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Abstract
Background Resistance to immune checkpoint inhibitors and targeted treatments for cancer is common; thus, novel immunotherapy agents are needed. Urelumab is a monoclonal antibody agonist that binds to CD137 receptors expressed on T cells. Here, we report two studies that evaluated urelumab in combination with cetuximab or nivolumab in patients with select, advanced solid tumors.
Methods CA186-018: Patients with metastatic colorectal cancer or metastatic squamous cell carcinoma of the head and neck (SCCHN) were treated in a dose-evaluation phase with urelumab 0.1 mg/kg (urelumab-0.1) every 3 weeks (Q3W)+cetuximab 250 mg/m2 (cetuximab-250) weekly; and in a dose-expansion phase with urelumab 8 mg flat dose (urelumab-8) Q3W+cetuximab-250 weekly. CA186-107: The dose-escalation phase included patients with previously treated advanced solid tumors (or treated or treatment-naive melanoma); patients received urelumab 3 mg flat dose (urelumab-3) or urelumab-8 every 4 weeks+nivolumab 3 mg/kg (nivolumab-3) or 240 mg (nivolumab-240) every 2 weeks. In the expansion phase, patients with melanoma, non-small cell lung cancer, or SCCHN were treated with urelumab-8+nivolumab-240. Primary endpoints were safety and tolerability, and the secondary endpoint included efficacy assessments.
Results CA186-018: 66 patients received study treatment. The most frequent treatment-related adverse events (TRAEs) were fatigue (75%; n=3) with urelumab-0.1+cetuximab-250 and dermatitis (45%; n=28) with urelumab-8+cetuximab-250. Three patients (5%) discontinued due to TRAE(s) (with urelumab-8+cetuximab-250). One patient with SCCHN had a partial response (objective response rate (ORR) 5%, with urelumab-8+cetuximab-250).
CA186-107: 134 patients received study treatment. Fatigue was the most common TRAE (32%; n=2 with urelumab-3+nivolumab-3; n=1 with urelumab-8+nivolumab-3; n=40 with urelumab-8+nivolumab-240). Nine patients (7%) discontinued due to TRAE(s) (n=1 with urelumab-3+nivolumab-3; n=8 with urelumab-8+nivolumab-240). Patients with melanoma naive to anti-PD-1 therapy exhibited the highest ORR (49%; n=21 with urelumab-8+nivolumab-240). Intratumoral gene expression in immune-related pathways (CD3, CD8, CXCL9, GZMB) increased on treatment with urelumab+nivolumab.
Conclusions Although the addition of urelumab at these doses was tolerable, preliminary response rates did not indicate an evident additive benefit. Nevertheless, the positive pharmacodynamics effects observed with urelumab and the high response rate in treatment-naive patients with melanoma warrant further investigation of other anti-CD137 agonist agents for treatment of cancer.
Trial registration numbers NCT02110082; NCT02253992.
- Nivolumab
- Clinical Trials as Topic
Data availability statement
Data may be obtained from a third party and are not publicly available. Bristol Myers Squibb will honor legitimate requests for clinical trial data from qualified researchers with a clearly defined scientific objective. Data sharing requests will be considered for phases II–IV interventional clinical trials that completed on or after January 1, 2008. In addition, primary results must have been published in peer-reviewed journals and the medicines or indications approved in the USA, EU, and other designated markets. Sharing is also subject to protection of patient privacy and respect for the patient’s informed consent. Data considered for sharing may include non-identifiable patient-level and study-level clinical trial data, full clinical study reports, and protocols. Requests to access clinical trial data may be submitted using the enquiry form at https://vivli.org/ourmember/bristol-myers-squibb/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Mechanistic data and preclinical evidence suggest that urelumab, an anti-CD137 agonist monoclonal antibody, may enhance the antitumor activity of the epidermal growth factor receptor inhibitor cetuximab, and the PD-1 inhibitor nivolumab.
WHAT THIS STUDY ADDS
The addition of urelumab at tolerable doses to either cetuximab or nivolumab for the treatment of patients with select, advanced solid tumors did not result in additive benefit.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
The high response rates observed in treatment-naive patients with melanoma indicate that urelumab and other anti-CD137 agents warrant further research for the treatment of cancers.
