Clinical Lung Cancer, Vol

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Docetaxel Combined With Bavituximab in Previously Treated, Advanced Nonsquamous NoneSmall-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,6 Chandra P. Belani7

Abstract This phase II trial was intended to investigate 2 doses of bavituximab (a phosphatidylserine-targeting antibody) or placebo combined with docetaxel in previously treated, advanced nonsquamous nonesmall-cell lung cancer. Because of a labeling discrepancy, the placebo and bavituximab 1 mg/kg arms were combined and compared with the bavituximab 3 mg/kg arm. This exploratory analysis showed similar toxicity between arms, and albeit without meeting the preset statistical end points because of the pooled control arm data, had trends favoring bavituximab 3 mg/kg. Background: Bavituximab is a phosphatidylserine-targeting antibody with a selective tumor, vascular-directed immune response. In this phase II trial the efficacy and safety of bavituximab combined with docetaxel for previously treated, advanced nonsquamous nonesmall-cell lung cancer were evaluated. Patients and Methods: Patients were randomized 1:1:1 to receive docetaxel 75 mg/m2 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 disease progression or unacceptable toxicity. The primary end point was overall response rate (ORR), with a predefined end point 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 compared with the 3 mg/kg group. Results: Efficacy end points in the bavituximab 3 mg/kg group (n ¼ 41) and in the placebo/bavituximab 1 mg/ kg group (n ¼ 80), respectively, were as follows: ORR, 17.1% (95% confidence interval [CI], 5.6%-28.6%) and ORR, 11.3% (95% CI, 4.3%-18.2%); median progression-free survival 4.5 and 3.3 months (hazard ratio [HR], 0.74 [95% CI, 0.45-1.21]; P ¼ .24); median overall survival 11.7 and 7.3 months (HR, 0.66 [95% CI, 0.40-1.10]; P ¼ .11). Toxicities were manageable and similar between arms. Conclusion: 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 end point, exploratory analyses suggest trends favoring the combination of bavituximab 3 mg/kg with docetaxel. This regimen is being evaluated in the ongoing, global, phase III SUNRISE trial.

Introduction Checkpoint inhibitors, particularly those targeting the programmed Recently, immunotherapy has emerged as a promising treatment death-1 (PD1) and PD ligand-1 (PDL1) pathways, have shown strategy for advanced nonesmall-cell lung cancer (NSCLC). promising efﬁcacy. In 2015, the US Food and Drug Administration

ClinicalTrials.gov identiﬁer: NCT01138163. 6Peregrine Pharmaceuticals, Inc, Tustin, CA 7Pennsylvania State Hershey Cancer Institute, Hershey, PA 1Harold C. Simmons Comprehensive Cancer Center, University of Texas South- western Medical Center, Dallas, TX Submitted: Nov 4, 2015; Revised: Feb 5, 2016; Accepted: Feb 9, 2016; Epub: 2Tennessee Oncology, PLLC, Nashville, TN Feb 19, 2016 3Medulla Chemotherapy and Immunotherapy Clinic, Tbilisi, Republic of Georgia Address for correspondence: David E. Gerber, MD, Division of Hematology-Oncology, 4Ironwood Cancer and Research Center, Chandler, AZ Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern 5Kyiv City Oncology Hospital, Kyiv, Ukraine Medical Center, 5323 Harry Hines Blvd, Mail Code 8852, Dallas, TX 75390-8852 E-mail contact: [email protected]

