Accepted Manuscript
Docetaxel Plus Bavituximab in Previously Treated, Advanced Nonsquamous Non– small-cell Lung Cancer
David E. Gerber, David R. Spigel, David Giorgadze, Mikhail Shtivelband, Olga V. Ponomarova, Joseph S. Shan, Kerstin B. Menander, Chandra P. Belani PII: S1525-7304(16)30007-9 DOI: 10.1016/j.cllc.2016.02.003 Reference: CLLC 455
To appear in: Clinical Lung Cancer
Received Date: 4 November 2015 Revised Date: 5 February 2016 Accepted Date: 9 February 2016
Please cite this article as: Gerber DE, Spigel DR, Giorgadze D, Shtivelband M, Ponomarova OV, Shan JS, Menander KB, Belani CP, Docetaxel Plus Bavituximab in Previously Treated, Advanced Nonsquamous Non–small-cell Lung Cancer, Clinical Lung Cancer (2016), doi: 10.1016/ j.cllc.2016.02.003.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT Docetaxel and bavituximab in nonsquamous NSCLC
Docetaxel Plus Bavituximab in Previously Treated, Advanced Nonsquamous Non–small-cell Lung Cancer
David E. Gerber, 1 David R. Spigel, 2 David Giorgadze, 3 Mikhail Shtivelband, 4 Olga V. Ponomarova, 5 Joseph S. Shan, 6 Kerstin B. Menander, 7 Chandra P. Belani 8
Affiliations:
1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center
5323 Harry Hines Blvd., Dallas, TX, USA
2Tennessee Oncology, PLLC
250 25th Ave North, Nashville, TN, USA [email protected] MANUSCRIPT 3Medulla Chemotherapy and Immunotherapy Clinic
6, Jikia Str, Tbilisi, Republic of Georgia
4Ironwood Cancer and Research Center
695 South Dobson Rd., Chandler, AZ, USA
5Kyiv City Oncology Hospital
69, Verkhovinnaya Str, Kyiv, Ukraine [email protected] 6Peregrine Pharmaceuticals, Inc.
14282 Franklin Avenue, Tustin, CA, USA
7Peregrine Pharmaceuticals, Inc.
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ACCEPTED MANUSCRIPT Docetaxel and bavituximab in nonsquamous NSCLC
14282 Franklin Avenue, Tustin, CA, USA
[email protected]; [email protected]
8Pennsylvania State Hershey Cancer Institute
500 University Dr., Hershey, PA, USA
Address for correspondence: David E. Gerber, MD, Division of Hematology-Oncology, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Mail Code 8852, Dallas, TX 75390-8852 E-mail contact: [email protected]
Word Counts: Abstract: 249 Text: 3,360 References: 37 Tables: 3 Figures: 2 Suppl Figures: 1
We request figures to be printed in color. MANUSCRIPT
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ACCEPTED MANUSCRIPT Docetaxel and bavituximab in nonsquamous NSCLC
Conflict of Interest:
D.E.G. receives research funding from Peregrine Pharmaceuticals, Inc. J.S.S. and K.B.M. are paid employees of Peregrine Pharmaceuticals, Inc. All remaining authors have declared no conflicts of interest.
MANUSCRIPT
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ACCEPTED MANUSCRIPT Docetaxel and bavituximab in nonsquamous NSCLC
Microabstract
This phase 2 trial was intended to investigate 2 doses of bavituximab (a phosphatidylserine- targeting antibody) or placebo added to docetaxel in previously treated, advanced nonsquamous non–small-cell lung cancer. Due to a labeling discrepancy, the placebo and bavituximab 1 mg/kg arms were combined and compared to the bavituximab 3 mg/kg arm. This exploratory analysis showed similar toxicity between arms, and albeit without meeting the pre- set statistical endpoints due to the pooled control arm data, had trends favoring bavituximab 3 mg/kg.
Abstract
Background: Bavituximab is a phosphatidylserine-targeting antibody with a selective tumor, vascular-directed immune response. This phase 2 trial evaluated efficacy and safety of bavituximab combined with docetaxel for previously MANUSCRIPT treated, advanced nonsquamous non– small-cell lung cancer.
Methods: Patients were randomized 1:1:1 to receive docetaxel 75 mg/m 2 every 21 days for up to 6 cycles combined with weekly, blinded infusions of placebo, bavituximab 1 mg/kg, or bavituximab 3 mg/kg until progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR), with a predefined endpoint of 26% in the bavituximab arms. After study unblinding, vial-coding discrepancies were discovered in the placebo and bavituximab 1 mg/kg groups. In exploratory analyses, data from these groups were pooled to form the control group and comparedACCEPTED with the 3 mg/kg group.