Introduction
Advances in immunotherapy have revolutionized the treatment of several cancers.1 Immunotherapy uses endogenous innate and adaptive immune cells to recognize and attack tumors. Activation of T cells, which can occur via coinhibitory and costimulatory signaling pathways, is a particularly critical step in the process.2 While select immunotherapy agents have proven efficacy and effectiveness, the development of primary and secondary resistance is common.3 Therefore, an unmet need exists to expand the diversity of the arsenal of immunotherapeutics and combine multiple agents.4 5
Relative to other immunotherapies (eg, checkpoint inhibitors), activating costimulatory signaling pathways has not been well explored. One potential therapeutic target for cancer treatment is CD137 (4-1BB), a tumor necrosis factor (TNF) superfamily type 1 membrane glycoprotein receptor expressed in lymphoid organs; its identified natural ligand is CD137L.6–8 On activation, CD137 surface expression is induced on many immune cells, including T cells (CD4+ and CD8+), natural killer (NK) T cells, regulatory T cells, eosinophils, and dendritic cells (DCs).9 10 Importantly, CD137 is not detected on the surface of resting T and B lymphocytes or activated B lymphocytes, making it a favorable biomarker for immune activation.11 12 Signaling through CD137 on CD137-positive DCs has been demonstrated to enhance and prolong T-cell responsiveness to alloantigens.13 Agonist monoclonal antibodies (mAbs) designed to bind to key immune-signaling players, like CD137, represent a potential new asset to immunotherapy. Such agonist antibodies could mimic cross-linking by the natural ligand and elicit a potent costimulatory signal on antigen-primed T cells.14 15
Urelumab (BMS-663513) is a fully human, immunoglobulin (Ig) G4 agonist mAb specific to the human CD137 receptor. On binding, urelumab activates the CD137 pathway, providing a strong costimulatory signal to T cells and boosting the antibody-dependent cell-mediated cytotoxicity (ADCC) of NK cells, which has been shown in the presence of cetuximab-activated NK cells.16 This signaling enhances production of cytokines (eg, interferon-γ (IFN-γ)), as well as T-cell survival, metabolic fitness, and proliferation.14 15 By increasing the host antitumor response, urelumab is hypothesized to improve the function of antigen-specific T cells.17
In a phase 1/2 clinical trial, urelumab demonstrated pharmacodynamic (PD) activity consistent with CD8 immune activation in patients with metastatic or locally advanced solid tumors (CA186-001; NCT00309023).18 Integrated safety analysis of preliminary monotherapy trials of urelumab demonstrated significant hepatotoxicity at doses ≥1.0 mg/kg, with the most frequent treatment-related adverse events (TRAEs) being increased aspartate aminotransferase (AST, 27%; grade 3/4, 14%), increased alanine aminotransferase (ALT, 27%; grade 3/4, 17%), and fatigue (24%; grade 3/4, 0%).18 Following two hepatoxicity-related deaths, a program hold and safety evaluation were conducted. Similarly, at 0.3 mg/kg, increased AST and fatigue were the most frequent TRAEs (both 14%), and further investigation of the 0.3 mg/kg dose was also stopped. Ensuing trials tested a lower dose of urelumab (0.1 mg/kg) for tolerability and potential liver toxicity. Fatigue (16%) and nausea (13%) were the most common TRAEs associated with the 0.1 mg/kg dose, and there were two treatment-related serious adverse events (SAEs) of grade 2 increased ALT, which resolved in 15 days with corticosteroid treatment, and grade 2 cutaneous rashes (erysipelas), which resolved in 5 days with antibiotic treatment.18 Thus, the maximum tolerated dose (MTD) was established as 0.1 mg/kg, with PD activity supporting the continued clinical evaluation of this dose as monotherapy and in combination with other immuno-oncology agents.
The clinical development of urelumab included the evaluation of several combination therapy regimens due to the unmet need for multimodal combination treatment approaches that target non-redundant pathways, especially for cancers that are or have become refractory to current standard-of-care options. Many epidermal growth factor receptor (EGFR)-positive cancers have acquired or innate resistance to tyrosine kinase inhibitors or mAbs.19 Preclinical studies using in vivo and in vitro tumor models of squamous cell carcinoma of the head and neck (SCCHN) demonstrated that CD137 agonists potentiate both ADCC and the antitumor effects of the EGFR antagonist cetuximab.16 Cetuximab was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic colorectal cancer (CRC; EGFR-positive without mutations in KRAS/NRAS) and locoregional, recurrent, and metastatic SCCHN. The mechanistic data for urelumab, coupled with the preclinical evidence, supported clinical evaluation of the hypothesis that urelumab would enhance the antitumor efficacy of cetuximab.
The anti-programmed cell death 1 protein (PD-1) mAb, nivolumab, functions to remove T-cell inhibition and is approved by the FDA for the treatment of several solid and hematological malignances.20 Although PD-1 and programmed cell death 1 ligand 1 (PD-L1) inhibitors have revolutionized the cancer treatment landscape, primary or secondary resistance to these agents is common.21 Preclinically, urelumab and nivolumab combination therapy elicited robust antitumor activity and increased IFN-γ expression compared with urelumab monotherapy.22 Therefore, the combination of urelumab with anti-PD-1 mAbs (eg, nivolumab) could provide, even at low, tolerable doses, the potential for a complementary combination to augment antitumor activity over either individual therapy alone, with a possible increase in level and duration of response (DOR).
In this article, we report the final results of two studies of urelumab in combination with cetuximab (CA186-018; phase 1b; NCT02110082) or with nivolumab (CA186-107; phase 1/2; NCT02253992) in patients with advanced solid tumors. The objectives of these studies were to evaluate the safety, efficacy, pharmacokinetics (PK), PD, and biomarkers associated with urelumab in these combination therapies.
Methods
CA186-018 (urelumab+cetuximab)
Study design and treatment
This study was a phase 1b, open-label, multicenter, dose-evaluation and cohort-expansion study of urelumab in combination with cetuximab in patients with advanced/metastatic CRC or SCCHN (online supplemental figure S1A). The objective of this study was to determine the safety, tolerability, and MTD of urelumab in combination with cetuximab in these patients.
Supplemental material
The trial consisted of two parts. In part 1 (dose evaluation), patients received an intravenous injection of urelumab at 0.1 mg/kg (hereafter referred to as urelumab-0.1) every 3 weeks (Q3W)+cetuximab weekly, with an initial dose of 400 mg/m2 then 250 mg/m2 thereafter (hereafter referred to as cetuximab-250). In part 2 (dose-cohort expansion), patients received intravenous urelumab (8 mg flat dose (hereafter referred to as urelumab-8) Q3W)+cetuximab-250. A flat dose of 8 mg (approximating 0.1 mg/kg based on the median patient body weight of 80 kg observed in past urelumab clinical studies) was instituted because recent analyses of mAbs demonstrated no advantages of body weight-based dosing over flat dosing in terms of reducing exposure variability. In both parts, the dosing period was ≤24 weeks (≤8 doses of urelumab).
Patient eligibility
Patients were ≥18 years of age with advanced/metastatic CRC that had progressed on or who had experienced intolerance to both irinotecan-based and oxaliplatin-based regimens. In addition, patients with advanced/metastatic SCCHN with no curative options available were also eligible for enrolment. Patients naive to anti-EGFR therapy or previously treated with EGFR inhibitors or immunotherapy were allowed. Patients must have had an Eastern Cooperative Oncology Group performance status (ECOG PS) of ≤1 and a life expectancy of ≥3 months. Key exclusion criteria included known or suspected brain metastasis or malignancy of the central nervous system (CNS), unless previously treated and progression-free for ≥8 weeks, with no immunosuppressive doses of systemic medications having been given within ≥2 weeks of enrolment; other concomitant or prior malignancies; and prior therapy with an anti-CD137 antibody. Exceptions to the “other malignancies” exclusion criterion included adequately treated basal cell or squamous cell skin cancer, localized prostate cancer, carcinoma in situ of the cervix, in situ ductal or lobular carcinoma of the breast, or other malignancies diagnosed >2 years ago that were treated with no evidence of disease during the interval and were considered by the investigator to present a low risk for recurrence.