(FDA) approved the anti-PD1 agent nivolumab for the treatment of limited by lack of comparator arms, results of these trials also sug- previously treated, advanced NSCLC after pivotal phase III trials gest that the additional use of bavituximab might enhance the ef- reported superior efficacy compared with docetaxel chemotherapy in ficacy of chemotherapy. In the first-line setting for advanced squamous and nonsquamous populations.1,2 The FDA also NSCLC, the use of the combination carboplatin-paclitaxel with approved the anti-PD1 antibody pembrolizumab for PDL1-positive bavituximab resulted in a response rate of 41%.19 In patients with advanced NSCLC.3 HER2-negative breast cancer, the use of paclitaxel with bavituximab In addition to and distinct from the widely studied immune resulted in a response rate of 80%, and bavituximab administration checkpoints PD1, PDL1, and cytotoxic T-lymphocyte antigen 4 increased numbers of circulating PS-positive apoptotic tumor (CTLA4), the anionic phospholipid phosphatidylserine (PS) has cells.20 On the basis of these data, we hypothesized that the com- been recognized for decades for exerting immunosuppressive phys- bination of bavituximab with docetaxel chemotherapy would be iologic effects.4-6 Specifically, exposed PS on apoptotic cells sup- well tolerated and would improve clinical outcomes in previously presses immune and inflammatory responses by binding to treated, advanced nonsquamous NSCLC. macrophage PS receptors, thereby signaling macrophage production of anti-inflammatory cytokines such as TGFb and interleukin (IL)- Patients and Methods 10 and preventing dendritic cell maturation and antigen presenta- This was designed to be a prospective, randomized, double-blind, tion.7 In preclinical models, PS-targeting antibodies counter both of placebo-controlled, multicenter, 3-arm, phase II study (see these effects, resulting in production of proinflammatory cytokines Supplemental Figure 1 in the online version). Patients were intended such as tumor necrosis factor-a and IL-1b, as well as induction of to be randomized (1:1:1) to docetaxel with placebo, docetaxel with cytotoxic T-lymphocyte immunity.8 PS targeting also results in bavituximab 1 mg/kg, or docetaxel with bavituximab 3 mg/kg. antivascular effects. Specifically, upon binding of anti-PS antibodies However, because of labeling discrepancies of the blinded investiga- to tumor vessels, bavituximab activates host effector (immune) tional product, some patients in the placebo group received some functions, such as antibody-dependent cellular cytotoxicity doses of bavituximab 1 mg/kg, and some patients in the bavituximab 1 (ADCC), resulting in rapid vessel destruction and subsequent tu- mg/kg group received some doses of placebo (see Results). Patients in mor necrosis.9 the bavituximab 3 mg/kg group were not affected by these events. The Because of differential exposure in malignant tissues, PS is a primary end point of this trial was overall response rate (ORR; relatively tumor-specific therapeutic target. In most tissues, PS is complete response þ partial response), assessed using an independent, restricted to the internal surface of the cell membrane.10 In contrast, blinded, central radiology review. Secondary end points included within solid tumors, hypoxia and other physiologic stresses disrupt progression-free survival (PFS), duration of response, overall survival this asymmetry. These processes result in exposure of PS on the (OS), safety, and PK parameters to assess drugedrug interaction. PFS outer membrane leaflet, where it is available for binding by PS- was a secondary end point, and because there were more events (less targeting therapies.11,12 There might be differences in expression censoring) on the basis of investigator assessment, which accounted of PS in different tumor types. A study of PS exposure in cell lines for the clinical progression compared with the PFS estimate on the derived from a variety of malignant melanomas, prostate cancer, basis of central review of solely radiographic data, we chose to report renal cancer, glioblastoma, and rhabdomyosarcoma reported PS PFS according to investigator assessment. exposure in the rhabdomyosarcoma cell line to be significantly This study (NCT01138163) was conducted according to the higher than the amount in the malignant melanoma cell line, Declaration of Helsinki and with approval from the institutional whereas levels in the glioblastoma cell line were lower.13 review boards of all participating study sites. All participants pro- Bavituximab is an unconjugated, chimeric immunoglobulin G1 vided written informed consent before any study-related procedures. monoclonal antibody (mAb) that localizes to anionic phospholipids expressed on tumor endothelium, principally PS. In preclinical Patient Population models of multiple tumor types, bavituximab inhibits tumor Eligible candidates for this study had histologically or cytologi- growth, prolongs survival, and enhances the effects of chemotherapy cally confirmed advanced stage, nonsquamous NSCLC with disease and radiation.12,14,15 Preclinical models have also shown tumor- progression after treatment with platinum-based doublet chemo- specific targeting by bavituximab.11,16,17 Additionally, the admin- therapy. Squamous histology was excluded because of the devel- istration of cytotoxic therapies, including chemotherapy and opment of Grade 5 hemoptysis in a patient with advanced ionizing radiation, further induces PS exposure, thereby enhancing squamous NSCLC in the setting of progressive tumor cavitation bavituximab binding and resulting in complementary effects when and therapeutic response in an earlier trial of carboplatin/paclitaxel combined with bavituximab.14,15 with bavituximab.21 Previous docetaxel treatment was not In a phase I trial of bavituximab in relapsed and refractory ma- permitted. Previous bevacizumab or tyrosine kinase inhibitor ther- lignancies, no maximum tolerated dose was reached.18 The 1 mg/kg apy was allowed. Additional eligibility criteria included the presence and 3 mg/kg weekly doses were well tolerated and, on the basis of of measurable disease (according to Response Evaluation Criteria in preclinical pharmacokinetic (PK) modeling, were considered the Solid Tumors 1.1),21 Eastern Cooperative Oncology Group likely preferred biologic doses. Considerations included antitumor (ECOG) performance status 0 to 2, life expectancy of at least 3 efficacy, possible depletion of cofactor protein b2-glycoprotein 1, months, adequate bone marrow, adequate renal function, adequate tolerability, and ADCC. In single-arm combination studies with hepatic function, and coagulation parameters. Patients were cytotoxic chemotherapy, the additional use of bavituximab generally excluded if they had New York Heart Association class III or IV did not increase the risk of adverse events (AEs).19,20 Although cardiac disease, a known history of bleeding diathesis or

