VOLUME 32 䡠 NUMBER 32 䡠 NOVEMBER 10 2014

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

Phase I/II Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Patients With Locally Advanced or Metastatic Breast Cancer Johanna Bendell, Mansoor Saleh, April A.N. Rose, Peter M. Siegel, Lowell Hart, Surendra Sirpal, Suzanne Jones, Jennifer Green, Elizabeth Crowley, Ronit Simantov, Tibor Keler, Thomas Davis, and Linda Vahdat See accompanying article on page 3659; listen to the podcast by Dr Connolly at www.jco.org/ podcasts Johanna Bendell and Suzanne Jones, Sarah Cannon Research Institute, Nashville, TN; Mansoor Saleh, Georgia Cancer Specialists, Atlanta, GA; April A.N. Rose and Peter M. Siegel, Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; Lowell Hart, Florida Cancer Specialists, Fort Myers; Surendra Sirpal, Hematology Oncology Associates, Lake Worth, FL; Jennifer Green, Elizabeth Crowley, Ronit Simantov, Tibor Keler, and Thomas Davis, Celldex Therapeutics; and Linda Vahdat, Weill Cornell Medical College, New York, NY. Published online ahead of print at www.jco.org on September 29, 2014. Supported by CuraGen Corporation (now Celldex Therapeutics). Presented at the Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 5, 2010; San Antonio Breast Cancer Symposium, San Antonio, TX, December 13, 2009; and the Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, June 2, 2009. Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical Trials repository link available on JCO.org. Corresponding author: Linda T. Vahdat, MD, Weill Cornell Medical College, New York, NY 10065; e-mail: [email protected]. © 2014 by American Society of Clinical Oncology 0732-183X/14/3232w-3619w/$20.00 DOI: 10.1200/JCO.2013.52.5683

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B

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T

R

A

C

T

Purpose Glycoprotein NMB (gpNMB), a novel transmembrane protein overexpressed in 40% to 60% of breast cancers, promotes metastases in animal models and is a prognostic marker of a poor outcome in patients. The antibody-drug conjugate glembatumumab vedotin consists of a fully human anti-gpNMB monoclonal antibody, conjugated via a cleavable linker to monomethyl auristatin E. Glembatumumab vedotin is generally well tolerated, with observed objective responses in advanced melanoma. This is, to our knowledge, the first study of glembatumumab vedotin in breast cancer. Patients and Methods Eligible patients had advanced/metastatic breast cancer with at least two prior chemotherapy regimens, including taxane, anthracycline, and capecitabine. A standard 3⫹3 dose escalation was followed by a phase II expansion. Immunohistochemistry for gpNMB was performed retrospectively for patients with available tumor tissue. Results Forty-two patients were enrolled. Dose-limiting toxicity (DLT) consisted of worsening neuropathy at 1.34 mg/kg. After excluding patients with baseline neuropathy more than grade 1, no DLT occurred through 1.88 mg/kg (the phase II dose). The phase II primary activity end point was met (12-week progression-free survival [PFS12] ⫽ 9 of 27 patients; 33%). Sixteen of 19 (84%) patients tested had gpNMB-positive tumors. At the phase II dose, median PFS was 9.1 weeks for all patients, 17.9 weeks for patients with triple-negative breast cancer (TNBC), and 18.0 weeks for patients with gpNMB-positive tumors. Two patients had confirmed partial responses; both had gpNMB-positive tumors and one had TNBC. Conclusion Glembatumumab vedotin has an acceptable safety profile. Preliminary evidence of activity in treatmentresistant metastatic breast cancer requires confirmation, such as the phase II randomized trial (EMERGE) that also examines the relationship between activity and gpNMB distribution/intensity. J Clin Oncol 32:3619-3625. © 2014 by American Society of Clinical Oncology

INTRODUCTION

Glycoprotein NMB (gpNMB; also known as osteoactivin, dendritic cell-heparin integrin ligand [DC-HIL], or hematopoietic growth factor inducible neurokinin-1 type [HGFIN]) is a novel type I transmembrane protein, originally identified by transcript profiling and tumor microarrays as a potential therapeutic target in melanoma and breast cancer.1-4 Expression of gpNMB is both on cell surfaces and intracellularly. Surface gpNMB may be cleaved by a sheddase, ADAM10,

to release a biologically active, soluble gpNMB molecule.5 It appears that gpNMB mediates intercellular adhesion, promotes tissue repair, and regulates cell growth and differentiation.6 In addition, gpNMB may down-modulate T-cell responses, including antitumor immune responses.7-9 Several tumors, including breast cancer, melanoma, and glioblastoma, overexpress gpNMB relative to normal tissue.2,6,10 Overexpression of gpNMB is reported in 40% to 60% of breast cancers.10,11 In addition, overexpression of gpNMB promotes invasion and metastasis of hepatocellular © 2014 by American Society of Clinical Oncology