Study endpoints and assessments
The primary endpoint was safety and tolerability as measured by incidence of AEs, SAEs, and TRAEs. Secondary efficacy endpoints were objective response rate (ORR, defined as the sum of complete responses (CR) and partial responses (PR)), DOR, and progression-free survival (PFS). ORR, DOR, and PFS were assessed based on Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1. Other secondary endpoints included PK, immunogenicity, and PD/biomarkers. PK was evaluated using maximum observed serum concentration (Cmax), trough observed serum concentration (Ctrough), time of maximum observed serum concentration (Tmax), area under the serum concentration-time curve from time zero extrapolated to infinite time (AUC(INF)), area under the serum concentration-time curve from time zero to the time of last quantifiable serum concentration (AUC(0-T)), elimination half-life (T1/2), total body clearance (CLT), and volume of distribution at steady state (Vss). The serum samples were analyzed for urelumab and cetuximab using a validated immunoassay. Immunogenicity was evaluated using occurrence of antidrug antibodies (ADAs).
CA186-107 (urelumab+ nivolumab)
Study design and treatment
This was a phase 1/2, open-label, dose-escalation, and cohort-expansion study of urelumab in combination with nivolumab in advanced/metastatic solid tumors or B-cell non-Hodgkin’s lymphoma (NHL), diffuse large cell lymphoma, and follicular lymphoma (online supplemental figure S1B). The objective of this study was to assess the safety and tolerability of urelumab given in combination with nivolumab, identify dose-limiting toxicities (DLTs), and determine the MTD of the combination. This manuscript will report study results from patients with advanced/metastatic solid tumors.
This trial was conducted in two parts. In the dose-escalation phase, patients received an intravenous injection of urelumab 3 mg (flat dose, hereafter referred to as urelumab-3) every 4 weeks (Q4W) in combination with nivolumab every 2 weeks (Q2W), or urelumab-8 Q4W in combination with nivolumab Q2W. Depending on time of enrolment, patients received nivolumab intravenous at either 3 mg/kg (hereafter referred to as nivolumab-3) or 240 mg (flat dose, hereafter referred to as nivolumab-240) Q2W. Urelumab doses were selected based on tolerability, efficacy, and PK observed in 346 patients treated with urelumab monotherapy. Patients enrolled in the dose-expansion phase received urelumab-8 Q4W+nivolumab-240 Q2W for ≤48 weeks.
Patient eligibility
The eligible patients were adults (age ≥18 years) who were previously treated for advanced or metastatic select solid tumors or B-cell NHL histologies during dose escalation. Data from patients with hematological malignancies are not reported in this manuscript. In the dose-expansion phase, patients were enrolled with treatment-naive or previously treated melanoma, previously treated non-small cell lung cancer (NSCLC), or SCCHN. Criteria for the cohort-expansion phase included ECOG PS ≤1. Key exclusion criteria were known CNS metastases (or CNS as the only source of disease) and other concomitant malignancies. Patients with ocular melanoma were excluded. Those with prior malignancies were excluded, except for adequately treated basal cell or squamous cell skin cancer, localized prostate cancer, carcinoma in situ of the cervix, or in situ ductal or lobular carcinoma of the breast. However, patients were eligible if they had other second malignancies diagnosed >2 years before and had received therapy with curative intent with no evidence of disease during the interval and were considered by the investigator to present a low risk for recurrence. Patients who previously received nivolumab were not eligible, with the exception of those with NSCLC and melanoma enrolled in the expansion cohorts, where prior anti-PD-(L)1 therapies were required.
Study endpoints and assessments
The primary endpoint was safety and tolerability as measured by incidence of AEs and SAEs. Secondary efficacy endpoints were best overall response (BOR), ORR (based on patients with a CR or PR), DOR, and PFS rate. Efficacy was assessed using RECIST V.1.1. Other secondary endpoints included PK, immunogenicity, and PD/biomarkers. PK was evaluated using Cmax, end of infusion concentration (Ceoinf), Tmax, Ctrough, AUC(0-T), and area under the serum concentration-time curve in one dosing interval (AUCTAU). Immunogenicity was evaluated using occurrence of ADAs.
Statistical analyses
Safety was evaluated in both studies according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. All recorded AEs were listed and tabulated by system organ class, preferred term, tumor type, and treatment arm. Medical Dictionary for Regulatory Activities, versions 19.1 and 22.1, was used for coding. Summary statistics were tabulated for the PK parameters by tumor type, dose, regimen, and study day and time on urelumab and cetuximab (CA186-018) or urelumab and nivolumab (CA186-107).
ADA PD and biomarker analyses
Once treatment was initiated, patients were counted as ADA-positive if (a) they had negative or missing ADA results at baseline and then had any ADA-positive postbaseline sample, or (b) they had positive ADA results at baseline and then had an ADA-positive postbaseline sample with ADA titer ≥4-fold higher than their positive titer at baseline.
