A randomized phase 2 study of etaracizumab, a monoclonal antibody against integrin αvβ3, ± dacarbazine in patients with stage IV metastatic melanoma

Authors


  • The authors thank Miriam Gitler, PhD, MedImmune, LLC, for her assistance in preparation of the manuscript.

Abstract

BACKGROUND:

The alpha v beta 3vβ3) integrin is involved in intracellular signaling regulating cell proliferation, migration, and differentiation and is important for tumor-induced angiogenesis.

METHODS:

This phase 2, randomized, open-label, 2-arm study was designed to capture safety data and evaluate the antitumor efficacy of etaracizumab (Abegrin), an IgG1 humanized monoclonal antibody against the αvβ3 integrin, in patients with previously untreated metastatic melanoma. The objective was to evaluate whether etaracizumab ± dacarbazine had sufficient clinical activity to warrant further study in a phase 3 clinical trial.

RESULTS:

One hundred twelve patients were randomized to receive etaracizumab alone (N = 57) or etaracizumab + dacarbazine (N = 55). Safety of etaracizumab ± dacarbazine was acceptable with infusion-related, gastrointestinal, and metabolic reactions being the most common adverse events (AEs). The majority of AEs were grade 1 or 2 in severity in both study arms; most events were not considered serious, except for cardiovascular (myocardial infarction, atrial fibrillation) and thromboembolic events, which occurred in 3 and 5 patients, respectively. None of the patients in the etaracizumab-alone study arm and 12.7% of patients in the etaracizumab + dacarbazine study arm achieved an objective response. The median duration of objective response in the etaracizumab + dacarbazine study arm was 4.2 months. Stable disease rate, time to progression (TTP), and progression-free survival (PFS) appeared to be similar between the 2 treatment arms. Stable disease occurred in 45.6% of patients in the etaracizumab-alone study arm and 40.0% of patients in the etaracizumab + dacarbazine study arm. Median TTP and median PFS were both 1.8 months in the etaracizumab-alone study arm and 2.5 and 2.6 months in the etaracizumab + dacarbazine study arm, respectively. Median overall survival was 12.6 months in the etaracizumab-alone study arm and 9.4 months in the etaracizumab + dacarbazine study arm.

CONCLUSIONS:

The survival results in both treatment arms of this study were considered unlikely to result in clinically meaningful improvement over dacarbazine alone. Cancer 2010. © 2010 American Cancer Society.

Worldwide, cutaneous melanoma accounts for an estimated 160,000 new cases and 41,000 deaths annually.1 Median survival for patients with stage IV disease, based on the American Joint Committee on Cancer (AJCC) criteria, is 6 months to 10 months, with an estimated 5-year survival rate of 6%-10% for patients with advanced disease.2, 3

Dacarbazine is the only US Food and Drug Administration (FDA)-approved chemotherapeutic agent for the treatment of metastatic melanoma in current usage. Single-agent response rates range from 7% to 20% for dacarbazine but are of short duration.4, 5 Historically, the median survival of patients treated with dacarbazine alone in phase 3 randomized studies is 6 months to 10 months.6-10 Interleukin-2 is an immunotherapeutic agent approved for the treatment of metastatic melanoma. Its multiorgan toxicity has limited its utility, which has never been established in a phase 3 trial. No other agents or combinations have proved to be more effective than single-agent dacarbazine.6-8, 11-15

Etaracizumab (Abegrin or MEDI-522; MedImmune, Gaithersburg, Md) is an IgG1 humanized monoclonal antibody engineered from the murine monoclonal LM609, an antibody directed against a conformational epitope of alpha v beta 3vβ3) integrin that is present on the surface of certain types of invasive tumor cells, angiogenic endothelial cells, and mature osteoclasts.16 Although it is expressed at low levels in most normal tissues, αvβ3 integrin is highly expressed in certain malignancies, such as melanoma, late-stage glioma, and renal cell carcinoma, as well as a limited number of cell types, such as endothelial cells involved in angiogenesis and mature osteoclasts involved in bone resorption.17-21 Preclinical studies using αvβ3 antagonists have reported inhibition of melanoma tumor growth independent of its antiangiogenic effects.22

