembatumumab vedotin Primary:

1.88 mg/kg IV PFS Patients with Day 1 of 21-day cycles metastatic TNBC overexpressing gpNMB Secondary: (≥ 25% tumor cells by IHC) ORR n=300 capecitabine (Xeloda®) DOR RANDOMIZE (2:1) RANDOMIZE 1250 mg/m2 BID Days 1-14 of 21-day cycles OS • Stratification:

 Line of chemotherapy for advanced disease 0-1 vs. 2 Tumor assessments  PFS after receipt of taxane therapy ≤ 6 months vs. PFS > 6 months (6 week intervals x 6 months; 9 week  Prior anthracycline therapy YES / NO intervals thereafter) until documented progression Survival follow-up (12 week intervals) Study initiated Dec 2013

Confidential (Do Not Reproduce without Celldex Permission Clinicaltrials.gov Identifier NCT01997333 8 Xeloda is a registered trademark of Genentech. METRIC Key Inclusion Criteria

• Patients with advanced carcinoma of the breast (histologically or cytologically confirmed) • gpNMB over-expression (≥25% of tumor epithelial cells positive by IHC) on samples obtained in the setting of advanced disease confirmed/determined at a central laboratory (Clarient) • ER and PR negativity defined as ER/PR: <10% of cells positive by IHC • HER2 negativity defined according to 2013 ASCO/CAP guidelines • Prior receipt of taxane-containing chemotherapy in any setting • Prior receipt of anthracycline containing chemotherapy in any setting, unless anthracycline therapy is not clinically indicated in the opinion of the treating investigator • 0-2 lines of chemotherapy for advanced disease • ECOG performance status 0 to 1 • Life expectancy ≥ 3 months

Confidential (Do Not Reproduce without Celldex Permission 9 METRIC Key Exclusion Criteria

• Subjects unable to provide informed consent and/or unable to comply with the study procedures • Investigational therapy within 4 weeks before planned start of study treatment • Persistent neuropathy > NCI-CTCAE v 4.0 Grade 1 at Randomization • Known active brain metastases unless previously treated and asymptomatic for 2 months and not progressive in size or number for 2 months prior to randomization • Significant cardiovascular disease

Confidential (Do Not Reproduce without Celldex Permission 10