Changes over time in PD response to urelumab in combination with cetuximab or nivolumab were measured by biomarkers monitored in peripheral blood and tumor tissue. Twenty-one cytokines were assessed in serum samples including α-2-macroglobulin, β-2 microglobulin, B-cell-activating factor, C-reactive protein, interleukin-10 (IL-10), IL-12p40, IL-18, IL-8, IFN-γ-induced protein 10, monocyte chemoattractant protein-1 (MCP-1), MCP-2, monokine induced by γ interferon (MIG, C-X-C motif chemokine ligand 9 (CXCL9)), macrophage inflammatory protein-1α (MIP-1α), MIP-1β, matrix metalloproteinase 3, regulated on activation normal T cell expressed and secreted, tissue inhibitor matrix metalloproteinase 1, TNF receptor 2, TNFα, vascular cell adhesion molecule, and von Willebrand factor. All cytokine data presented were obtained from patients treated with urelumab-8. Changes in immune-related gene expression in whole blood during treatment were evaluated by quantitative PCR in samples collected at baseline and at protocol-specified time points.
For CA186-107 (urelumab+nivolumab), tumor-cell PD-L1 expression was measured using the PD-L1 immunohistochemistry (IHC) 28-8 pharmDx assay (Agilent Technologies, Santa Clara, California, USA) and reported as the percentage of tumor cells with PD-L1 cell-membrane staining at any level. PD-L1, CD137, and CD8 IHC were performed by Mosaic Laboratories (Lake Forest, California, USA). RNA sequencing was performed on formalin-fixed, paraffin-imbedded tumor samples for gene expression analyses.
Results
CA186-018 (urelumab+ cetuximab)
Baseline characteristics and patient disposition
Of the 109 enrolled patients (defined as having signed informed consent), 61% (n=66) received treatment (online supplemental figure S2). Table 1 presents the baseline demographic and clinical characteristics. The median age of treated patients was 56 years (range: urelumab-0.1, 54–64 years; urelumab-8, 32–79 years), and they were mostly male (64%) and white (85%) across both cohorts. Among 62 patients in the dose-expansion urelumab-8 group, 44 (71%) had a diagnosis of CRC, and 18 (29%) had SCCHN. Of the treated patients, 97% (n=60) had received prior systemic therapy.
Patient baseline characteristics and demographics in CA186-018 (urelumab+cetuximab) and CA186-107 (urelumab+nivolumab)
Safety
In the dose-evaluation urelumab-0.1 group (n=4), the most common any-grade TRAE was fatigue (75% (n=3), table 2). One patient (25%) had a grade 3 TRAE of increased blood bilirubin. No TRAEs led to discontinuation in this group (online supplemental table S1A). In the dose-expansion urelumab-8 group (n=62), the most common any-grade TRAE was dermatitis (45%, n=28; table 2). Nine (15%) grade 3/4 TRAEs occurred (n=1 each: grade 4 neutropenia; grade 3 neutropenia, amylase increased, lipase increased, white cell count decreased, hypophosphatemia, decreased appetite, dermatitis, and pneumonia). Three patients (5%) discontinued due to a TRAE (grade 3 pneumonia, n=1; grade 2 hypersensitivity to cetuximab, n=1; and grade 2 infusion-related reaction to cetuximab, n=1; online supplemental table S1A). Two patients (3%) had treatment-related SAEs (n=1, grade 3 pneumonia that required treatment; n=1, grade 2 infusion-related reaction; online supplemental table S1A). One patient experienced a thromboembolic event and a middle cerebral arterial stroke during the study that resulted in death, but these AEs were deemed unrelated to study treatment.
Summary of adverse events in studies CA186-018 (urelumab+cetuximab) and CA186-107 (urelumab+nivolumab)
Clinical activity and pharmacology
Antitumor activity and efficacy
No objective confirmed response occurred in the CRC cohort (n=47); the best response observed was stable disease (SD) at 36.2% (n=17, including n=3 with urelumab-0.1 and n=14 with urelumab-8; figure 1). Among patients with SCCHN (n=19), 1 patient (5.3%) in the urelumab-8 cohort expansion achieved a confirmed PR, which was ongoing at the end of the study, and 57.9% (n=11) experienced SD Patients who experienced SD in the SCCHN cohort included 100% (n=1) of those who received urelumab-0.1 and cetuximab-250 and 55.6% (n=10) of those who received urelumab-8 and cetuximab (table 3). Response durations for individual tumors, grouped by cancer type, are shown in online supplemental figure S3A–C.
Best overall response for evaluation and expansion cohorts for CA186-018 (urelumab+cetuximab) and CA186-107 (urelumab+nivolumab) by dose and tumor type in all treated patients as determined by investigator
Duration of SD of patients with CRC who achieved SD as the BOR in CA186-018 (urelumab+cetuximab). Symbols represent censored observations. BOR, best overall response; CRC, colorectal cancer; Q3W, every 3 weeks; SD, stable disease.
PK and ADAs
Plots of mean urelumab serum concentrations versus time exposures were comparable at the urelumab-0.1 and urelumab-8 doses (online supplemental figure S4A). PK parameters of Cmax, AUCTAU, and concentration at the end of a dosing interval (CTAU) were comparable between the urelumab-0.1 and urelumab-8 doses (online supplemental table S2). Of all 66 treated patients, ADAs against urelumab were detected in 4 patients (6%) at baseline and in 31 patients (47%) after treatment. Seventeen patients (26%) had neutralizing urelumab ADAs (online supplemental table S3A).
PD biomarker analyses
Cytokine levels in serum, including IP10 (CXCL10), MIG (CXCL9), MIP-1β (CCL4), MCP-4, IL-18, and MCP-2, increased after treatment with urelumab+cetuximab, and their elevation was consistent with the known mechanism of action of this combination therapy (online supplemental figure S5A). Temporal changes in mRNA expression of IFN-induced target genes in whole blood (including CXCL9, GBP1, MX1, OAS1, and RSAD2) were also observed (online supplemental figure S5B).
CA186-107 (urelumab+nivolumab)
Baseline characteristics and patient disposition
Out of 228 patients enrolled (defined as having signed informed consent), 59% (n=134) received treatment (online supplemental figure S2). Table 1 presents baseline demographic and clinical characteristics. Across all treatment groups, 51% of patients (n=68) had melanoma. The median age was approximately 66 years, 69% were male, and 91% were white. Ninety-three (69%) enrolled patients had received prior systemic therapy.