170 - Clinical Lung Cancer May 2016 David E. Gerber et al coagulopathy, cavitary tumors, or tumors abutting large blood As a result of these events, exploratory data analyses were per- vessels, clinically significant bleeding within 12 months (unless the formed by comparing the bavituximab 3 mg/kg group with a cause was identified and adequately treated), symptomatic cardiac or combined control group, including the bavituximab 1 mg/kg and cerebrovascular disease within 6 months, ongoing use of anticoag- placebo groups. All results were reported for the intent-to-treat ulants, Grade 2 peripheral neuropathy, or clinically active brain population. Because this approach was not prespecified in the metastases. Per the study protocol, brain magnetic resonance im- protocol or the statistical analysis plan, the analyses presented are aging was not required for eligibility and was not performed considered exploratory. routinely, but could be performed at the discretion of the treating Cox proportional hazard model parameter estimates were used to physician if brain involvement was suspected. Testing for epidermal analyze PFS and OS. This model included the following disease and growth factor receptor (EGFR) mutations or anaplastic lymphoma clinical characteristics: treatment, tumor stage (IIIB vs. IV), tumor kinase (ALK) rearrangements were not required for eligibility, nor histology (adenocarcinoma vs. other), and number of organs were EGFR or ALK status captured for trial participants. involved (1 vs. 2).