Preclinical data suggest that a minimum continuous trough concentration of 10-30 μg/mL of etaracizumab induces in vitro and in vivo antitumor activity, including inhibition of angiogenesis, direct inhibition of melanoma tumor growth (ie, delay in tumor progression), and antibody-dependent, cell-mediated cytotoxicity of melanoma cells independent of antiangiogenic activity. In human tissue cross-reactivity studies, etaracizumab binding was detected mainly in endothelium, smooth muscle, selected epithelial cells, and cells of the lamina propria.

Previous phase 1 studies demonstrated that the safety profile of weekly etaracizumab at 8 mg/kg doses was acceptable, and pharmacokinetics resulted in trough concentrations shown in preclinical studies to be associated with biologic activity.23 In a phase 1 study of the saturation of αvβ3 by etaracizumab in patients with metastatic melanoma that tested 1, 4, and 8 mg/kg, 8 mg/kg proved to be the optimal biologic dose.24 The present phase 2 uncontrolled multicenter study was designed to evaluate the efficacy and safety profile of etaracizumab (8 mg/kg) alone or in combination with dacarbazine, and to assess whether 1 of the 2 regimens would merit further study. This report presents the results of the study through 12 months postrandomization of the last patient plus approximately 2 years of long-term follow-up.

MATERIALS AND METHODS

Patient Eligibility

Patients eligible to enter the study were at least 18 years old with histologically confirmed unresectable, stage IV melanoma with at least 1 measurable lesion. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Patients who had prior adjuvant immunotherapy or surgery were eligible, provided that therapy/surgery occurred at least 4 weeks before randomization. Eligibility also required adequate renal function (serum creatinine ≤1.5 mg/dL), hepatic function (bilirubin ≤1.5 mg/dL, aspartate aminotransferase [AST]/alanine aminotransferase [ALT] ≤3 times the upper limit of normal [ULN], alkaline phosphatase ≤3 times ULN), and bone marrow function (white blood cell ≥3000/mm3, absolute neutrophil count [ANC] ≥1500/mm3, platelet count ≥100,000/mm3).

Patients were excluded if they had prior chemotherapy, radiotherapy, hormonal therapy, or biologics for metastatic melanoma. Concurrent therapy for cancer was not allowed. Patients with known brain metastases or primary brain tumors, ocular melanoma, symptomatic pleural effusion, or ascites requiring paracentesis were also excluded. Patients with any history or evidence of pulmonary embolism or thrombophlebitis (including deep-vein thrombosis) requiring anticoagulant therapy (eg, warfarin or heparin) or requiring therapeutic anticoagulation, as well as patients with prior myocardial infarction or angina or uncontrolled/refractory hypertension within 6 months before randomization, were excluded.

Local institutional review boards approved the protocol, and patients provided written informed consent before enrollment.

Treatment Plan

Patients were randomized using a 1:1 ratio to receive etaracizumab or etaracizumab + dacarbazine with the following stratification factors: site of distant metastases (AJCC Stage IV, M1a vs M1b vs M1c) and geographic region. Patients randomized to the etaracizumab treatment arm received etaracizumab weekly (8.0 mg/kg intravenous [IV] over 30 minutes [±5 minutes]). The duration of each treatment cycle was 3 weeks, regardless of the number of etaracizumab doses administered, but could be extended up to 5 weeks. Treatment cycles were repeated until unacceptable toxicity, disease progression, or patient withdrawal for any other reason. Patients randomized to the etaracizumab + dacarbazine study arm received the same weekly doses of etaracizumab followed by dacarbazine (1000 mg/m2 as a 60-minute IV infusion [±10 minutes]) given once at Week 1 of every 3-week treatment cycle. Dacarbazine was to be administered no earlier than 60 minutes (±10 minutes) after the completion of the etaracizumab infusion.