Results: Efficacy endpoints in the bavituximab 3 mg/kg group (n=41) and in the placebo/bavituximab 1 mg/kg group (n=80), respectively, were as follows: ORR 17.1% (95% CI
5.6%, 28.6%) and 11.3% (95% CI 4.3%, 18.2%); median progression-free survival 4.5 and 3.3
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months (HR 0.74 [95% CI 0.45, 1.21], P=.24); median overall survival 11.7 and 7.3 months (HR
0.66 [95% CI 0.40, 1.10], P=.11). Toxicities were manageable and similar between arms.
Conclusions: The combination of bavituximab and docetaxel is well tolerated. Although no firm efficacy conclusions can be drawn and the trial did not meet the predefined primary endpoint, exploratory analyses suggest trends favoring the addition of bavituximab 3 mg/kg to docetaxel.
This regimen is being evaluated in the ongoing, global, phase 3 SUNRISE trial.
ClinicalTrials.gov Identifier: NCT01138163
Keywords
Immunotherapy; Phosphatidylserine; Macrophages; MANUSCRIPT Tumor microenvironment; Monoclonal antibody
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Introduction
Recently, immunotherapy has emerged as a promising treatment strategy for advanced non–small-cell lung cancer (NSCLC). Checkpoint inhibitors, particularly those targeting the programmed death-1 (PD1) and PD-ligand 1 (PDL1) pathways, have shown promising efficacy.
In 2015, the United States (US) Food and Drug Administration (FDA) approved the anti-PD1 agent nivolumab for the treatment of previously treated, advanced NSCLC after pivotal phase 3 trials demonstrated superior efficacy compared with docetaxel chemotherapy in both squamous and nonsquamous populations.1,2 The FDA also approved the anti-PD1 antibody pembrolizumab for PDL1-positive advanced NSCLC. 3
In addition to and distinct from the widely studied immune checkpoints PD1, PDL1, and cytotoxic T-lymphocyte antigen 4 (CTLA4), the anionic phospholipid phosphatidylserine (PS) has been recognized for decades for exerting immunosuppressive physiologic effects. 4-6 Specifically, exposed PS on apoptotic cells suppres MANUSCRIPTses immune and inflammatory responses by binding to macrophage PS receptors, thereby signaling macrophage production of anti- inflammatory cytokines such as TGF β and IL-10 and preventing dendritic cell maturation and antigen presentation. 7 In preclinical models, PS-targeting antibodies counter both of these effects, resulting in production of proinflammatory cytokines such as TNF α and IL-1β, as well as induction of cytotoxic T-lymphocyte immunity. 8 PS targeting also results in antivascular effects.
Specifically, upon binding of anti-PS antibodies to tumor vessels, bavituximab activates host effector (immune) functions, such as antibody-dependent cellular cytotoxicity (ADCC), resulting in rapid vessel destructionACCEPTED and subsequent tumor necrosis. 9 Due to differential exposure in malignant tissues, PS is a relatively tumor-specific therapeutic target. In most tissues, PS is restricted to the internal surface of the cell membrane.10 By contrast, within solid tumors, hypoxia and other physiologic stresses disrupt
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this asymmetry. These processes result in exposure of PS on the outer membrane leaflet, where it is available for binding by PS-targeting therapies. 11,12 There may be differences in expression of PS in different tumor types. A study of PS exposure in cell lines derived from a variety of malignant melanomas, prostate cancer, renal cancer, glioblastoma, and rhabdomyosarcoma found PS exposure in the rhabdomyosarcoma cell line to be significantly higher than the amount in the malignant melanoma cell line, whereas levels in the glioblastoma cell line were lower. 13
Bavituximab is an unconjugated, chimeric IgG1 monoclonal antibody (mAb) that localizes to anionic phospholipids expressed on tumor endothelium, principally PS. In preclinical models of multiple tumor types, bavituximab inhibits tumor growth, prolongs survival, and enhances the effects of chemotherapy and radiation.12,14,15 Preclinical models have also demonstrated tumor-specific targeting by bavituximab. 11,16,17 Additionally, the administration of cytotoxic therapies, including chemotherapy and ionMANUSCRIPTizing radiation, further induces PS exposure, thereby enhancing bavituximab binding and resulting in complementary effects when combined with bavituximab. 14,15
In a phase 1 trial of bavituximab in relapsed and refractory malignancies, no maximum tolerated dose was reached. 18 Both 1 mg/kg and 3 mg/kg weekly doses were well tolerated and, based on preclinical pharmacokinetic (PK) modeling, were considered the likely preferred biologic doses. Considerations included antitumor efficacy, possible depletion of cofactor protein
β2-glycoprotein 1 ( β2GP1), tolerability, and ADCC. In single-arm combination studies with cytotoxic chemotherapy, the addition of bavituximab generally did not increase the risk of adverse events (AEs).ACCEPTED19,20 Although limited by lack of comparator arms, these trials also suggest that the addition of bavituximab may enhance the efficacy of chemotherapy. In the first-line setting for advanced NSCLC, combination carboplatin-paclitaxel plus bavituximab had a response rate of 41%. 19 In HER2-negative breast cancer, paclitaxel plus bavituximab had a
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response rate of 80%, and bavituximab administration increased numbers of circulating PS- positive apoptotic tumor cells. 20 On the basis of these data, we hypothesized that the addition of bavituximab to docetaxel chemotherapy would be well tolerated and would improve clinical outcomes in previously treated, advanced nonsquamous NSCLC.