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Bendell et al

carcinoma, glioma, and breast cancer cells, decreases tumor cell apoptosis, and promotes angiogenesis in preclinical models.4,5,10,12,13 In addition, gpNMB correlates with reduced time to recurrence and overall survival in breast cancer.10 In triple-negative breast cancer (TNBC), which is defined by the lack of overexpression of the estrogen, progesterone, and HER2 receptors, epithelial expression of gpNMB has been reported in approximately one third of cases and is associated with recurrence.10 Glembatumumab vedotin (CDX-011; formerly CR011vcMMAE) is an antibody-drug conjugate consisting of CR011, a fully human IgG2 monoclonal antibody against gpNMB, conjugated via a valine-citrulline link to the potent microtubule inhibitor monomethyl auristatin E (MMAE).14,15 The MMAE-linker technology (also used in the lymphoma therapy brentuximab vedotin) is designed to maintain stability of glembatumumab vedotin in the bloodstream and to release MMAE by proteolytic cleavage after internalization into lysosomes of gpNMB-expressing cells.16 The efficacy of glembatumumab vedotin observed in preclinical models2,10,17 contributed to the rationale for initial studies in melanoma and breast cancer. A phase I study in melanoma identified 1.88 mg/kg once every 3 weeks as the maximum tolerated dose and recommended a phase II dose in that population.18 This phase I/II study was designed to assess the hypothesis that glembatumumab would be safe and active in patients with locally advanced and metastatic breast cancer and to explore the relationship between gpNMB expression and response.

PATIENTS AND METHODS This clinical study (protocol CR011-CLN-20) included a phase I dose escalation to establish the maximum tolerated dose, followed by an openlabel, single-arm Simon two-stage19 phase II expansion to assess the safety, tolerability, and efficacy of glembatumumab vedotin. The study was conducted at five participating institutions in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines, after approval by a local human investigations committee, and in accord with an assurance filed with and approved by the Department of Health and Human Services, where appropriate. All patients signed written informed consent before any protocol-specific procedures. Patients The study was open to women at least 18 years of age, with pathologically confirmed locally advanced or metastatic carcinoma of the breast, progressive within 6 months of last therapy. Eligible patients had received at least two prior chemotherapeutic regimens for breast cancer, with at least one given in the locally advanced or metastatic setting. Unless the patient was not eligible or intolerant to any of these agents, prior treatments must have included an anthracycline, a taxane, and capecitabine, as well as trastuzumab for patients with HER2-overexpressing tumors. There were no restrictions regarding the number of prior treatments with hormonal, biologic, or immunotherapeutic agents. A wash-out of at least 2 weeks was required for most anticancer therapies (including chemotherapy, radiation, and hormonal therapy). HER2-targeted agents and investigational therapy were to be discontinued at least 3 weeks before initiation of study treatment. Additional eligibility requirements included measurable or evaluable disease,20 Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, life expectancy of at least 3 months, and adequate renal, hepatic, and bone marrow function. Patients who were pregnant, breast-feeding, or had active brain metastases or any other significant, active, concurrent medical illness that would have precluded study treatment were ineligible. The study was revised during dose escalation to exclude patients with persistent residual neuropathy more than grade 1. 3620