Efficacy Assessments

The antitumor activity primary endpoints were objective tumor response rate, early disease progression rate, and time to progression (TTP). Duration of objective response, overall survival (OS), and progression-free survival (PFS) were secondary endpoints.

Tumor measurements were performed at screening and after every 2 cycles of treatment until documentation of disease progression. Tumor measurements were repeated at least 4 weeks later in patients who achieved a complete or partial response to treatment. Tumor assessments were based on Response Evaluation Criteria in Solid Tumors guidelines.25

Safety Profile Assessments

Safety profile endpoints included adverse events (AEs), serious adverse events (SAEs), and changes in clinical laboratory evaluations, vital signs, and urinalysis. Toxicity grading was based on NCI CTC 3.0.26 Routine laboratory screening and study tests included CBC with differential, platelets, prothrombin time/partial thromboplastin time, serum chemistries, and thyroxin and thyroid stimulating hormone (screening only).

Statistical Analyses

One of the primary endpoints was objective tumor response, defined as either complete or partial response, confirmed at least 4 weeks after the initial response. Other primary endpoints were early disease progression rate, defined as the proportion of patients with disease progression at the end of 2 treatment cycles, and TTP. Duration of objective response, OS, and PFS were secondary endpoints. For patients without disease progression or death due to disease before study end or start of alternative cancer therapy, TTP and duration of objective response were censored on the last tumor assessment date. For patients who had not progressed or died by the end of study, PFS was censored on the last date patients were known to be alive. OS was determined from the day of randomization until death, or for surviving or lost-to-follow-up patients, OS was censored on the last date patients were known to be alive.

For each of the TTP, duration of objective response, PFS, and OS, the median and corresponding confidence intervals (CIs) as well as plots of overall time-to-event distribution were obtained using Kaplan-Meier estimates.27 The effects of prognostic factors on OS were investigated using the Cox proportional hazard regression27 with backward selection procedure. Significance testing was 2-sided at the 0.05 level. Subgroup comparisons by baseline patient characteristics (sex, age, ECOG performance status, and LDH ratio [baseline LDH/upper limit of laboratory-specific norm for LDH]) and stratification factors (AJCC staging and geographic region) were explored for the primary (objective tumor response, early disease progression rate, and TTP) and secondary (PFS and OS) endpoints. No formal statistical testing for the safety endpoints were planned or performed. No power analysis was performed for sample size determination. P values and CIs reported in this article were not adjusted for multiple comparisons or multiple endpoints.

RESULTS

Patient Characteristics and Disposition

A total of 112 patients with stage IV melanoma were enrolled between September 23, 2003, and May 20, 2004, to receive etaracizumab alone (N = 57) or etaracizumab + dacarbazine (N = 55) at 23 sites in the United States (20 sites), Australia (2 sites), and United Kingdom (1 site). Patient baseline characteristics are provided in Table 1. All but 2 patients (1 in each study arm) discontinued treatment at 12 months after enrollment of the last patient. The most common reason for discontinuation was disease progression (etaracizumab alone, 46 of 56 [82.1%]; etaracizumab + dacarbazine, 45 of 54 [83.3%]), and AEs (etaracizumab alone, 7 of 56 [12.5%]; etaracizumab + dacarbazine, 3 of 54 [5.6%]). One patient (1.9%) in the etaracizumab + dacarbazine study arm withdrew consent, and 3 of 56 (5.4%) and 5 of 54 (9.3%) in the etaracizumab-alone study arm and etaracizumab + dacarbazine study arm, respectively, discontinued because of other reasons (eg, physician decision, patient decision, suspected progression, surgical intervention, adrenocortical adenoma). Three patient populations were analyzed during this trial: intent-to-treat, evaluable, and safety populations. All 112 patients (57 in the etaracizumab-alone study arm and 55 in the etaracizumab + dacarbazine study arm) were included in the intent-to-treat and safety patient populations. The evaluable patient population included 53 of 57 (93.0%) patients in the etaracizumab-alone study arm and 48 of 55 (87.3%) patients in the etaracizumab + dacarbazine study arm. Reasons for excluding patients from the evaluable patient population included the administration of less than 1 cycle of etaracizumab and the absence of postbaseline tumor assessment.