Materials and Methods
This was designed to be a prospective, randomized, double-blind, placebo-controlled, multicenter, 3-arm, phase 2 study (see supplemental figure). Patients were intended to be randomized (1:1:1) to docetaxel plus placebo, docetaxel plus bavituximab 1 mg/kg, or docetaxel plus bavituximab 3 mg/kg. However, due to labeling discrepancies of the blinded investigational product, some patients in the placebo group received some doses of bavituximab 1 mg/kg, while some patients in the bavituximab 1 mg/kg group received some doses of placebo (see
Results). Patients in the bavituximab 3 mg/kg group were not affected by these events. The primary endpoint of this trial was overall response rateMANUSCRIPT (ORR; complete response [CR] + partial response [PR]), as assessed by an independent, blinded, central radiology review. Secondary endpoints included progression-free survival (PFS), duration of response (DR), overall survival
(OS), safety, and pharmacokinetic (PK) parameters to assess drug–drug interaction. PFS was a secondary endpoint, and because there were more events (less censoring) based on investigator assessment, which accounted for the clinical progression compared to the PFS estimate based on central review of solely radiographic data, we chose to report PFS by investigator assessment.
This studyACCEPTED (NCT01138163) was conducted according to the Declaration of Helsinki and with approval from the institutional review boards of all participating study sites. All participants provided written informed consent prior to any study-related procedures.
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Patient Population
Eligible candidates for this study had histologically or cytologically confirmed advanced stage, nonsquamous NSCLC with disease progression after treatment with platinum-based doublet chemotherapy. Squamous histology was excluded due to the development of grade 5 hemoptysis in a patient with advanced squamous NSCLC in the setting of progressive tumor cavitation and therapeutic response in an earlier trial of carboplatin/paclitaxel plus bavituximab. 21 Prior docetaxel was not permitted. Prior bevacizumab or tyrosine kinase inhibitor therapy was allowed. Additional eligibility criteria included the presence of measurable disease
(by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1), 21 Eastern Cooperative
Oncology Group (ECOG) performance status 0 to 2, life expectancy of at least 3 months, adequate bone marrow, adequate renal function, adequate hepatic function, and coagulation parameters. Patients were excluded if they had New York Heart Association class III or IV cardiac disease, a known history of bleeding diathesis or coagulopathy, cavitary tumors or tumors abutting large blood vessels, clinically significant MANUSCRIPT bleeding within 12 months (unless the cause was identified and adequately treated), symptomatic cardiac or cerebrovascular disease within 6 months, ongoing use of anticoagulants, grade 2 or higher peripheral neuropathy, or clinically active brain metastases. Per the study protocol, brain magnetic resonance imaging
(MRI) was not required for eligibility and was not performed routinely, but could be performed at the discretion of the treating physician if brain involvement was suspected. Testing for epidermal growth factor receptor ( EGFR ) mutations or anaplastic lymphoma kinase ( ALK ) rearrangements were not required for eligibility, nor were EGFR or ALK status captured for trial participants.