Safety
Across treatment groups, the most common any-grade TRAE was fatigue (32% (n=43), table 2). One (17% (n=6)) grade 3/4 TRAE (lipase increased) occurred in the urelumab-3+nivolumab-3 group, while none occurred in the urelumab-8+nivolumab-3 group. Twenty-three (19% (n=124)) grade 3/4 TRAEs were reported in the urelumab-8+nivolumab-240 group (lipase increased, n=8; ALT increased, n=5; AST increased, n=3; amylase increased, n=3; anemia, n=2; pruritus, n=1; alkaline phosphatase increased, n=1). The incidence of TRAEs leading to discontinuation was low (0%–17% across treatment groups: 17% (n=1) with urelumab-3+nivolumab-3; 0 with urelumab-8+nivolumab-3; and 7% (n=8) with urelumab-8+nivolumab-240 (online supplemental table S1B). Drug-related SAEs occurred in 11 patients (10 with urelumab-8+nivolumab-240: pneumonitis (n=2), acute kidney injury (n=1), autoimmune hepatitis (n=1), diabetes insipidus (n=1), diabetes mellitus/diabetes ketoacidosis (n=1), investigations including elevated ALT, AST, and GGT (n=1), pharyngeal hemorrhage (n=1), tumor hemorrhage/pain (n=1), tracheal obstruction (n=1); and one with urelumab-3+nivolumab-3: enteritis/ileus). One death was attributed to a drug-related SAE (pharyngeal hemorrhage) in a patient with SCCHN (online supplemental table S1B).
Clinical activity and pharmacology
Antitumor activity and efficacy
Antitumor activity was observed with urelumab-8+nivolumab-240, primarily in the PD-1-naive melanoma cohort (n=43), in which an ORR of 49% was demonstrated: n=6 CRs and n=15 PRs (table 3). The median DOR was 21.2 months (figure 2). Response durations for patients with anti-PD-1-naive melanoma, grouped by PD-L1-positive or PD-L1-negative responders and non-responders, are shown in online supplemental figure S3D–F. Among the PD-1-experienced melanoma cohort (n=20), the ORR was 10%, with one patient who achieved a PR (DOR of 3.7 months; prior treatment with ipilimumab, then nivolumab) and a second patient with a PR that was unconfirmed. The ORR was 5% in the PD-1-naive NSCLC cohort (n=20), in which a PR was observed in one patient with a DOR of 7.5 months. An ORR of 5% was also demonstrated in the PD-1-experienced NSCLC cohort (n=20), with one patient having a PR with a DOR of 2.8 months. Among the SCCHN group (n=21), the ORR was 5%, including one patient who demonstrated a CR with a DOR of 23 months.
Best percentage reduction from baseline in sum of diameters of target lesions in patients with PD-1-naive melanoma who had a target lesion at baseline and ≥1 on-treatment tumor assessment in CA186-107 (urelumab+nivolumab). Best reduction is defined as maximum reduction in sum of diameters of target lesions (negative value means a true reduction, positive value means an increase only observed over time). Diamond symbols represent responders. White diamonds indicate PR. Black diamonds indicate CR. CR, complete response; PD-1, programmed death-1; PR, partial response; Q2W, every 2 weeks; Q4W, every 4 weeks; urelumab-8, urelumab 8 mg flat dose.
PK and ADAs
Plots of mean urelumab serum concentrations versus time exposures were comparable for treatments B (urelumab-8 Q4W+nivolumab-3 Q2W) and D (urelumab-8 Q4W+nivolumab-240 Q2W); however, urelumab serum concentrations were consistently lower for treatment A (urelumab-3 Q4W+nivolumab-3 Q2W) (online supplemental figure S4B). Urelumab exposures were more than dose proportional for urelumab-3 and urelumab-8 doses (online supplemental table S2).
At baseline, 4% of patients (n=5) were ADA positive for urelumab, and 48% (n=54) were ADA positive after initiation of treatment. Of the 54 patients who were ADA positive for urelumab, 54% (n=29) were considered persistent positive, and 35% (n=19) were neutralizing ADA positive (online supplemental table S3B).
PD/biomarker analyses
Baseline tumor expression of PD-L1, CD137, and CD8 was not associated with a therapeutic response (figure 3A), and PD-L1 expression remained largely unchanged during treatment with urelumab+nivolumab (figure 3B). In patients with melanoma, gene expression associated with immune and inflammation processes was upregulated, while expression of genes related to melanin and pigmentation was downregulated within tumors on treatment (figure 3C). Gene expression of CD3, CD8, CXCL9, and GZMB increased within the tumor on treatment with urelumab+nivolumab (figure 3D). The most commonly upregulated and downregulated genes after combination treatment with urelumab+nivolumab are shown in online supplemental table S4. Cytokine-associated biomarker levels in serum, including MIG (CXCL9), IP10 (CXCL10), ITAC (CXCL11), MIP-1β (CCL4), and IL2Rα, were increased after treatment with urelumab+nivolumab, and their elevation is consistent with known mechanism of action of this combination therapy (figure 4A). Expression of IFN-induced genes CXCL9, GBP1, MX1, OAS1, and RSAD2 significantly increased (p<0.05) during treatment with urelumab+nivolumab (figure 4B).
Tumor-based results from patients with melanoma in CA186-107 (urelumab+nivolumab). (A) Baseline IHC expression levels by response to urelumab+nivolumab. (B) PD-L1 IHC in tumors before and after treatment with urelumab+nivolumab. (C) Gene expression changes in tumors after urelumab+nivolumab treatment. (D) Log-scale gene expression changes in tumors after urelumab+nivolumab treatment. For all box and whisker plots, the height of the box is IQR (Q3–Q1). The bottom and top borders of the box represent the upper bounds of quartile 1 (25%) and quartile 3 (75%). The bold lines represent the median. The lower and upper error bars reflect quartile 1–1.5×IQR and quartile 3+1.5×IQR, respectively. Dots represent individual data. AOV, analysis of variance; CR, complete response; FC, fold change; FPKM, fragments per kilobase of transcript per million reads; IHC, immunohistochemistry; IQR, inter-quartile range; NS, not significant; PD, progressive disease; PD-L1, programmed cell death 1 ligand 1; PR, partial response; RNAseq, RNA sequencing; SD, stable disease.