© 2014 by American Society of Clinical Oncology

Study Design and Treatment Given the heavily pretreated patient population in this study, a classical 3⫹3 dose escalation design was incorporated, with a starting dose of 1.34 mg/kg and escalation to 1.88 mg/kg, which is the recommended phase II dose in patients with melanoma. Dose-limiting toxicity (DLT) was defined as any of the following occurring in cycle 1: grade 3 or 4 nonhematological drug-related toxicity unamenable to supportive care within 72 hours; grade 4 neutropenia lasting more than 5 days or associated with fever more than 100.5°F; grade 4 thrombocytopenia; or more than grade 2 peripheral sensory neuropathy not resolving within 4 weeks of study drug discontinuation. Phase II expansion patients received 1.88 mg/kg after assessment of tolerability in phase I. The phase II expansion was conducted according to a Simon two-stage design, which required at least two of the initial 16 patients to be progression-free at 12 weeks before proceeding with enrollment to 25 total patients. Glembatumumab vedotin was administered as a 90 minute intravenous infusion, once every 3 weeks (day 1 of repeated 21 day cycles). Delays of up to 3 weeks and up to two dose reductions (to dose levels of 1.34, 1.0, and 0.75 mg/kg, as applicable) were permitted for toxicity. Dosing continued until unmanageable treatment-related toxicities, disease progression, or death. On-Study Evaluation Safety parameters assessed at baseline and study visits included physical examination, vital signs, ECOG performance status, hematology, blood chemistry, and urinalysis. ECGs and ophthalmic examinations were performed at baseline and end of treatment. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) version 3.0. Tumor response was assessed by the investigator according to RECIST.20 Radiographic assessment of all suspected disease sites was performed within 4weeks before treatment and every 6 weeks during treatment. For patients who discontinued treatment in the absence of progression, tumor assessments continued every 3 months until progression or initiation of alternate therapy. Statistical Methodology and End Point Analysis The primary objectives of the study were to evaluate the safety and determine the recommended phase II dose of glembatumumab vedotin in patients with locally advanced and metastatic breast cancer. All treated patients were included in safety analyses. A major secondary objective (the primary efficacy end point) was to determine 12-week progression-free survival (PFS12) for the phase II expansion cohort. With consideration to published reports suggesting a median PFS of 3 months in less heavily pretreated patients,21 an uninteresting PFS12 (P0) was defined as ⱕ 10% and a clinically interesting PFS12 (P1) was defined as ⱖ 30%. A sample size of 25 patients was calculated on the basis of the Simon two-stage design (optimal version) to provide 90% power with 0.1 significance level for testing. If at least five of 25 patients were progression free at 12 weeks, glembatumumab vedotin would be deemed worthy of further development. Additional secondary objectives included assessments of objective response rate (ORR), time to response, duration of response, and overall PFS. For PFS analyses, progression was assumed on radiographic evidence of progression per RECIST, symptomatic deterioration (clinical progression), initiation of any alternate cancer therapy, or death (from any cause). Time to event analyses were calculated from the date of first administration of glembatumumab vedotin (day 1), and estimated by using the KaplanMeier method. Patients who discontinued study without a progression event were censored at the last evaluable tumor assessment or were excluded from analysis if missing evaluable postbaseline tumor assessments. Correlative Study The relationship between gpNMB expression and clinical response to glembatumumab vedotin was retrospectively examined for the subset of patients with available archived tumor specimens who consented to participate in optional correlative studies. Immunohistochemistry for gpNMB was performed by using a polyclonal goat anti-gpNMB antibody (R&D Systems, JOURNAL OF CLINICAL ONCOLOGY

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Phase I/II Study of Glembatumumab Vedotin in Breast Cancer

Minneapolis, MN) and a biotinylated donkey antigoat secondary antibody (Jackson ImmunoResearch Laboratories, West Grove, PA). Sections were developed with diaminobenzidine and counterstained with hematoxylin. Because this was the first clinical investigation targeting gpNMB in breast cancer, a positive result was defined by using a standard threshold of ⱖ 5% of epithelial or stromal cells expressing gpNMB, consistent with prior studies that evaluated the prognostic implications of gpNMB expression.10

RESULTS

Forty-two patients were enrolled at five centers from June 2008 to August 2009. Fourteen patients participated in the dose-escalation study portion, and 28 patients participated in the phase II expansion phase. A total of 34 patients (six in dose escalation; 28 in expansion) were treated at the predefined maximum dose of 1.88 mg/kg. Patient Characteristics Participants’ pretreatment characteristics and prior therapies are summarized in Table 1. All enrollees were female with heavily pretreated metastatic breast cancer. Dosing and Toxicity Two DLTs, consisting of worsening baseline neuropathy (from grade 1 to grade 2, and from grade 2 to grade 3), occurred at the starting dose level of 1.34 mg/kg. The protocol was consequently revised to exclude patients with more than grade 1 baseline neuropathy. Dose escalation was reinitiated, starting with the 1.0 mg/kg dose, and proceeded through the predefined maximum dose of 1.88 mg/kg with no additional DLT. The overall median duration of treatment was 9 weeks (range, 3 to 72) for patients treated at 1.88 mg/kg (the phase II dose) and 6 weeks (range, 3 to 12) for patients treated at lower doses. Dose reductions were implemented for eight (24%) of the 34 patients treated with the phase II dose and one (13%) of the eight patients treated at lower doses. Reasons for dose reduction were rash, peripheral sensory neuropathy, dehydration, and neutropenia. No patients required a second dose reduction. The majority of patients discontinued study treatment for progressive disease. At the phase II dose, five (15%) patients discontinued as a result of toxicity (two cases of grade 3 peripheral sensory neuropathy, and single cases of grade 2 rash, acute renal failure, and dermatologic bullae), although two additional patients withdrew consent. At lower doses, one (13%) patient discontinued treatment as a result of toxicity (decreased appetite, fatigue, and peripheral sensory neuropathy). Treatment-related toxicity is summarized in Table 2. Fatigue, rash, nausea, peripheral sensory neuropathy, and neutropenia were most frequent. Rash was predominantly transient, nonpruritic erythema. More extensive dermatologic toxicity occurred in some patients with erythema progressing to a pruritic, maculopapular rash. Peripheral neuropathy was predominantly sensory, tended to be cumulative, and resolved over time with dose delays and reductions. Treatment-related serious adverse events occurred in three patients receiving the phase II dose. One patient developed dermatologic bullae involving approximately 10% of body-surface area approximately 1 week after the first glembatumumab vedotin dose. Study treatment was permanently discontinued, antibiotics and steroids www.jco.org

Table 1. Pretreatment Patient Characteristics

Age, years Median Range ECOG performance status 0 1 2 Duration, years Since first diagnosis Median Range Metastatic or locally advanced disease Median Range Visceral metastases (liver and/or lung) Receptor statusⴱ ER positive PR positive HER2 positive Triple negative Prior anticancer regimens Median Range Taxane Capecitabine Anthracycline Hormonal therapy Gemcitabine Bevacizumab Vinorelbine Ixabepilone Trastuzumab Lapatinib Investigational agents Prior radiation therapy

Low Doses (1.0 and 1.34 mg/kg; n ⫽ 8)

Phase II Dose (1.88 mg/ kg; n ⫽ 34)

No.