Study TreatmentACCEPTED
Patients received docetaxel 75 mg/m 2 intravenously (IV) on day 1 of a 21-day cycle plus blinded study treatment (either placebo weekly, bavituximab 1 mg/kg weekly, or bavituximab 3 mg/kg weekly) for up to 6 cycles. Before administration of blinded study treatment, which was
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given at least 30 minutes after docetaxel, patients received premedication with a corticosteroid and an antihistamine (the recommended regimen was hydrocortisone 250 mg IV and diphenhydramine 50 mg IV). Patients who completed 6 cycles of combination therapy without disease progression or unacceptable toxicity continued to receive either placebo or bavituximab
1 mg/kg or 3 mg/kg weekly until disease progression or toxicity. There was no dose modification of blinded treatment.
Assessments
Safety assessments were performed on study day 1 of each cycle and included history and physical examination, vital signs, ECOG performance status, AE assessment, complete blood count, chemistries, coagulation parameters, D-dimer, human antichimeric antibody
(HACA), and electrocardiogram. D-dimer and coagulation parameters were followed because of a hypothetical risk of bavituximab inducing a clinical antiphospholipid antibody syndrome. AEs and their severity were classified using the CommonMANUSCRIPT Terminology Criteria for Adverse Events (CTCAE) version 4.02.
Tumor response was assessed radiographically every 2 cycles during combination treatment and every 3 cycles during the monotherapy period. A subset of the overall study population participated in a PK substudy. All patients, including those who discontinued protocol therapy, were followed for response until progression and for OS.
Statistical Analysis
Forty patients were planned for randomization to each study treatment (120 patients total), assuming ACCEPTEDa 7.5% dropout rate, for 37 evaluable patients per arm. With a 1-sided alpha of
0.10, this provided 78% power to detect a difference between 8% ORR (control arm) and 26%
ORR (bavituximab arms). Separate analyses comparing the docetaxel plus placebo group to each of the docetaxel plus bavituximab groups (1 mg/kg and 3 mg/kg) were planned. However,
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due to labeling discrepancies of the blinded investigational product, some patients in the placebo group received some doses of bavituximab 1 mg/kg, while some patients in the bavituximab 1 mg/kg group received some doses of placebo.
As a result of these events, exploratory data analyses were performed by comparing the bavituximab 3 mg/kg group to a combined control group, including both the bavituximab 1 mg/kg and placebo groups. All results were reported for the intent-to-treat population. Because this approach was not prespecified in the protocol or the statistical analysis plan, the analyses presented are considered exploratory.
Cox proportional hazard model parameter estimates were used to analyze PFS and OS.
This model included the following disease and clinical characteristics: treatment, tumor stage
(IIIB vs. IV), tumor histology (adenocarcinoma vs. other), and number of organs involved (1 vs.
≥ 2). MANUSCRIPT Results
A total of 121 patients were enrolled and randomized. The first patient enrolled in
October of 2010 and the last patient enrolled in October of 2011. Of the 121 patients enrolled,
119 received study treatment. Following study unblinding, discrepancies between some patient
PK sample-test results and patient treatment code assignments were discovered. An extensive review of these discrepancies was completed, confirming the initial observations and revealing additional label discrepancies between vials labeled as placebo and vials labeled as 1 mg/kg bavituximab. ThereACCEPTED was no evidence that patients randomized to 3 mg/kg bavituximab received anything other than accurately labeled investigational product. This was concluded after retrieving used and unused vials of the investigational product, as well as all available patient samples for antidrug antibody (ADA) testing. In the bavituximab 3 mg/kg arm, all tested vials and samples were consistent with their labeling.
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Given the intact integrity of the data obtained from the 3 mg/kg bavituximab arm, additional exploratory efficacy analyses were performed. In the analyses, which are presented in this manuscript, the 3 mg/kg bavituximab group was compared with the combined control group of 1 mg/kg bavituximab and placebo.
Patient Characteristics and Treatment Exposure
Of the 121 enrolled patients, 80 were in the combined control group, and 41 were in the bavituximab 3 mg/kg group. Demographic and disease characteristics were generally well balanced between the groups (Table 1).
Overall, 41 patients completed 6 cycles of combination treatment. Of these, 29 received maintenance therapy with the blinded investigational product. The median number of cycles administered to patients was 4 for both groups. The mean total number of blinded treatment doses administered was 13.7 in the combined control placebo/bavituximab 1 mg/kg group and 16.8 in the bavituximab 3 mg/kg group. The median MANUSCRIPT number of maintenance treatment doses was 4 (range 1 to 6) in the bavituximab 3 mg/kg group and 4 (range 1 to 6) in the combined control group. In the safety population, 7 of 79 patients (8.9%) in the combined control group had a dose reduction, whereas 3 of 40 patients (7.5%) in the bavituximab 3 mg/kg group had a dose reduction. A patient was considered to have had a dose reduction if the patient received a planned docetaxel dose of ≤ 65 mg/m 2.