CA186-107 (urelumab+nivolumab). (A) Cytokine-associated biomarkers with the greatest increase after treatment included MIG (CXCL9), IP10 (CXCL10), ITAC (CXCL11), MIP-1β (CCL4), and IL2Ra. (B) Change from baseline of IFN-induced target gene expression in whole blood after treatment with urelumab+nivolumab. For all box and whisker plots, the height of the box is IQR (Q3–Q1). The bottom and top borders of the box represent the upper bounds of quartile 1 (25%) and quartile 3 (75%). The bold lines represent the median. The lower and upper error bars reflect quartile 1–1.5×IQR and quartile 3+1.5× IQR, respectively. Dots represent individual data. C, cycle; D, day GBP1, guanylate binding protein 1; IL-2Ra, interleukin-2 receptor subunit α; IP10 (CXCL10), interferon γ-induced protein 10 (C-X-C motif chemokine ligand 10); ITAC (CXCL11), interferon-inducible T-cell α chemoattractant (C-X-C motif chemokine ligand 11); MIG (CXCL9), monokine induced by γ interferon (C-X-C motif chemokine ligand 9); MIP-1β (CCL4), macrophage inflammatory protein-1β (C-C motif ligands 4); MX1, MX dynamin like GTPase 1; OAS1, 2'−5'-oligoadenylate synthetase 2; RSAD2, radical s-adenosyl methionine domain containing 2.
Discussion
We report here data from two phase 1/2 trials that aimed to evaluate the safety, tolerability, PK, PD, immunogenicity, and preliminary efficacy of novel combinations of urelumab with cetuximab (CA186-018) or nivolumab (CA186-107).
The combination of urelumab-0.1 or urelumab-8 with cetuximab-240 was well tolerated and did not appear to have additive toxicity profiles beyond the expected safety profile of cetuximab. Furthermore, no significant treatment-related liver toxicity was observed in either cohort. Among this combination trial of 66 treated patients, one grade 3 treatment-related case of blood bilirubin increase occurred in the urelumab-0.1 group. The combination of urelumab+cetuximab demonstrated limited antitumor activity in patients with advanced/metastatic CRC or SCCHN solid tumors beyond what would be expected for cetuximab monotherapy. Results from cetuximab monotherapy studies indicated that patients with EGFR-expressing, recurrent metastatic CRC experienced an overall response rate of 11% and a median DOR of 4.2 months.23 Patients with recurrent or metastatic SCCHN demonstrated an overall response rate of 13% and a median DOR of 5.8 months.24
Urelumab-3 or urelumab-8 in combination with nivolumab-3 or nivolumab-240 demonstrated a manageable safety profile with limited liver toxicity. Elevated transaminase levels were observed at grades 3 or higher in 8 of the 134 treated patients, leading to drug delay or discontinuations in 3 patients. Also, the other reported TRAEs appeared to be consistent with the known safety profile of nivolumab monotherapy.
Antitumor activity was observed with urelumab-8 and nivolumab combination treatment, specifically in patients with PD-(L)1-naive melanoma (ORR, 49%); however, the demonstrated efficacy with the combination was not distinguishable from what was demonstrated with nivolumab in previous monotherapy trials.25 For example, in CheckMate 067, patients with treatment-naive metastatic melanoma experienced an ORR of 44% with nivolumab monotherapy.26 The urelumab doses used in this trial, therefore, while tolerable, may be suboptimal in their effect on the therapeutic target.
In the current study, 2 confirmed responses occurred among patients in the anti-PD-1-experienced cohorts. A PR was experienced by 1 patient in the PD-1-experienced melanoma cohort (pretreated with ipilimumab and nivolumab) and by 1 patient in the PD-1-experienced NSCLC population (pretreated with bevacizumab, carboplatin, and pemetrexed). Rechallenge with nivolumab following disease progression on nivolumab in patients with metastatic melanoma has been conducted, and results suggest that PFS tends to be shorter at rechallenge.27 While we cannot conclude that combination treatment with urelumab+nivolumab increases antitumor activity beyond nivolumab monotherapy in the PD-1-naive or PD-1-experienced settings, investigating the intrinsic features of tumor and host in patients where the combination was associated with response may reveal new insights. Ultimately, evidence in favor of this combination would need to be derived from a well-balanced, randomized controlled trial.
The PK profile of urelumab was not altered when given in combination with cetuximab or with nivolumab, indicating no PK interaction between these agents. Taken together, the PK findings suggest greater contribution of the target-mediated clearance due to non-saturation of CD137 at lower urelumab doses. Urelumab demonstrated immunogenicity with an ADA-positive rate of approximately 50% in both trials; but, when given in combination, urelumab did not appear to alter the immunogenicity of cetuximab or nivolumab. Rates of ADA positivity observed with cetuximab and nivolumab in combination with urelumab are consistent with the reported ADA rate for both agents during monotherapy treatment.24 25 The effects of urelumab ADAs on PK, safety, and efficacy are unknown and warrant further analyses using pooled data from different trials to provide sufficient sample size.