No.

%

56 35-63 6 2 0

%

59 33-76 75 25

15 17 2

44 50 6

6.9 3.9-15.3

6.0 1.7-32.6

3.7 1.2-15.3 7 88

3.4 0.6-28.6 29 85

4 4 1 3

20 11 10 10

50 50 13† 38 7 3-9

8 8 6 5 6 6 6 2 2 1 2 7

59 32 29 29 7 2-18

100 100 75 63 75 75 75 25 25 13 25 88

34 33 32 25 21 18 17 15 12 9 6 25

100 97 94 74 62 53 50 44 35 26 18 74

Abbreviations: ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PR, progesterone receptor. ⴱ Receptor status was determined by local testing. †HER-2/neu status is unknown for one patient.

were administered, and the event resolved within 2 weeks. A second patient developed grade 1 nausea, grade 3 dehydration, and laboratory findings of grade 3 acute renal failure 1 week after the first glembatumumab vedotin dose. Study treatment was also discontinued and the event improved after approximately 2 weeks of outpatient treatment with fluid and electrolyte replacement. The third patient was hospitalized during the eighth cycle of glembatumumab vedotin treatment as a result of grade 3 vomiting and nausea. This event resolved within 4 days and the patient continued on treatment. One patient treated at the phase II dose developed grade 4 neutropenia, which was not considered a serious adverse event. No additional grade 4 to 5 treatment-related toxicity occurred. All deaths on study were attributed to progression of disease. © 2014 by American Society of Clinical Oncology

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Table 2. Treatment-Related Toxicity

Any Severity

Any Severity

%

CTCAE Grade 3-4 No.

%

2 2

25 25

2 3 1 2 4

25 38 13 25 50

2 1

25 13

1

13

3 2

38 25

1

13

1

13

No.

%

5 13

15 38

12 8 5 19 13 4

35 24 15 56 38 12

14 5 5 17 11

41 15 15 50 32

CTCAE Grade 3-4 No.

9

%

26

*

80 NE

60

*

40 *

20

1 2 3 4 1 2 3 4 5 6 7 8 9 10 11 12 14 13 15 1 2 1

3 6 3

3

9

1 2

3 6

Expression Analysis of gpNMB Nineteen patients (15 treated at the phase II dose and four treated at lower doses) had archival tumor tissue evaluated for gpNMB expression. Submitted samples were obtained at a median of 2.8 (range, 0.9 to 13.7) years before study entry. Eleven samples (60%) were obtained before onset of advanced disease. As shown in Figure 1, gpNMB expression was predominantly localized to the stromal compartment, and highly variable, with 16 (84%) of these patient cases showing staining in at least 5% to 85% of tumor stroma cells. Only four (21%) of the screened tumors had gpNMB expression in ⱖ 5% of epithelial cells, and no tumors had gpNMB in more than 20% of epithelial cells. Activity The primary efficacy end point for the phase II portion of this study was met. PFS12 was 33% for the 27 evaluable patients treated in the phase II expansion cohort. For secondary efficacy analyses (Table 3), these 27 patients were pooled with the six additional patients treated at the phase II dose (1.88 mg/kg) in the dose-escalation study portion. For all 33 evaluable patients treated at the phase II dose, PFS12 was 36% and ORR was 12% (6% confirmed). For patients experiencing partial response (PR), time to response was 5.4, 6.0, 6.1, and 13.7 weeks, and respective maximum tumor shrinkage (sum of the longest diameters of target lesions; SLD) was 60%, 43%, 64%, and 34%. Two patients had confirmed PR. One patient with PR at 5 weeks had RECIST-defined progression at 35 weeks as a result of more than a 20% increase in SLD over nadir (response duration of 30 weeks). However, as SLD was increased by only 3 mm from nadir and decreased 38% from baseline, the patient was considered to have a © 2014 by American Society of Clinical Oncology

Tumor epithelium Tumor stroma

0

NOTE. Includes events assessed as related to glembatumumab vedotin by the investigator and occurring in ⬎ 10% of patients overall, or in ⬎ 1 patient at NCI-CTCAE severity grade 3-4. There were no grade 5 treatment-related adverse events. Abbreviations: CTCAE, Common Terminology Criteria for Adverse Events; NCI, National Cancer Institute.