Post-study therapy was administered to 41.5% (17/41) of patients in the bavituximab 3 mg/kg group and to 31.3% (25/80) of patients in the combined control group.
Efficacy ACCEPTED
Due to the labeling error and pooling of the placebo and bavituximab 1 mg/kg arms, efficacy analyses are considered exploratory. The primary endpoint of ORR was 11.3% (95% CI
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4.3% to 18.2%) in the combined control placebo/bavituximab 1 mg/kg group and 17.1% (95% CI
5.6% to 28.6%) in the bavituximab 3 mg/kg group ( P = .37). Stable disease was observed in
50.0% and 48.8% of patients in the groups, respectively. Radiographic response is summarized in Table 2.
Median PFS, based on the investigator’s assessment, was 4.5 months in the bavituximab 3 mg/kg arm, compared with 3.3 months in the combined control group (hazard ratio [HR] 0.74; 95% confidence interval [CI] 0.45 to 1.21; P = .24) (Figure 1). No statistically significant differences were observed when treatment groups were analyzed based on disease stage, histology, or number of organs involved ( P = .73; HR 0.913).
There was a trend toward improved OS in the bavituximab 3 mg/kg group (Figure 2). In the bavituximab 3 mg/kg arm, median OS was 11.7 months compared with 7.3 months in the combined control group (HR 0.66; 95% CI 0.40 to 1.10; P = .11). No statistically significant differences were observed when treatment groups MANUSCRIPTwere analyzed based on clinical disease and prior treatment characteristics in the Cox proportional hazard model.
Toxicity
In the combined control placebo/bavituximab 1 mg/kg group, 82% of patients experienced at least one AE on study, compared with 95% in the bavituximab 3 mg/kg group.
The most commonly reported AEs were fatigue, nausea, and neutropenia. Grade 3 or higher toxicity occurred in 35 patients (45%) in the combined control group and in 22 patients (55%) in the bavituximab 3 mg/kg group (Table 3). Discontinuation of study drug due to an AE occurred in 9 patients (11%)ACCEPTED in the combined control group and 9 patients (23%) in the bavituximab 3 mg/kg group.
Treatment-related AEs were reported in 34 patients (43%) in the placebo/bavituximab
1 mg/kg group and in 25 patients (63%) in the bavituximab 3 mg/kg group. The most frequently
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reported treatment-related AEs in the combined control group were fatigue (11%), asthenia
(10%), and neutropenia (10%). The most frequently reported treatment-related AEs in the bavituximab 3 mg/kg group were nausea (20%), fatigue (15%), and anorexia (15%). No patient experienced a fatal event considered related to the study treatment during the study. Grade 3 treatment-related AEs occurred in 22 patients (55.0%) in the bavituximab 3 mg/kg group and in
35 patients (44.3%) in the combined control group. In the bavituximab 3 mg/kg arm, grade ≥ 3 treatment-related AEs occurring in at least 5% of patients included neutropenia (22.5%), anemia
(12.5%), leukopenia (7.5%), fatigue (7.5%), asthenia (7.5%), palmar-plantar erythrodysesthesia syndrome (7.5%), febrile neutropenia (5.0%), and pneumonia (5.0%). In the combined control group, grade ≥ 3 treatment-related AEs occurring in at least 5% of patients included neutropenia (20.3%), leukopenia (11.4%), fatigue (10.1%), febrile neutropenia (6.3%), and pneumonia (5.1%). Overall, 7 serious thromboembolic AEs occurredMANUSCRIPT in 6 patients during the study: Five patients in the placebo/bavituximab 1 mg/kg group had events of pulmonary embolism (PE), cerebrovascular accident (CVA), and deep vein thrombosis (DVT); 1 patient in the 3 mg/kg group had a DVT. All but one event was CTCAE grade 3 or lower, and all but one event resolved by the end of the study.
PK Analysis
Seventeen patients from the overall study population (11 patients in the placebo/bavituximab 1 mg/kg group and 6 patients in the bavituximab 3 mg/kg group) participated in a ACCEPTEDPK substudy to investigate the drug–drug interaction between bavituximab and docetaxel. No significant differences were observed in PK parameters when bavituximab was administered with (cycle 2, day 1) or without (cycle 1, day 8) docetaxel.