Study Treatment Results Patients received docetaxel 75 mg/m2 intravenously (i.v.) on A total of 121 patients were enrolled and randomized. The first day 1 of a 21-day cycle with blinded study treatment (either patient enrolled in October of 2010 and the last patient enrolled in placebo weekly, bavituximab 1 mg/kg weekly, or bavituximab 3 October of 2011. Of the 121 patients enrolled, 119 received study mg/kg weekly) for up to 6 cycles. Before administration of blinded treatment. After study unblinding, discrepancies between some study treatment, which was given at least 30 minutes after patient PK sample test results and patient treatment code assign- docetaxel, patients received premedication with a corticosteroid ments were discovered. An extensive review of these discrepancies and an antihistamine (the recommended regimen was hydrocor- was completed, confirming the initial observations and revealing tisone 250 mg i.v. and diphenhydramine 50 mg i.v.). Patients additional label discrepancies between vials labeled as placebo and who completed 6 cycles of combination therapy without disease vials labeled as 1 mg/kg bavituximab. There was no evidence that progression or unacceptable toxicity continued to receive either patients randomized to 3 mg/kg bavituximab received anything placebo or bavituximab 1 mg/kg or 3 mg/kg weekly until disease other than accurately labeled investigational product. This was progression or toxicity. There was no dose modification of blinded concluded after retrieving used and unused vials of the investiga- treatment. tional product, as well as all available patient samples for antidrug antibody (ADA) testing. In the bavituximab 3 mg/kg arm, all tested Assessments vials and samples were consistent with their labeling. Safety assessments were performed on study day 1 of each cycle Because of the intact integrity of the data obtained from the 3 and included history and physical examination, vital signs, ECOG mg/kg bavituximab arm, additional exploratory efficacy analyses performance status, AE assessment, complete blood count, chem- were performed. In the analyses, which are presented in this report, istries, coagulation parameters, D-dimer, human antichimeric the 3 mg/kg bavituximab group was compared with the combined antibody (HACA), and electrocardiogram. D-dimer and coagulation control group of 1 mg/kg bavituximab and placebo. parameters were followed because of a hypothetical risk of bavituximab inducing a clinical antiphospholipid antibody syndrome. Patient Characteristics and Treatment Exposure AEs and their severity were classified using the Common Termi- Of the 121 enrolled patients, 80 were in the combined control nology Criteria for Adverse Events version 4.02 (CTCAE). group, and 41 were in the bavituximab 3 mg/kg group. De- Tumor response was assessed radiographically every 2 cycles mographic and disease characteristics were generally well balanced during combination treatment and every 3 cycles during the between the groups (Table 1). monotherapy period. A subset of the overall study population Overall, 41 patients completed 6 cycles of combination treat- participated in a PK substudy. All patients, including those who ment. Of these, 29 received maintenance therapy with the blinded discontinued protocol therapy, were followed for response until investigational product. The median number of cycles administered disease progression and for OS. to patients was 4 for both groups. The mean total number of blinded treatment doses administered was 13.7 in the combined Statistical Analysis control placebo/bavituximab 1 mg/kg group and 16.8 in the bavi- Forty patients were planned for randomization to each study tuximab 3 mg/kg group. The median number of maintenance treatment (120 patients total), assuming a 7.5% dropout rate, for 37 treatment doses was 4 (range, 1-6) in the bavituximab 3 mg/kg evaluable patients per arm. With a 1-sided a of 0.10, this provided group and 4 (range, 1-6) in the combined control group. In the 78% power to detect a difference between 8% ORR (control arm) safety population, 7 of 79 patients (8.9%) in the combined control and 26% ORR (bavituximab arms). Separate analyses comparing the group had a dose reduction, whereas 3 of 40 patients (7.5%) in the docetaxel with placebo group with each of the docetaxel with bavi- bavituximab 3 mg/kg group had a dose reduction. A patient was tuximab groups (1 mg/kg and 3 mg/kg) were planned. However, considered to have had a dose reduction if the patient received a because of labeling discrepancies of the blinded investigational planned docetaxel dose of 65 mg/m2. product, some patients in the placebo group received some doses of Poststudy therapy was administered to 41.5% (17 of 41) of pa- bavituximab 1 mg/kg, and some patients in the bavituximab 1 mg/kg tients in the bavituximab 3 mg/kg group and to 31.3% (25 of 80) of group received some doses of placebo. patients in the combined control group.

Clinical Lung Cancer May 2016 - 171 Docetaxel and Bavituximab in Nonsquamous NSCLC