3622

Cells Expressing gpNMB by IHC (%)

Phase II Dose (1.88 mg/kg; n ⫽ 34)

No. Hematologic Anemia Neutropenia Nonhematologic Alopecia Decreased appetite Dysgeusia Fatigue Nausea Pain in extremity Peripheral sensory neuropathy Pruritus Pyrexia Rash Vomiting

100

Low Doses (1.0 and 1.34 mg/kg; n ⫽ 8)

Low Doses (1.0 and 1.34 mg/kg)

Phase II Dose (1.88 mg/kg)

Fig 1. Glycoprotein NMB (gpNMB) expression analysis. Results of immunohistochemistry (IHC) for gpNMB are presented for the 19 patients with available tissue who consented for this optional correlative analysis. (*) Patients who experienced partial response. NE indicates one patient who discontinued treatment as a result of toxicity before on-study radiographic assessment.

clinically persistent response and permitted to continue study treatment. Additional shrinkage (to a maximum of 60%) was observed until treatment was discontinued as a result of neuropathy at 81 weeks, for overall response duration of 76⫹ weeks. The second patient maintained PR for 21 weeks. Analysis of gpNMB expression was performed for 15 patients treated at the phase II dose. ORR was 18%, and PFS12 was 73% for the 11 evaluable patients with gpNMB-positive tumors. No responses were seen in the three patients with gpNMB-negative tumors. The two confirmed durable PR occurred in patients with gpNMB-positive tumors. Expression of gpNMB was not assessed for the two patients with transient response. For the 10 evaluable patients with TNBC (as determined by local testing), ORR was 20% (10% confirmed), and PFS12 was 60%. All four patients who had both TNBC and gpNMB-positive tumors remained progression-free at 12 weeks. The patient with clinical response duration of 76⫹ weeks (described previously) had triple negative and gpNMB-positive disease. ORR for HER2positive patients was 22% (11% confirmed), but this was not associated with apparent benefit in PFS, as compared with HER2negative patients. DISCUSSION

This phase I/II study demonstrated that glembatumumab vedotin, an antibody-drug-conjugate targeting gpNMB, has an acceptable safety profile and antitumor activity in patients with metastatic breast cancer who have failed standard therapies. The primary efficacy end point was met, with PFS12 of 33%. The observed ORR of 12% (6% confirmed) and median PFS of 9.1 weeks are favorable results in these heavily pretreated patients (with a median of seven prior anticancer regimens). Consistent with previously published data,10 gpNMB expression was detected in 84% of patients (n ⫽ 19) with available tissue, JOURNAL OF CLINICAL ONCOLOGY

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Phase I/II Study of Glembatumumab Vedotin in Breast Cancer

Table 3. Efficacy Analyses Subgroup Analyses: Phase II Dose (1.88 mg/kg; n ⫽ 34)ⴱ

All Study Patients (N ⫽ 42)

Progression free at 12 wks No. % PFS, weeks Median 95% CI Best response† PR No. % Confirmed PR No. % SD or better No. %

Not TNBC (n ⫽ 24)ⴱ

gpNMB Positive (n ⫽ 12)ⴱ

gpNMB Negative (n ⫽ 3)

gpNMB Positive and TNBC (n ⫽ 4)

6 of 10 60

6 of 23 26

8 of 11 73

1 of 3 33

4 of 4 100

9.1 5.7 to 18.3

17.9 9.1 to 19.9

6.1 5.9 to 11.9

18.0 15.7 to 26.1

15.1 5.7 to 19.9

22.2 17.4 to 35.0

2 of 9 22

2 of 24 8

2 of 10 20

2 of 23 9

2 of 11 18

0 of 3 0

1 of 4 25%

0 of 7 0

1 of 9 11

1 of 24 4

1 of 10 10

1 of 23 4

2 of 11 18

0 of 3 0

1 of 4 25

2 of 7 25

5 of 9 56

14 of 24 58

8 of 10 80

11 of 23 48

9 of 11 82

2 of 3 66

4 of 4 100

Phase II Dose (1.88 mg/kg; n ⫽ 34)ⴱ

Low Doses (1.0 and 1.34 mg/ kg; n ⫽ 8)ⴱ

12 of 33 36

0 of 7 0

9.1 6.1 to 17.4

6.0 5.4 to 9.1

4 of 33 12

1 of 7 14

2 of 33 6 19 of 33 58

HER2 Positive (n ⫽ 10)ⴱ 3 of 9 30 10.4 4 to 19.1

HER2 Negative (n ⫽ 24)

TNBC (n ⫽ 10)

9 of 24 38

Abbreviations: PFS, progression-free survival; PR, partial response; SD, stable disease; TNBC, triple-negative breast cancer. ⴱ Two patients (one each at 1.34 and 1.88 mg/kg) discontinued the study as a result of adverse events in the absence of any postbaseline tumor assessments and were thus excluded from efficacy analyses. †Tumor response assessed by RECIST. Confirmed PR refers to a response seen on repeat assessments performed at least 4 weeks after the criteria for response were first met. Responses were not confirmed in two patients: one experienced progression at the subsequent visit, whereas the second discontinued treatment as a result of toxicity. A best response of SD required criteria for SD to be met at least 5 weeks after initiation of treatment.