Treatment with urelumab+cetuximab or nivolumab led to increases in mRNA expression of IFN-γ-induced genes and upregulation of inflammatory cytokines in the periphery; however, these changes did not correspond with response. The increase observed in both studies was consistent with mechanism of action of urelumab+cetuximab or nivolumab, given that all have independently shown the ability to induce expression or increase the levels of IFN-γ-related genes and cytokines.18 28 29 This increase in activity may have been influenced by patients with specific biological features, immune profiles, and number and type of prior therapies. Furthermore, despite evidence of PD changes, only modest antitumor activity was observed. Within melanoma tumors, the expression of genes associated with immune and inflammatory processes increased, including CD3, CD8, CXCL9, and GZMB, on treatment with urelumab+nivolumab. Interestingly, genes related to melanin and pigmentation were downregulated in melanoma tumors on treatment. These genes are involved in the development of melanocytes, which are also the cell type associated with melanoma.30 The decrease in the expression of genes related to melanin and pigmentation may be due to a decrease in the proportion of melanocytes in the tumor microenvironment after treatment with urelumab+nivolumab. In parallel, we observed an increased expression of immune and inflammation genes that was possibly related to an increase in the number of immune cells in the tumor microenvironment after treatment with urelumab+nivolumab. Indeed, a 2016 study showed that patients with melanoma treated with a PD-1 blockade resulted in upregulation of differentially expressed genes involved in an adaptive immune response (ie, increased expression of antigen presentation molecules and markers of T-cell activation).31 Furthermore, a subsequent study of nivolumab revealed that on-therapy expression changed in patients with melanoma, who demonstrated a marked upregulation of numerous immune pathways that was more pronounced in patients who responded to treatment.32
While urelumab combination therapies demonstrated modest efficacy, their PD, PK, and safety profiles support future investigation into CD137-targeted agents as potential therapies. Experimental data demonstrate that agonistic anti-CD137 mAbs induce and improve antitumor immunity in a variety of cancer models. Utomilumab, another IgG2 monoclonal 4-1BB agonist that has been tested in a clinical setting, demonstrated no observable DLTs or liver enzyme elevations.33 However, utomilumab is considered a weaker agonist, driving less 4-1BB signaling and lower induction of nuclear factor ĸB, with little clinical effect as a monotherapy.34–36 Next-generation CD137 agonists like GEN1046 and NM21-1480 (both of which target PD-L1 and CD137) may be more tolerable with an improved therapeutic window; both are currently being tested in phase 1 clinical trials. Currently, there is ongoing effort to develop approaches that increase anti-CD137 delivery while reducing systemic exposure and CD137-related toxicity.35 37 Strategies under investigation include the use of bispecific antibodies targeting CD137 and a tumor antigen or stromal component; the creation of masked antibodies that are released by tumor-specific proteases; and the delivery of antibodies by intratumoral administration.37 In addition, combination therapies that combine anti-CD137 antibodies with antibodies targeting CD4, S100A4, and T-cell immunoglobulin and mucin domain 3, have been investigated.36 Together, these strategies may lead to enhanced delivery of anti-CD137 agents, and in turn, improved patient outcomes.37
We acknowledge the limitations of these studies. The study designs were non-randomized and single-arm with no monotherapy comparator arm, the patient populations were heavily pretreated (56% and 35% had ≥2 prior lines of therapy in CA186-018 and CA186-107, respectively), and the tumor types were heterogeneous, making it challenging to draw meaningful conclusions. Furthermore, the potential for liver toxicity observed at 1 mg/kg urelumab limited the dose levels in these trials to a likely subtherapeutic dose of urelumab 8 mg (approximately 0.1 mg/kg). Currently, no specific risk factors have been identified that might predispose patients to develop liver toxicity. Preclinical data with agonist CD137 mAbs suggest that the observed liver toxicity in mice was a result of hepatic infiltration by lymphocytes.38–40
While increases in IFN-γ-induced target genes and inflammatory cytokines were observed with urelumab-8 combination therapy, suggesting immune activation at this dose, the addition of urelumab-8 did not surpass the clinical outcomes seen with cetuximab or nivolumab as monotherapies. The effects of anti-CD137 antibodies offer therapeutic potential for cancer treatment, but further developments are needed to optimize their full application.37
Data availability statement
Data may be obtained from a third party and are not publicly available. Bristol Myers Squibb will honor legitimate requests for clinical trial data from qualified researchers with a clearly defined scientific objective. Data sharing requests will be considered for phases II–IV interventional clinical trials that completed on or after January 1, 2008. In addition, primary results must have been published in peer-reviewed journals and the medicines or indications approved in the USA, EU, and other designated markets. Sharing is also subject to protection of patient privacy and respect for the patient’s informed consent. Data considered for sharing may include non-identifiable patient-level and study-level clinical trial data, full clinical study reports, and protocols. Requests to access clinical trial data may be submitted using the enquiry form at https://vivli.org/ourmember/bristol-myers-squibb/.
Ethics statements
Patient consent for publication
Ethics approval
Both studies were conducted in accordance with Good Clinical Practice, as defined by the International Conference on Harmonization and in accordance with the ethical principles underlying European Union Directive 2001/20/EC and the US Code of Federal Regulations, Title 21, Part 50 (21CFR50). The protocols were approved by each study site’s independent ethics committee or institutional review board prior to study initiation. Informed consent was obtained prior to any study-related procedure in adherence to the ethical principles described in the Declaration of Helsinki.
Acknowledgments
The authors thank the patients who participated in the study and their family members, as well as the investigators and staff who conducted the study. Sponsorship of this study and article processing charges were funded by Bristol Myers Squibb, Princeton, NJ. Medical writing and editorial assistance was provided by Clara Huesing, PhD, of SciMentum, a Nucleus Global company, and by Sandra Page, PhD and Agata Shodeke, PhD, both of Spark (a division of Prime, New York, USA) and funded by Bristol Myers Squibb. The authors are fully responsible for all content and editorial decisions for this manuscript.
References
Supplementary materials
Supplementary Data
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Footnotes
Contributors DTL, JN, SS, AS, JH, RS, and SE contributed to the design of the study; NIK, PAO, RLF, TC, DS, DL, JN, MRS, FB, WS, JJL, IM, and NHS contributed to the acquisition of the dataset; all authors contributed to the analysis of the data, and their interpretation. All authors reviewed and revised the work and approved the final draft for submission. NHS is guarantor for this article and accepts full responsibility for the work.
Funding This study was sponsored by Bristol Myers Squibb.