Antidrug Antibodies
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The presence of nonneutralizing (binding) HACAs, or ADAs, was assessed at baseline and after administration of blinded study drug using an electrochemiluminescence assay. A positive ADA response was observed in 51% of the patients in the placebo/bavituximab 1 mg/kg group, confirming that a significant proportion of patients in the combined control group were exposed to 1 mg/kg bavituximab. Among patients in the bavituximab 3 mg/kg group, 65% had a confirmed ADA-positive response. The presence of binding ADAs did not correlate with the safety or efficacy outcome measures outlined in the study.
Discussion
Bavituximab is a unique, first-in-class mAb targeting exposed PS. Multiple preclinical models have demonstrated the tumor-specific targeting, 11,16,17 immune-modulating properties,8,22 vascular-targeting effects, 9,23 and antitumor efficacy8,9,12,14,15,22,23 of bavituximab. Further, the coadministration of cytotoxic chemotherapy enhances PS exposure, resulting in complementary effects. 14,15 On the basis of the preclinical rationale andMANUSCRIPT evidence, this phase 2 clinical trial evaluated the combination of bavituximab plus docetaxel chemotherapy in previously treated, advanced nonsquamous NSCLC. Although the patients were originally intended to be randomized (1:1:1) to docetaxel plus placebo, docetaxel plus bavituximab 1 mg/kg, and docetaxel plus bavituximab 3 mg/kg, labeling discrepancies of the blinded investigational product occurred. As a result, some patients in the placebo group received some doses of bavituximab 1 mg/kg, while some patients in the bavituximab 1 mg/kg group received some doses of placebo. However, patients in the bavituximab 3 mg/kg group were not affected by this occurrence. ACCEPTED Because of these events, it is not possible to draw firm conclusions from this trial.
Nevertheless, some efficacy and safety trends merit discussion, particularly those observed in the docetaxel plus bavituximab 3 mg/kg arm. Notably, preclinical modeling suggests that
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bavituximab 3 mg/kg weekly represents the best biologic dose based on target saturation at higher levels. 18 In this trial, all efficacy endpoints (ORR, PFS, and OS) were numerically improved in the docetaxel plus bavituximab 3 mg/kg arm. Further, clinical outcomes in this arm compare favorably with historic controls. OS exceeded 11 months vs. 7 to 9 months with docetaxel monotherapy reported in earlier clinical trials.24-26 The ORR of 17%—although falling short of the 26% required to achieve the primary endpoint of the trial—represents an approximate doubling of rates typically seen with docetaxel. The clinical efficacy of docetaxel plus bavituximab 3 mg/kg also appears comparable to that of other docetaxel combinations, including the vascular endothelial growth factor receptor antibody ramucirumab and the multitargeted angiokinase inhibitor nintedanib. 26,27
The coadministration of docetaxel and bavituximab appeared feasible. PK analysis demonstrated no clinically relevant drug–drug interaction between the 2 drugs. Although more than 50% of patients in the bavituximab 3 mg/kg groMANUSCRIPTup developed ADAs, infusion reactions were uncommon and mild. Toxicities that have been reported with vascular-targeting therapies include bleeding, thrombosis, hypertension, wound-healing complications, proteinuria, and visceral perforations. 28,29 In this trial, there was a lower incidence of vascular events in the docetaxel plus bavituximab 3 mg/kg arm (n = 1; DVT) than in the combined docetaxel plus placebo/bavituximab 1 mg/kg arm (n = 5; DVT, PE, CVA). There were no instances of clinically significant, treatment-emergent bleeding, proteinuria, hypertension, or visceral perforation.
Further, vascular events in both arms of this trial did not exceed those expected with docetaxel monotherapy or in the general context of progressive advanced malignancy.30-33 Separately, immune checkpointACCEPTED inhibitors targeting CTLA4, PD1, and PDL1 have been associated with numerous immune-related AEs, including pneumonitis, colitis, hepatitis, hypophysitis, dermatitis, and nephritis. 1,34-37 By contrast, overt immune-related toxicities have not been observed with bavituximab.
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Given the rapidly changing landscape of advanced NSCLC treatment, the potential role of bavituximab warrants comment. Immune checkpoint inhibitors, such as nivolumab and pembrolizumab, have demonstrated unprecedented effects in broad populations, offering patients more options than ever before. Yet despite the promise of these agents, the clear majority of patients with NSCLC treated with checkpoint inhibitor immunotherapy either do not respond or eventually progress. At that point, these patients remain in need of new and more effective therapies. In contrast to approved checkpoint inhibitors, there is a strong rationale and preclinical evidence supporting particular benefit when bavituximab is combined with cytotoxic chemotherapy. 14,15 Finally, due to a distinct mechanism of action and lack of apparent immune- mediated toxicity, combinations of bavituximab plus checkpoint inhibitors also represent a promising strategy.