and was most frequent in the stromal compartment. In the subset of 11 patients with gpNMB-positive samples, ORR was 18%, and median PFS was 18 weeks. There were no responses in the three patients with tumors lacking gpNMB expression. Interestingly, tumor responses were observed in patients with gpNMB expression in tumor stroma only. This finding might be explained by the bystander effect, in which free MMAE is released during apoptosis of gpNMB-positive stromal cells, resulting in local concentrations high enough to kill neighboring tumor cell populations.22,23 Four patients had tumors with gpNMB expression in the epithelial compartment, although all had expression in less than 20% of epithelial cells. One of these patients experienced durable PR. Although intriguing, these data are subject to several limitations, including the retrospective nature of the analysis and the small number of patients for whom tissue samples were submitted. As well, analyzed samples included those obtained in earlier stages of disease and stored for a range of 1 to 13 years. Little is known about the heterogeneity of gpNMB expression at metastatic sites and the longevity of gpNMB in archival samples. Encouraging evidence of activity was also seen in the subset of patients with treatment-refractory TNBC. Patients with TNBC have been previously reported to have a higher response rate to standard therapies, but a paradoxically shorter disease-free survival as a result of a high relapse rate.24,25 However, in the 10 TNBC patients treated with glembatumumab vedotin in this trial, a 20% ORR (10% confirmed) and 17.9 week median PFS was observed, as compared with 9% ORR (4% confirmed) and 6.1 week median PFS for the patients who did not have TNBC. Observed toxicity was similar to that seen in the study of glembatumumab vedotin in metastatic melanoma.18 Compared with the www.jco.org

agents most recently approved for refractory breast cancer,21,26 hematologic toxicity appears to be less frequent and less severe, although a mild to moderate rash may be more frequent. Because gpNMB expression is seen in normal epithelium, treatment-related rash may be a consequence of glembatumumab vedotin targeting gpNMBexpressing epithelial cells. DLT of worsening peripheral neuropathy was seen at the starting dose level; however, no further DLT occurred after revision of the protocol to exclude significant pre-existing neuropathy. Glembatumumab vedotin’s toxicity profile resembles that of brentuximab vedotin,27 which is not surprising given that the antibody component of each drug is conjugated to the microtubule inhibitor MMAE. In conclusion, results of this trial suggest that glembatumumab vedotin has an acceptable and manageable safety profile, and that activity may be enhanced in patients with TNBC and/or tumor expression of gpNMB. Although encouraging, these results are from a small number of patients, only a portion of whom were tested for gpNMB retrospectively. To confirm and better characterize glembatumumab vedotin’s activity in relation to distribution and intensity of gpNMB expression, a phase II randomized trial (EMERGE), which randomly assigned patients with advanced, gpNMB-expressing, heavily pretreated breast cancer to receive either glembatumumab vedotin or investigator’s choice of single-agent chemotherapy, has been conducted.11 Subgroup analyses in EMERGE suggested the greatest benefit from glembatumumab vedotin in patients whose tumors overexpressed gpNMB in ⱖ 25% of epithelial cells (by central analysis using an optimized and validated immunohistochemistry method), enabling an appropriate definition for gpNMB overexpression in future studies. As well, apparent benefit in patients with TNBC was again observed. © 2014 by American Society of Clinical Oncology

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A pivotal phase II trial (METRIC), in which 300 women with metastatic, gpNMB overexpressing TNBC will be randomly assigned (2:1) to receive glembatumumab vedotin or capecitabine, has been initiated. The primary analysis end points are ORR and PFS, and the trial is designed to support an application for accelerated approval if either is positive. Studies of glembatumumab vedotin in other gpNMB-positive cancers, including cutaneous and uveal melanomas, osteosarcoma, and squamous cell lung cancer, are also planned.

Simantov, Celldex Therapeutics (C), Tibor Keler, Celldex Therapeutics (C), Thomas A. Davis, Celldex Therapeutics (C) Consultant or Advisory Role: None Stock Ownership: Jennifer A. Green, Celldex Therapeutics; Elizabeth Crowley, Celldex Therapeutics; Tibor Keler, Celldex Therapeutics; Thomas A. Davis, Celldex Therapeutics Honoraria: None Research Funding: Mansoor N. Saleh, Celldex Therapeutics; Lowell L. Hart, Celldex Therapeutics; Surendra K. Sirpal, Celldex Therapeutics; Linda T. Vahdat, Celldex Therapeutics Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None

AUTHOR CONTRIBUTIONS AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Jennifer A. Green, Celldex Therapeutics, (C), Elizabeth Crowley, Celldex Therapeutics (C), Ronit