Table 1. Patient Baseline Characteristics
ParameterEtaracizumab n=57Etaracizumab +Dacarbazine n=55
Age, yNo. (%)No. (%)
  • ECOG indicates Eastern Cooperative Oncology Group.

  • a

    Does not include missing/unknown data.

  • b

    The ratio of baseline LDH/upper limit of laboratory-specific LDH norm.

 Mean±SD56.7±13.759.9±13.4
 Median53.060.0
 Range25-8719-84
 ≤5532 (56.1)20 (36.4)
 >55 to <655 (8.8)14 (25.5)
 ≥6520 (35.1)21 (38.2)
Sex  
 Male38 (66.7)38 (69.1)
 Female19 (33.3)17 (30.9)
ECOG performance status
 040 (72.7)47 (85.5)
 115 (27.3)8 (14.5)
 Missing20
Time from initial diagnosis of melanoma to randomization, mo  
 Na5043
 Median24.613.4
 Range0.7-210.50.7-150.8
M classification  
 M000
 M1a6 (10.5)5 (9.1)
 M1b15 (26.3)19 (34.5)
 M1c36 (63.2)31 (56.4)
LDH ratiob  
 <1.143 (75.4)44 (80.0)
 ≥1.114 (24.6)11 (20.0)
No. of target lesions  
 112 (21.1)11 (20.0)
 212 (21.1)10 (18.2)
 312 (21.1)11 (20.0)
 411 (19.3)6 (10.9)
 ≥510 (17.5)17 (30.9)
Prior cancer treatment  
 Surgery50 (87.7)50 (90.9)
 Chemotherapy2 (3.5)2 (3.6)
 Radiotherapy10 (17.5)8 (14.5)
 Biologics therapy4 (7.0)2 (3.6)
 Hormonal therapy1 (1.8)0
 Immunotherapy20 (35.1)19 (34.5)

Disease Response and TTP

Table 2 summarizes the disease response to etaracizumab ± dacarbazine in the intent-to-treat population as well as PFS and OS. Disease responses were all partial and observed in the etaracizumab + dacarbazine treatment group. Objective response was 12.7% (7 of 55) in the etaracizumab + dacarbazine study arm and 0% in the etaracizumab study arm. Stable disease and early disease progression rates as well as TTP were similar across the 2 treatment groups. Thus, stable disease, as best treatment outcome during the study, occurred in 45.6% (26 of 57) patients in the etaracizumab-alone study arm and 40.0% (22 of 55) patients in the etaracizumab + dacarbazine study arm. Early disease progression rate was 47.4% in the etaracizumab-alone study arm and 40.0% in the etaracizumab + dacarbazine study arm.

Table 2. Disease Response and Survival
ParameterEtaracizumab n=57Etaracizumab +Dacarbazine n=55
No. (%)No. (%)
Best tumor response  
 Complete response00
 Partial response07 (12.7)
 Objective response07 (12.7)
 Stable disease26 (45.6)22 (40.0)
 Progressive disease27 (47.4)22 (40.0)
 Not evaluable1 (1.8)0
 Missing3 (5.3)4 (7.3)
Time to progression, mo  
 Median [95% confidence interval]1.8 [1.3-2.8]2.5 [1.6-3.2]
 Range0.1-14.90.0-10.3
Progression-free survival, mo  
 Median [95% confidence interval]1.8 [1.3-2.8]2.6 [1.6-3.4]
 Range0.1-37.50.6-33.1
Overall survival, mo  
 Median [95% confidence interval]12.6 [6.8-14.2]9.4 [7.6-13.1]
 Range0.1-37.50.8-40.7

Median time to progression was 1.8 months in the etaracizumab-alone study arm and 2.5 months in the etaracizumab + dacarbazine study arm. The median duration of objective response was 4.2 months in the etaracizumab + dacarbazine study arm. Similar results (objective tumor response, early disease progression rate, time to progression, duration of objective response, duration of stable disease) were observed for the evaluable patient population (data not shown).