Conclusion MANUSCRIPT Bavituximab is a first-in-class mAb targeting PS with immune modulating and vascular- targeting properties. Although an investigational product-labeling error in some study arms prevents drawing firm conclusions from this phase 2 trial in previously treated, advanced nonsquamous NSCLC, encouraging safety and efficacy signals were observed with the docetaxel plus bavituximab 3 mg/kg weekly arm. This combination is currently being studied in the randomized phase 3 SUNRISE trial (NCT01999673). Although the emergence of checkpoint inhibitor immunotherapy and docetaxel combinations have complicated the advanced NSCLC treatment landscape, the potential for a novel and apparently well-tolerated immunomodulatory agent to improveACCEPTED upon the efficacy of existing therapeutic options represents an important consideration for these patients.
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Clinical Practice Points
• Bavituximab is a unique, first-in-class, PS-targeting mAb with immune-modulating and
vascular-targeting properties.
• In preclinical models, administration of cytotoxic chemotherapy results in increased
exposure of PS and complementary effects with PS-targeting therapies.
• This 3-arm, phase 2 clinical trial evaluated the addition of bavituximab 1 mg/kg IV
weekly, bavituximab 3 mg/kg IV weekly, or placebo IV weekly to standard docetaxel 75
mg/m 2 every 21 days. After study unblinding, vial coding discrepancies were discovered
in the placebo and bavituximab 1 mg/kg groups. Thus, in exploratory analyses, data
from these 2 groups were pooled to form the control group and compared to the
bavituximab 3 mg/kg group, which was not affected by the coding error.
• The addition of bavituximab did not appear to substantially alter the safety profile
expected for docetaxel. • The combination of docetaxel plus bavituximab MANUSCRIPT demonstrated promising preliminary efficacy in terms of ORR, PFS, and OS. A phase 3 trial of docetaxel with or without
bavituximab 3 mg/kg (SUNRISE) is under way.
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Acknowledgments
This work was supported by Peregrine Pharmaceuticals, Inc., and by an American Society of
Clinical Oncology Career Development Award (to D.E.G.). Peregrine Pharmaceuticals, Inc., participated in the study design; collection, analysis, and interpretation of the data; writing of the report; and the decision to submit for publication.
Editorial assistance was provided by Impact Communication Partners, Inc.
Disclosures
D.E.G. receives research funding from Peregrine Pharmaceuticals, Inc. J.S.S. and K.B.M. are paid employees of Peregrine Pharmaceuticals, Inc. All remaining authors have declared no conflicts of interest. MANUSCRIPT
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12. Beck AW,ACCEPTED Luster TA, Miller AF, et al. Combination of a monoclonal anti- phosphatidylserine antibody with gemcitabine strongly inhibits the growth and metastasis of orthotopic pancreatic tumors in mice. Int J Cancer 2006; 118:2639-43.
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14. Huang X, Bennett M, Thorpe PE. A monoclonal antibody that binds anionic phospholipids on tumor blood vessels enhances the antitumor effect of docetaxel on human breast tumors in mice. Cancer Res 2005; 65:4408-16.
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Tables
Table 1. Patient Demographics and Disease Characteristics
Combined Control (Placebo and Bavituximab 1 mg/kg) Bavituximab 3 mg/kg N = 80 N = 41 Mean age (years) ± SD 60 ± 11 61 ± 9 Sex, n (%)
Male 49 (61) 27 (66) Female 31 (39) 14 (34) Race, n (%)
White 54 (68) 20 (49) South Asian 24 (30) 18 (44) Black 2 (2) 3 (7) Stage, n (%)
IIIB 7 (9) 4 (10) IV 73 (91) 37 (90) Histology, n (%)
Adenocarcinoma 72 (90) 32 (78) Other MANUSCRIPT8 (10) 9 (22) ECOG performance status, n (%) N = 79 N = 40 0-1 69 (87) 31 (77) 2 10 (13) 9 (23) Abbreviations: ECOG = Eastern Cooperative Oncology Group; SD = standard deviation.