95% CI, 0.45-1.21; P ¼ .24; Figure 1). No statistically significant Table 1 Patient Demographic and Disease Characteristics differences were observed when treatment groups were analyzed on Combined Control the basis of disease stage, histology, or number of organs involved (Placebo and Bavituximab (P ¼ .73; HR, 0.913). Bavituximab 1 mg/kg) 3 mg/kg There was a trend toward improved OS in the bavituximab 3 mg/ Characteristic (n [ 80) (n [ 41) kg group (Figure 2). In the bavituximab 3 mg/kg arm, median OS Mean Age ± SD, Years 60 11 61 9 was 11.7 months compared with 7.3 months in the combined Sex, n (%) control group (HR, 0.66; 95% CI, 0.40-1.10; P ¼ .11). No sta- Male 49 (61) 27 (66) tistically significant differences were observed when treatment Female 31 (39) 14 (34) groups were analyzed on the basis of clinical disease and previous Race, n (%) treatment characteristics in the Cox proportional hazard model. White 54 (68) 20 (49) South Asian 24 (30) 18 (44) Toxicity Black 2 (2) 3 (7) In the combined control placebo/bavituximab 1 mg/kg group, Stage, n (%) 82% of patients experienced at least 1 AE during the study, IIIB 7 (9) 4 (10) compared with 95% in the bavituximab 3 mg/kg group. The most IV 73 (91) 37 (90) commonly reported AEs were fatigue, nausea, and neutropenia. Histology, n (%) Grade 3 toxicity occurred in 35 patients (45%) in the combined control group and in 22 patients (55%) in the bavituximab 3 mg/kg Adenocarcinoma 72 (90) 32 (78) group (Table 3). Discontinuation of study drug because of an AE Other 8 (10) 9 (22) occurred in 9 patients (11%) in the combined control group and 9 ECOG Performance n [ 79 n [ 40 Status, n (%) patients (23%) in the bavituximab 3 mg/kg group. 0-1 69 (87) 31 (77) Treatment-related AEs were reported in 34 patients (43%) in 2 10 (13) 9 (23) the placebo/bavituximab 1 mg/kg group and in 25 patients (63%) in the bavituximab 3 mg/kg group. The most frequently reported Abbreviation: ECOG ¼ Eastern Cooperative Oncology Group. 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 Efficacy mg/kg group were nausea (20%), fatigue (15%), and anorexia Because of the labeling error and pooling of the placebo and (15%). No patient experienced a fatal event considered related to bavituximab 1 mg/kg arms, efficacy analyses are considered the study treatment during the study. Grade 3 treatment-related exploratory. The primary end point of ORR was 11.3% (95% AEs occurred in 22 patients (55.0%) in the bavituximab 3 mg/ confidence interval [CI], 4.3%-8.2%) in the combined control kg group and in 35 patients (44.3%) in the combined control placebo/bavituximab 1 mg/kg group and 17.1% (95% CI, 5.6%- group. In the bavituximab 3 mg/kg arm, Grade 3 treatment- 28.6%) in the bavituximab 3 mg/kg group (P ¼ .37). Stable disease related AEs occurring in at least 5% of patients included neu- was observed in 50.0% and 48.8% of patients in the groups, tropenia (22.5%), anemia (12.5%), leukopenia (7.5%), fatigue respectively. Radiographic response is summarized in Table 2. (7.5%), asthenia (7.5%), palmar-plantar erythrodysesthesia syn- Median PFS, on the basis of the investigator’s assessment, was 4.5 drome (7.5%), febrile neutropenia (5.0%), and pneumonia months in the bavituximab 3 mg/kg arm, compared with 3.3 (5.0%). In the combined control group, Grade 3 treatment- months in the combined control group (hazard ratio [HR], 0.74; 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%). Table 2 Best Radiographic Response According to Treatment Overall, 7 serious thromboembolic AEs occurred in 6 patients Group during the study: 5 patients in the placebo/bavituximab 1 mg/kg group had events of pulmonary embolism (PE), cerebrovascular Combined Control (Placebo and accident (CVA), and deep vein thrombosis (DVT); 1 patient in the Bavituximab Bavituximab 3 mg/kg group had a DVT. All but 1 event was CTCAE Grade 3, Response 1 mg/kg) (n [ 80) 3 mg/kg (n [ 41) and all but 1 event resolved by the end of the study. CR 1 (1.3) 0 (0.0) PR 8 (10.0) 7 (17.1) Pharmacokinetic Analysis SD 40 (50.0) 20 (48.8) Seventeen patients from the overall study population (11 patients PD 14 (17.5) 6 (14.6) in the placebo/bavituximab 1 mg/kg group and 6 patients in the Missing or Not 10 (12.5) 4 (9.8) bavituximab 3 mg/kg group) participated in a PK substudy to Evaluable investigate the drugedrug interaction between bavituximab and Non-CR/Non-PD 7 (8.8) 4 (9.8) docetaxel. No significant differences were observed in PK parame-

Data are presented as n (%). Intent-to-treat population. Column percentage totals might not ters when bavituximab was administered with (cycle 2, day 1) or equal 100 due to rounding. without (cycle 1, day 8) docetaxel.

172 - Clinical Lung Cancer May 2016 David E. Gerber et al

Figure 1 KaplaneMeier Curve for Progression-Free Survival (Intent-to-Treat Population)

Abbreviation: Bavi ¼ bavituximab.