PFS and OS

Kaplan-Meier estimates for PFS and OS for each treatment arm are presented in Table 2 and Figure 1. At a median follow-up of 11.2 months (range, 0.1-40.7), median PFS was 1.8 months in the etaracizumab-alone study arm and 2.6 months in the etaracizumab + dacarbazine study arm (Table 2). Median OS was 12.6 months in the etaracizumab-alone study arm and 9.4 months in the etaracizumab + dacarbazine study arm (Table 2).

Figure 1.

Kaplan-Meier plots of (A) progression-free survival and (B) overall survival in patients treated with etaracizumab ± dacarbazine.

Results of subgroup analyses by baseline patient characteristics showed that for both treatment arms, females had longer median PFS and longer median OS than males. Similarly, patients with ECOG performance status of 0 had longer median OS than patients with ECOG performance status of 1. In addition, LDH ratio ≥1.1 was associated with adverse PFS and OS outcomes. The impact of prognostic factors such as age, gender, ECOG performance status, M classification, and LDH ratio on OS was analyzed using Cox regression. Only LDH ratio, M classification, and gender reached statistical significance (P = .0005, P = .033, and P = .015, respectively). On the basis of the hazard ratio estimates, it can be concluded that patients with an LDH ratio ≥1.1 had 69.5% higher risk of death compared with patients with a LDH ratio <1.1 (hazard ratio of 2.27 [95% CI, 1.43-3.61]), and patients with M1c melanoma had 60.8% higher risk of death compared with patients with other M classifications (hazard ratio of 1.55 [95% CI, 1.04-2.33]). Also, male patients had 63.6% higher risk of death compared with female patients (hazard ratio of 1.75 [95% CI, 1.12-2.74]). Other factors that appeared to adversely affect survival were lack of subsequent anticancer therapy and increased length of time from initial diagnosis to randomization.

Similar results (median PFS and OS time) were observed for the evaluable patient population.

Safety Profile

The median number of treatment cycles was 2.0 in the etaracizumab-alone study arm and 3.0 in the etaracizumab + dacarbazine study arm up to 12 months after the last patient was randomized. One of the 2 patients who remained on the study as of 12 months after the last patient was randomized had received a total of 53 treatment cycles. The other patient discontinued treatment after a total of 39 cycles of treatment. At the completion of the long-term follow-up (11.2 months; range, 0.1-40.7), 14% (8 of 57) of patients in the etaracizumab-alone study arm and 7.3% (4 of 55) of patients in the etaracizumab + dacarbazine study arm were alive.

Table 3 summarizes the AEs that occurred in ≥6 patients (≥11%) in either treatment arm. The most frequently occurring AEs were infusion-related, gastrointestinal-related, or metabolic. Among the most common events (occurring in ≥15 patients) reported by patients in either the etaracizumab-alone study arm or etaracizumab + dacarbazine study arm were fatigue, nausea, hyperglycemia, chills, and anemia. Other commonly reported events in the etaracizumab-alone study arm were pyrexia, hypocalcemia, and diarrhea, and in the etaracizumab + dacarbazine study arm, thrombocytopenia, constipation, leukopenia, and neutropenia. The majority of AEs in both study arms was grade 1 or 2 in severity and was considered not serious. Table 4 summarizes the grade ≥3 AEs that occurred in ≥2 patients (≥4%) in either treatment arm. The most common grade ≥3 AEs occurring in patients in the etaracizumab-alone study arm were fatigue and pulmonary embolism. The most common grade ≥3 AEs occurring in patients in the etaracizumab + dacarbazine study arm were neutropenia, thrombocytopenia, and leukopenia, anemia, and lymphopenia, perhaps because of the addition of dacarbazine.