REFERENCES 1. Ripoll VM, Irvine KM, Ravasi T, et al: gpNMB is induced in macrophages by IFN-gamma and lipopolysaccharide and acts as a feedback regulator of proinflammatory responses. J Immunol 178:65576566, 2007 2. Tse KF, Jeffers M, Pollack VA, et al: CR011, a fully human monoclonal antibody-auristatin E conjugate, for the treatment of melanoma. Clin Cancer Res 12:1373-1382, 2006 3. Abdelmagid SM, Barbe MF, Rico MC, et al: Osteoactivin, an anabolic factor that regulates osteoblast differentiation and function. Exp Cell Res 314:2334-2351, 2008 4. Rose AA, Pepin F, Russo C, et al: Osteoactivin promotes breast cancer metastasis to bone. Mol Cancer Res 5:1001-1014, 2007 5. Rose AA, Annis MG, Dong Z, et al: ADAM10 releases a soluble form of the gpNMB/osteoactivin extracellular domain with angiogenic properties. PLoS One 5:e12093, 2010 6. Kuan CT, Wakiya K, Dowell JM, et al: Glycoprotein nonmetastatic melanoma protein B, a potential molecular therapeutic target in patients with glioblastoma multiforme. Clin Cancer Res 12:19701982, 2006 7. Selim AA: Osteoactivin bioinformatic analysis: Prediction of novel functions, structural features, and modes of action. Med Sci Monit 15:MT19MT33, 2009 8. Singh M, Del Carpio-Cano F, Belcher JY, et al: Functional roles of osteoactivin in normal and disease processes. Crit Rev Eukaryot Gene Expr 20: 341-357, 2010 9. Zhou LT, Liu FY, Li Y, et al: gpNMB/osteoactivin, an attractive target in cancer immunotherapy. Neoplasma 59:1-5, 2012

Conception and design: Mansoor N. Saleh, Elizabeth Crowley, Ronit Simantov, Linda T. Vahdat Financial support: Thomas A. Davis Administrative support: Thomas A. Davis Provision of study materials or patients: Johanna C. Bendell, Mansoor N. Saleh, Lowell L. Hart, Thomas A. Davis Collection and assembly of data: Johanna C. Bendell, April A.N. Rose, Peter M. Siegel, Lowell L. Hart, Surendra K. Sirpal, Suzanne Jones, Jennifer A. Green, Elizabeth Crowley, Ronit Simantov, Linda T. Vahdat Data analysis and interpretation: Johanna C. Bendell, Suzanne Jones, Jennifer A. Green, Elizabeth Crowley, Tibor Keler, Thomas A. Davis Manuscript writing: All authors Final approval of manuscript: All authors

10. Rose AA, Grosset AA, Dong Z, et al: Glycoprotein nonmetastatic B is an independent prognostic indicator of recurrence and a novel therapeutic target in breast cancer. Clin Cancer Res 16:21472156, 2010 11. Yardley D, Weaver R, Melisko M, et al: A randomized phase 2 study of the antibody-drug conjugate CDX011 in advanced GPNMB-overexpressing breast cancer: The EMERGE study. Cancer Res 72:543s, 2012 (suppl; abstr P6-10-01) 12. Rich JN, Shi Q, Hjelmeland M, et al: Bonerelated genes expressed in advanced malignancies induce invasion and metastasis in a genetically defined human cancer model. J Biol Chem 278:1595115957, 2003 13. Onaga M, Ido A, Hasuike S, et al: Osteoactivin expressed during cirrhosis development in rats fed a choline-deficient, L-amino acid-defined diet, accelerates motility of hepatoma cells J Hepatol 39:779785, 2003 14. Keir CH, Vahdat LT: The use of an antibody drug conjugate, glembatumumab vedotin (CDX011), for the treatment of breast cancer. Expert Opin Biol Ther 12:259-263, 2012 15. Naumovski L, Junutula JR: Glembatumumab vedotin, a conjugate of an anti-glycoprotein nonmetastatic melanoma protein B mAb and monomethyl auristatin E for the treatment of melanoma and breast cancer. Curr Opin Mol Ther 12:248-257, 2010 16. Sutherland MS, Sanderson RJ, Gordon KA, et al: Lysosomal trafficking and cysteine protease metabolism confer target-specific cytotoxicity by peptide-linked anti-CD30-auristatin conjugates. J Biol Chem 281:10540-10547, 2006 17. Pollack VA, Alvarez E, Tse KF, et al: Treatment parameters modulating regression of human melanoma xenografts by an antibody-drug conjugate (CR011-vcMMAE) targeting GPNMB. Cancer Chemother Pharmacol 60:423-435, 2007