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Table 2. Best Radiographic Response by Treatment Group
N (%) Combined Control (Placebo and Bavituximab 1 mg/kg) Bavituximab 3 mg/kg (N = 80) (N = 41) CR 1 (1.3) 0 (0.0)
PR 8 (10.0) 7 (17.1)
SD 40 (50.0) 20 (48.8)
PD 14 (17.5) 6 (14.6)
Missing or not evaluable 10 (12.5) 4 (9.8)
Non-CR/non-PD 7 (8.8) 4 (9.8)
Intent-to-treat population. Column percentage totals may not equal 100 due to rounding. Abbreviations: CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease.
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Table 3. AEs Occurring in at Least 10% of Patients in a Treatment Group (Safety Population)
Placebo and Bavituximab Bavituximab 1 mg/kg 3 mg/kg (N = 79) (N = 40) All Grades Grades 3/4 All Grades Grades 3/4 Preferred Term N (%) N (%) N (%) N (%)
Fatigue 23 (29.1%) 8 (10.1%) 14 (35.0%) 3 (7.5%) Nausea 22 (27.8%) 0 (0.0%) 15 (37.5%) 0 (0.0%) Neutropenia 19 (24.1%) 16 (20.3%) 13 (32.5%) 9 (22.5%) Cough 17 (21.5%) 0 (0.0%) 10 (25.0%) 0 (0.0%) Edema, peripheral 16 (20.3%) 0 (0.0%) 6 (15.0%) 0 (0.0%) Diarrhea 16 (20.3%) 0 (0.0%) 7 (17.5%) 1 (2.5%) Anemia 14 (17.7%) 1 (1.3%) 10 (25.0%) 5 (12.5%) Alopecia 14 (17.7%) 0 (0.0%) 8 (20.0%) 0 (0.0%) Pyrexia 13 (16.5%) 0 (0.0%) 8 (20.0%) 0 (0.0%) Asthenia 13 (16.5%) 1 (1.3%) 12 (30.0%) 3 (7.5%) Leukopenia 12 (15.2%) 9 (11.4%) 4 (10.0%) 3 (7.5%) Anorexia 12 (15.2%) 1 (1.3%) 11 (27.5%) 0 (0.0%) Constipation 12 (15.2%) 0 (0.0%) 7 (17.5%) 1 (2.5%) Dyspnea 11 (13.9%) MANUSCRIPT 2 (2.5%) 5 (12.5%) 1 (2.5%) Vomiting 9 (11.4%) 0 (0.0%) 6 (15.0%) 0 (0.0%) Arthralgia 8 (10.1%) 0 (0.0%) 8 (20.0%) 1 (2.5%) Pain in extremity 8 (10.1%) 0 (0.0%) 5 (12.5%) 0 (0.0%) Chest pain 8 (10.1%) 1 (1.3%) 8 (20.0%) 0 (0.0%) Headache 8 (10.1%) 1 (1.3%) 3 (7.5%) 1 (2.5%) Back pain 8 (10.1%) 0 (0.0%) 8 (20.0%) 0 (0.0%) Peripheral sensory 7 (8.9%) 1 (1.3%) 4 (10.0%) 0 (0.0%) neuropathy Productive cough 7 (8.9%) 0 (0.0%) 7 (17.5%) 0 (0.0%) Dizziness 6 (7.6%) 1 (1.3%) 4 (10.0%) 0 (0.0%) Dyspnea, exertional 5 (6.3%) 0 (0.0%) 4 (10.0%) 0 (0.0%) Weight decreased 5 (6.3%) 0 (0.0%) 4 (10.0%) 0 (0.0%) Hypotension 4 (5.1%) 1 (1.3%) 6 (15.0%) 0 (0.0%) Dehydration 4 (5.1%) 1 (1.3%) 4 (10.0%) 1 (2.5%) Stomatitis ACCEPTED 4 (5.1%) 0 (0.0%) 4 (10.0%) 1 (2.5%) Abdominal pain 3 (3.8%) 0 (0.0%) 5 (12.5%) 0 (0.0%) Mucosal inflammation 2 (2.5%) 0 (0.0%) 5 (12.5%) 0 (0.0%)
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Figures
Figure 1. Progression-Free Survival
MANUSCRIPT Bavi = bavituximab.
Figure 2. Overall Survival
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Bavi = bavituximab.
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Supplemental Figure
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Figure Legends
Figure 1. Kaplan-Meier Curve for PFS (Intent-to-Treat Population)
Figure 2. Kaplan-Meier Curve for OS (Intent-to-Treat Population)
Supplemental Figure 1. Study Flow Diagram. The Summary of Efficacy Was Performed
Comparing the Bavituximab 3 mg/kg Group With the Combined Control Group of
Placebo/Bavituximab 1 mg/kg Based on the Intent-to-Treat Population
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