Table 3. Summary of Adverse Events (Any Grade) That Occurred in ≥6 Patients (≥11%) in Either Treatment Arm
MedDRA Preferred TermEtaracizumab n=57Etaracizumab +Dacarbazine n=55
No. (%)No. (%)
  1. MedDRA indicates medical dictionary for regulatory activities.

Fatigue30 (52.6)27 (49.1)
Nausea27 (47.4)39 (70.9)
Hyperglycemia21 (36.8)17 (30.9)
Chills20 (35.1)19 (34.5)
Pyrexia18 (31.6)13 (23.6)
Anemia17 (29.8)17 (30.9)
Hypocalcemia17 (29.8)14 (25.5)
Diarrhea15 (26.3)11 (20.0)
Constipation14 (24.6)20 (36.4)
Anorexia14 (24.6)10 (18.2)
Vomiting13 (22.8)14 (25.5)
Arthralgia13 (22.8)9 (16.4)
Hypophosphatasemia13 (22.8)6 (10.9)
Insomnia12 (21.1)11 (20.0)
Dizziness12 (21.1)8 (14.5)
Hyponatremia12 (21.1)7 (12.7)
Headache11 (19.3)9 (16.4)
Blood alkaline phosphatase increased10 (17.5)8 (14.5)
Alanine aminotransferase increased10 (17.5)7 (12.7)
Pain10 (17.5)3 (5.5)
Dyspnea9 (15.8)8 (14.5)
Hypoalbuminemia8 (14.0)9 (16.4)
Myalgia8 (14.0)6 (10.9)
Back pain8 (14.0)5 (9.1)
Thrombocytopenia7 (12.3)22 (40.0)
Cough7 (12.3)9 (16.4)
Hematuria7 (12.3)9 (16.4)
Abdominal pain7 (12.3)6 (10.9)
Anxiety7 (12.3)5 (9.1)
Hypersensitivity7 (12.3)5 (9.1)
Hypotension6 (10.5)9 (16.4)
Aspartate aminotransferase increased6 (10.5)7 (12.7)
Chest pain6 (10.5)6 (10.9)
Edema peripheral6 (10.5)6 (10.9)
Hyperhidrosis6 (10.5)0 (0.0)
Influenza-like illness4 (7.0)7 (12.7)
Leukopenia3 (5.3)18 (32.7)
Hypokalemia3 (5.3)6 (10.9)
Neutropenia2 (3.5)17 (30.9)
Lymphopenia2 (3.5)8 (14.5)
Table 4. Summary of Grade ≥3 Adverse Events That Occurred in ≥2 Patients (≥4%) in Either Treatment Arm
MedDRA Preferred TermEtaracizumab n=57Etaracizumab +Dacarbazine n=55
No. (%)No. (%)
  1. MedDRA indicates medical dictionary for regulatory activities.

Fatigue3 (5.3)2 (3.6)
Pulmonary embolism3 (5.3)1 (1.8)
Lymphopenia2 (3.5)3 (5.5)
Pain2 (3.5)0 (0.0)
Hyperglycemia2 (3.5)0 (0.0)
Back pain2 (3.5)0 (0.0)
Metastatic malignant melanoma2 (3.5)0 (0.0)
Thrombocytopenia1 (1.8)6 (10.9)
Anemia1 (1.8)5 (9.1)
Dyspnea1 (1.8)2 (3.6)
Neutropenia0 (0.0)9 (16.4)
Leukopenia0 (0.0)6 (10.9)
Activated partial thromboplastin time prolonged0 (0.0)2 (3.6)
Syncope0 (0.0)2 (3.6)