Antidrug Antibodies occurred. As a result, some patients in the placebo group received The presence of non-neutralizing (binding) HACAs, or ADAs, some doses of bavituximab 1 mg/kg, and some patients in the was assessed at baseline and after administration of blinded study bavituximab 1 mg/kg group received some doses of placebo. drug using an electrochemiluminescence assay. A positive ADA However, patients in the bavituximab 3 mg/kg group were not response was observed in 51% of the patients in the placebo/bavi- affected by this occurrence. tuximab 1 mg/kg group, confirming that a significant proportion of Because of these events, it is not possible to draw firm conclu- patients in the combined control group were exposed to 1 mg/kg sions from this trial. Nevertheless, some efficacy and safety trends bavituximab. Among patients in the bavituximab 3 mg/kg group, merit discussion, particularly those observed in the docetaxel with 65% had a confirmed ADA-positive response. The presence of bavituximab 3 mg/kg arm. Notably, preclinical modeling suggests binding ADAs did not correlate with the safety or efficacy outcome that bavituximab 3 mg/kg weekly represents the best biologic dose measures outlined in the study. on the basis of target saturation at higher levels.18 In this trial, all efficacy end points (ORR, PFS, and OS) were numerically Discussion improved in the docetaxel with bavituximab 3 mg/kg arm. Further, Bavituximab is a unique, first-in-class mAb targeting exposed PS. clinical outcomes in this arm compare favorably with historic con- Multiple preclinical models have shown the tumor-specific target- trols. OS exceeded 11 months versus 7 to 9 months with docetaxel ing,11,16,17 immune-modulating properties,8,22 vascular-targeting monotherapy reported in earlier clinical trials.24-26 The ORR of effects,9,23 and antitumor efficacy8,9,12,14,15,22,23 of bavituximab. 17%—although falling short of the 26% required to achieve the Further, the coadministration of cytotoxic chemotherapy enhances primary end point of the trial—represents an approximate doubling PS exposure, resulting in complementary effects.14,15 On the basis of rates typically seen with docetaxel. The clinical efficacy of of the preclinical rationale and evidence, in this phase II clinical trial docetaxel with bavituximab 3 mg/kg also appears comparable with the combination of bavituximab with docetaxel chemotherapy in that of other docetaxel combinations, including the vascular endo- previously treated, advanced nonsquamous NSCLC patients was thelial growth factor receptor antibody ramucirumab and the mul- evaluated. Although the patients were originally intended to be titargeted angiokinase inhibitor nintedanib.26,27 randomized (1:1:1) to docetaxel with placebo, docetaxel with The coadministration of docetaxel and bavituximab appeared bavituximab 1 mg/kg, and docetaxel with bavituximab 3 mg/kg, feasible. PK analysis showed no clinically relevant drugedrug labeling discrepancies of the blinded investigational product interaction between the 2 drugs. Although > 50% of patients in

Clinical Lung Cancer May 2016 - 173 Docetaxel and Bavituximab in Nonsquamous NSCLC

Figure 2 KaplaneMeier Curve for Overall Survival (Intent-to-Treat Population)

Abbreviation: Bavi ¼ bavituximab.

the bavituximab 3 mg/kg group developed ADAs, infusion re- either do not respond or eventually develop disease progression. At actions were uncommon and mild. Toxicities that have been re- that point, these patients remain in need of new and more effective ported with vascular-targeting therapies include bleeding, therapies. In contrast to approved checkpoint inhibitors, there is a thrombosis, hypertension, wound-healing complications, pro- strong rationale and preclinical evidence supporting particular teinuria, and visceral perforations.28,29 In this trial, there was a benefit when bavituximab is combined with cytotoxic chemo- lower incidence of vascular events in the docetaxel with bavitux- therapy.14,15 Finally, because of a distinct mechanism of action and imab 3 mg/kg arm (n ¼ 1; DVT) than in the combined docetaxel lack of apparent immune-mediated toxicity, the combination of with placebo/bavituximab 1 mg/kg arm (n ¼ 5; DVT, PE, CVA). bavituximab with checkpoint inhibitors also represents a promising There were no instances of clinically significant, treatment- strategy. emergent bleeding, proteinuria, hypertension, or visceral perfora- tion.Further,vasculareventsinbotharmsofthistrialdidnot Conclusion exceed those expected with docetaxel monotherapy or in the Bavituximab is a first-in-class mAb targeting PS with immune general context of progressive advanced malignancy.30-33 Sepa- modulating and vascular-targeting properties. Although an investi- rately, immune checkpoint inhibitors targeting CTLA4, PD1, and gational product-labeling error in some study arms prevents drawing PDL1 have been associated with numerous immune-related AEs, firm conclusions from this phase II trial in previously treated, including pneumonitis, colitis, hepatitis, hypophysitis, dermatitis, advanced nonsquamous NSCLC, encouraging safety and efficacy and nephritis.1,34-37 In contrast, overt immune-related toxicities signals were observed with the docetaxel with bavituximab 3 mg/kg have not been observed with bavituximab. weekly arm. This combination is currently being studied in the Because of the rapidly changing landscape of advanced NSCLC randomized phase 3 SUNRISE trial (NCT01999673). Although treatment, the potential role of bavituximab warrants comment. the emergence of checkpoint inhibitor immunotherapy and doce- Immune checkpoint inhibitors, such as nivolumab and pem- taxel combinations have complicated the advanced NSCLC treat- brolizumab, have shown unprecedented effects in broad pop- ment landscape, the potential for a novel and apparently ulations, offering patients more options than ever before. However, well-tolerated immunomodulatory agent to improve upon the effi- despite the promise of these agents, the clear majority of patients cacy of existing therapeutic options represents an important with NSCLC treated with checkpoint inhibitor immunotherapy consideration for these patients.