18. Hamid O, Sznol M, Pavlick AC, et al: Frequent dosing and GPNMB expression with CDX-011 (CR011-vcMMAE), an antibody-drug conjugate (ADC), in patients with advanced melanoma. J Clin Oncol 28:15s, 2010 (suppl; abstr 8525) 19. Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1-10, 1989 20. Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 45:228-247, 2009 21. Perez EA, Lerzo G, Pivot X, et al: Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol 25:3407-3414, 2007 22. Kovtun YV, Audette CA, Ye Y, et al: Antibodydrug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen. Cancer Res 66:3214-3221, 2006 23. Okeley NM, Miyamoto JB, Zhang X, et al: Intracellular activation of SGN-35, a potent antiCD30 antibody-drug conjugate. Clin Cancer Res 16:888-897, 2010 24. Gluz O, Liedtke C, Gottschalk N, et al: Triplenegative breast cancer– current status and future directions. Ann Oncol 20:1913-1927, 2009 25. Hudis CA, Gianni L: Triple-negative breast cancer: An unmet medical need. Oncologist 16 Suppl 1:1-11, 2011 26. Cortes J, O’Shaughnessy J, Loesch D, et al: Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): A phase 3 open-label randomised study. Lancet 377:914-923, 2011 27. Younes A, Bartlett NL, Leonard JP, et al: Brentuximab vedotin (SGN-35) for relapsed CD30positive lymphomas. N Engl J Med 363:1812-1821, 2010

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Phase I/II Study of Glembatumumab Vedotin in Breast Cancer

GLOSSARY TERMS

angiogenesis: the process involved in the generation of new blood vessels. Although this is a normal process that naturally occurs and is controlled by so-called on and off switches, blocking tumor angiogenesis (antiangiogenesis) disrupts the blood supply to tumors, thereby preventing tumor growth.

antibody-drug conjugate: an antibody chemically linked to a therapeutic cytotoxic agent providing targeted delivery of the cytotoxic agent preferentially to cancer cells expressing the antigen recognized by the antibody.

immunohistochemistry: the application of antigen-antibody interactions to histochemical techniques. Typically, a tissue section is mounted on a slide and incubated with antibodies (polyclonal or monoclonal) specific to the antigen (primary reaction). The antigen-antibody signal is then amplified by using a second antibody conjugated to a complex of peroxidase-antiperoxidase, avidin-biotin-peroxidase, or avidin-biotin alkaline phosphatase. In the presence of substrate and chromogen, the enzyme forms a colored deposit at the sites of antibody-antigen binding. Immunofluorescence is an alternate approach to visualize antigens. In this technique, the primary antigen-antibody signal is amplified by using a second antibody conjugated to a fluorochrome. On ultraviolet light absorption, the fluorochrome emits its own light at a longer wavelength (fluorescence), thus allowing localization of antibody-antigen complexes.

monoclonal antibody: an antibody that is secreted from a single clone of apoptosis: also called programmed cell death. Apoptosis is a signaling pathway that leads to cellular suicide in an organized manner. Several factors and receptors are specific to the apoptotic pathway. The net result is that cells shrink and develop blebs on their surface, and their DNA undergoes fragmentation.

HER2/neu (human epidermal growth factor receptor 2): also called ErbB2. HER2/neu belongs to the epidermal growth factor receptor (EGFR) family and is overexpressed in several solid tumors. Like EGFR, it is a tyrosine kinase receptor whose activation leads to proliferative signals within the cells. On activation, the human epidermal growth factor family of receptors are known to form homodimers and heterodimers, each with a distinct signaling activity. Because HER2 is the preferred dimerization partner when heterodimers are formed, it is important for signaling through ligands specific for any members of the family. It is typically overexpressed in several epithelial tumors.

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an antibody-forming cell. Large quantities of monoclonal antibodies are produced from hybridomas, which are produced by fby using single antibodyforming cells to tumor cells. The process is initiated with initial immunization against a particular antigen, stimulating the production of antibodies targeted to different epitopes of the antigen. Antibody-forming cells are subsequently isolated from the spleen. By fusing each antibody-forming cell to tumor cells, hybridomas can each be generated with a different specificity and targeted against a different epitope of the antigen.

RECIST (Response Evaluation Criteria in Solid Tumors): a model proposed by the Response Evaluation Criteria Group by which a combined assessment of all existing lesions, characterized by target lesions (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment.

stromal cells: the noncancer cells in tumors. The stroma is distinct from the parenchyma, which consists of the key functional elements of an organ. triple-negative: breast tumors that are negative for progesterone and estrogen and that underexpress HER2.

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Bendell et al

Acknowledgment We thank Mark Calcamuggio (The Write Company) for assistance with manuscript writing and Anne Clarke (Celldex Therapeutics) for assistance with clinical trial management.

© 2014 by American Society of Clinical Oncology

JOURNAL OF CLINICAL ONCOLOGY

Information downloaded from jco.ascopubs.org and provided by at Ondokuz Mayis Universitesi on November 11, 2014 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 193.140.28.22

II study of the antibody-drug conjugate glembatumumab vedotin in patients with locally advanced or metastatic breast cancer.

Glycoprotein NMB (gpNMB), a novel transmembrane protein overexpressed in 40% to 60% of breast cancers, promotes metastases in animal models and is a p...
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