Table 5 summarizes the major organ-associated SAEs that occurred in any patient in the study. One patient in the etaracizumab-alone study arm died of acute myocardial infarction, and 1 patient in the etaracizumab + dacarbazine study arm died of pulmonary embolism. Serious cardiac disorders occurred in 2 patients in the etaracizumab-alone study arm and 1 patient in the etaracizumab + dacarbazine study arm. In the etaracizumab-alone study arm, these events included 1 each of grade 4 and 5 acute myocardial infarction judged as treatment-related. Grade 3 atrial fibrillation occurred in the etaracizumab + dacarbazine study arm and was considered unrelated to treatment. Pulmonary embolism occurred in 3 patients in the etaracizumab-alone study arm and 1 patient in the etaracizumab + dacarbazine study arm; thrombosis occurred in 1 patient in the etaracizumab-alone study arm. Each event was considered serious, but only 1 pulmonary embolism event on each study arm was judged as being treatment-related.

Table 5. Summary of Major Organ-Associated Serious Adverse Events That Occurred in Any Patient in Either Treatment Arm
MedDRA Preferred TermEtaracizumab n=57Etaracizumab +Dacarbazine n=55
No. (%)No. (%)
  1. MedDRA indicates medical dictionary for regulatory activities.

Pulmonary embolism3 (5.3)1 (1.8)
Abdominal pain2 (3.5)1 (1.8)
Dyspnea2 (3.5)0 (0.0)
Acute myocardial infarction1 (1.8)0 (0.0)
Myocardial infarction1 (1.8)0 (0.0)
Gastrointestinal hemorrhage1 (1.8)0 (0.0)
Upper gastrointestinal hemorrhage1 (1.8)0 (0.0)
Cerebrospinal fluid leakage1 (1.8)0 (0.0)
Guillain-Barré syndrome1 (1.8)0 (0.0)
Peripheral motor neuropathy1 (1.8)0 (0.0)
Spinal cord compression1 (1.8)0 (0.0)
Hydronephrosis1 (1.8)1 (1.8)
Respiratory distress1 (1.8)0 (0.0)
Thrombosis1 (1.8)0 (0.0)
Atrial fibrillation0 (0.0)1 (1.8)
Malignant pleural effusion0 (0.0)1 (1.8)
Bronchial obstruction0 (0.0)1 (1.8)
Obstructive airways disorder0 (0.0)1 (1.8)
Pleural effusion0 (0.0)1 (1.8)
Hypotension0 (0.0)1 (1.8)

Hypersensitivity reactions occurred in 7 patients in the etaracizumab-alone study arm and in 5 patients in the etaracizumab + dacarbazine study arm. Each reaction was mild, and none of them resulted in treatment discontinuation. Gastrointestinal events (eg, diverticulum, gastrointestinal hemorrhage, rectal hemorrhage) occurred in 3 patients in the etaracizumab-alone study arm and 1 patient in the etaracizumab + dacarbazine study arm. Two events (upper gastrointestinal hemorrhage and gastrointestinal hemorrhage, each grade 3) were serious, but neither event was considered treatment-related or required treatment discontinuation. One event (grade 2 rectal hemorrhage) in the etaracizumab + dacarbazine study arm was considered possibly treatment-related.

Elevation of serum alkaline phosphatase, ALT, AST, and blood glucose, as well as reduction of serum calcium, sodium, phosphate, and albumin levels were observed at similar rates in patients on both treatment arms.

The majority of AEs exhibited by the 2 patients who remained on study as of 12 months after the last patient was randomized was grade 1 or 2 in severity. The patient in the etaracizumab-alone study arm reported SAEs of rib fracture (grade 3), dyspnea (grade 3), cellulitis (grade 2), anxiety (grade 3), and abdominal pain (grade 3). These events were considered to be unrelated or remotely drug-related (cellulitis). The patient in the etaracizumab + dacarbazine study arm reported SAEs of osteonecrosis (grade 3) and catheter sepsis (grade 3); neither event was considered to be etaracizumab-related.