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The combination of docetaxel with bavituximab showed prom- Adverse Events Occurring in at Least 10% of Patients Table 3 fi in a Treatment Group (Safety Population) ising preliminary ef cacy in terms of ORR, PFS, and OS. A phase III trial of docetaxel with or without bavituximab 3 mg/kg Placebo and (SUNRISE) is under way. Bavituximab Bavituximab 1 mg/kg (n [ 79) 3 mg/kg (n [ 40) Acknowledgments Grades Grades Preferred Term All Grades 3/4 All Grades 3/4 This work was supported by Peregrine Pharmaceuticals, Inc, and by an American Society of Clinical Oncology Career Development Fatigue 23 (29.1) 8 (10.1) 14 (35.0) 3 (7.5) Award (to D.E.G.). Peregrine Pharmaceuticals, Inc participated in Nausea 22 (27.8) 0 (0.0) 15 (37.5) 0 (0.0) the study design; collection, analysis, and interpretation of the data; Neutropenia 19 (24.1) 16 (20.3) 13 (32.5) 9 (22.5) writing of the report; and the decision to submit for publication. Cough 17 (21.5) 0 (0.0) 10 (25.0) 0 (0.0) Editorial assistance was provided by Impact Communication Part- Edema, Peripheral 16 (20.3) 0 (0.0) 6 (15.0) 0 (0.0) ners, Inc. 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) Disclosure Asthenia 13 (16.5) 1 (1.3) 12 (30.0) 3 (7.5) D.E.G. receives research funding from Peregrine Pharmaceuti- Leukopenia 12 (15.2) 9 (11.4) 4 (10.0) 3 (7.5) cals, Inc. J.S.S. and K.B.M. are paid employees of Peregrine Phar- Anorexia 12 (15.2) 1 (1.3) 11 (27.5) 0 (0.0) maceuticals, Inc. The remaining authors have stated that they have Constipation 12 (15.2) 0 (0.0) 7 (17.5) 1 (2.5) no conflicts of interest. Dyspnea 11 (13.9) 2 (2.5) 5 (12.5) 1 (2.5) Vomiting 9 (11.4) 0 (0.0) 6 (15.0) 0 (0.0) Supplemental Data Arthralgia 8 (10.1) 0 (0.0) 8 (20.0) 1 (2.5) Supplemental figure accompanying this article can be found in Pain in Extremity 8 (10.1) 0 (0.0) 5 (12.5) 0 (0.0) the online version at http://dx.doi.org/10.1016/j.cllc.2016.02.003. 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) References Peripheral Sensory 7 (8.9) 1 (1.3) 4 (10.0) 0 (0.0) 1. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced Neuropathy squamous-cell nonesmall-cell lung cancer. N Engl J Med 2015; 373:123-35. Productive Cough 7 (8.9) 0 (0.0) 7 (17.5) 0 (0.0) 2. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous nonesmall-cell lung cancer. N Engl J Med 2015; 373:1627-39. Dizziness 6 (7.6) 1 (1.3) 4 (10.0) 0 (0.0) 3. Herbst RS, Baas P, Kim DW, et al. 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