DISCUSSION

We report the results of a randomized multicenter phase 2 study of etaracizumab in patients with stage IV melanoma. Patients were randomized 1:1 to receive etaracizumab (8 mg/kg/week) as a single agent or combined with dacarbazine (1000 mg/m2 once every 3 weeks). The study was designed to evaluate whether one of the regimens warranted further phase 3 clinical study.

Etaracizumab ± dacarbazine does not appear to be more effective for treatment of metastatic melanoma than historic experience with single-agent dacarbazine and other inactive drugs.28 The median OS time of 12.6 months for the etaracizumab-alone study arm and 9.4 months for the etaracizumab + dacarbazine study arm appears comparable to historical data for dacarbazine alone (6-10 months) in similar patient populations.6-10 The tumor response rate of 12.7% for etaracizumab + dacarbazine was also comparable to historical rates for dacarbazine alone (10%-20%),4-8 but etaracizumab alone showed no tumor response. Median PFS for the 2 treatment arms (1.8-2.6 months) are similar to historical data for dacarbazine alone (1.5-2.3 months) in similar patient populations.7, 9, 10

On the basis of the data from 70 phase 2 multicenter cooperative group studies in 2100 patients analyzed by Korn et al,28 median PFS was 1.7 months (95% CI, 1.6-1.8 months), median OS was 6.2 months (95% CI, 5.9-6.5 months), and 1-year survival was 25.5% (95% CI, 23.6%-27.4%). There are important differences in the patient population of this study and the one presented by Korn et al. Many of the patients analyzed by Korn et al28 had brain metastases and/or an ECOG performance status of 2-3. Patients in the present study had a significantly better median survival than patients analyzed the study by Korn et al. Thus, the OS outcome at 1 year (40% in the etaracizumab-alone study arm and 51% in the etaracizumab + dacarbazine study arm) was initially viewed as encouraging, although longer follow-up did not reveal sustained differences, and the exclusion of patients with an ECOG performance status of 2-3 and evidence of brain disease may have contributed to the more optimistic earlier findings.28

In general, ECOG performance status, LDH, M classification, age, and sex predicted survival in patients with metastatic melanoma as shown in other studies.3, 28, 29

It is important to note that tumor response rate and TTP/PFS in the etaracizumab + dacarbazine study arm did not correlate with improved survival. Tumor response rate of 0% and shorter TTP/PFS for etaracizumab were associated with the best survival in this study. Whether this lack of concordance between the survival and response rate is related to the capacity for biologics, like bevacizumab, or small-molecule agents, like erlotinib and sorafenib, to prolong PFS (erlotinib and sorafenib)30, 31 or OS (bevacizumab and sorafenib)31, 32 without achieving objective response, or because of variability in these outcomes that requires a larger sample size to be reliably assessed, is presently uncertain.

The safety profile of etaracizumab ± dacarbazine was generally acceptable in this study. As expected in a combination with dacarbazine, hematologic toxicity occurred more frequently and with a higher severity with etaracizumab + dacarbazine than with etaracizumab alone. The majority of AEs in either treatment arm were considered not serious with the exception of myocardial infarction in 2 patients, atrial fibrillation in 1 patient, and thromboembolic events in 5 patients. These AEs have also been reported with other antiangiogenic agents.33

The OS for both study arms was judged to be no different from many other inactive agents including dacarbazine; thus, further phase 3 study was not deemed to be reasonable. Although further studies could explore whether higher doses (>10 mg/kg) of etaracizumab alone or in combination with dacarbazine may be more effective in metastatic melanoma, at the present time, clinical development of etaracizumab has been interrupted until its precise mechanism of action is understood.

CONFLICT OF INTEREST DISCLOSURES

Drs. Hersey, Sosman, O'Day, Richards, Bedikian, Gonzalez, Sharfman, Weber, Logan, and Kirkwood received research funding from MedImmune. Drs. Buzoianu and Hammershaimb are employees of MedImmune.

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