Competing interests NIK reports consulting fees from Bristol Myers Squibb, Merck, Jounce, Novartis, Regeneron, Genzyme, Iovance, Castle Biosciences, Nektar, Replimune, and Instil Bio; research funding (to institute) from Bristol Myers Squibb, Merck, Celgene, Novartis, GSK, HUYA, Regeneron, Replimune, Modulation Therapeutics; participation on a data safety monitoring board with Incyte, AstraZeneca; participation in a study steering committee with Bristol Myers Squibb, Nektar, Regerenon, Replimune; and ownership of common stock in Bellicum, Amarin, and Asensus Surgical. PAO reports grants from Bristol Myers Squibb, Neon Therapeutics, Merck, Pfizer, Novartis, Celldex, Xencor, Roche/Genentech, Oncorus; consulting fees from Bristol Myers Squibb, Evaxion, Merck, Roche/Genentech, Novartis, Immunetune, LG Chem; leadership or fiduciary role with NCCN. RF reports grants or contracts from AstraZeneca/MedImmune, Bristol Myers Squibb, Merck, Novasenta, Tesaro; consulting fees with Adagene, Aduro Biotech, Bicara Therapeutics, Brooklyn ImmunoTherapeutics, Catenion, EMD Serono, Everest Clinical Research Corporation, F. Hoffman-La Roche Ltd., Federation Bio, Genocea Biosciences, Kowa Research Institute, Mirati Therapeutics, Nanobiotix, Novartis, Novasenta, PPD Development, Sanofi, Zymeworks; participation on a data safety monitoring or advisory board with Coherus BioSciences, Eisai Europe Ltd., Genmab, Hookipa, Instil Bio, Lifescience Dynamics, MacroGenics, MeiraGtx, Merck, Mirror Biologics, Numab Therapeutics AG, OncoCyte, Pfizer, Rakuten Medical, Seagen, SIRPant Immunotherapeutics, Vir Biotechnology, stock or stock options with Novasenta. TC reports speaker fees/honoraria from AstraZeneca, Bristol Myers Squibb, Clinical Care Options, IDEOlogy Health, Mark Foundation for Cancer Research, Medscape, OncLive, PeerView, Physicians’ Education Resource, Roche, and Society for Immunotherapy of Cancer; advisory role/consulting fees from Arrowhead Pharmaceuticals, Bristol Myers Squibb, Genentech, MedImmune/AstraZeneca, Merck, Pfizer, and Regeneron; institutional research funding from Bristol Myers Squibb, EMD Serono, and MedImmune/AstraZeneca; and travel, food and/or beverage expenses from AstraZeneca, Bristol Myers Squibb, Dava Oncology, Genentech, IDEOlogy Health, International Association for the Study of Lung Cancer, OncLive, Parker Institute for Cancer Immunotherapy, Physicians’ Education Resource, and Society for Immunotherapy of Cancer. DS reports research funding to the institution from Bristol Myers Squibb, MSD, Novartis, Amgen, Roche, Array; patient fees to the institution for clinical studies from Bristol Myers Squibb, MSD, Novartis, Merck-EMD, Philogen, Pfizer, Array, InflaRX, Nektar, Sun Pharma; consulting fees/honoraria from Bristol Myers Squibb, MSD, Novartis, Merck-EMD, Philogen, Pfizer, Array, InflaRX, Nektar, Sun Pharma, OncoSec, Replimune, NeraCare, Sandoz, Ultimovacs; reimbursement from the Society for Immunotherapy of Cancer, Bristol Myers Squibb, Roche, Medscape Oncology and PeerView Institute for travel; nonfinancial support from Bristol Myers Squibb, MSD, Novartis, Merck-EMD, Pierre-Fabre, Pfizer, InFlaRX, NeraCare, Nektar, Sun Pharma, Sandoz; consulting/advisory role fees from MedImmune, AstraZeneca, Bristol Myers Squibb, Merck& Co., Genentech, Arrowhead Pharmaceuticals, and EMD Serono; institutional clinical research funding from Boehringer Ingelheim, MedImmune, AstraZeneca, EMD Serono, and Bristol Myers Squibb. DTL reports serving on advisory boards for Merck, Bristol Myers Squibb, Nouscom, G1 Therapeutics, and Janssen; receiving research funding from Merck, Bristol Myers Squibb, Curegenix, Nouscom, and AbbVie; speaking honoraria from Merck; being an inventor of licensed intellectual property related to technology for mismatch repair deficiency for diagnosis and therapy (WO2016077553A1) from Johns Hopkins University. MRS reports support for present manuscript from Bristol Myers Squibb; participation on a data safety monitoring or advisory board with Pilant Therapeutics; stock or stock options with Bristol Myers Squibb. FB reports financial interest with AbbVie, ACEA, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eisai, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd., Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, MedImmune, Merck, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis, Takeda. WS reports grants and personal fees from Bristol Myers Squibb, Merck, and Novartis; personal fees from Regeneron; and grants from Genentech. JJL reports grants or contracts from AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus, Day One, EMD Serono, F-star, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, MacroGenics, Merck, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, Xencor; consulting fees from 7 Hills, Bright Peak, Exo, F-star, Inzen, RefleXion, Xilio, Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, Saros, Stipe, Tempest, AbbVie, Alnylam, Atomwise, Bayer, Bristol Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, KSQ, Janssen, Ikena, Inzen, Immatics, Immunocore, Incyte, Instil, IO Biotech, MacroGenics, Merck, Mersana, Nektar, Novartis, Partner, Pfizer, Pioneering Medicines, PsiOxus, Regeneron, Ribon, Roivant, Servier, Stingthera, Synlogic, Synthekine; provisional patents in cancer immunotherapy (serial no. 15/612,657) and microbiome biomarkers for anti-PD-1/PD-L1 responsiveness: diagnostic, prognostic, and therapeutic uses thereof (PCT/US18/36052); participation on a data safety monitoring board or advisory board with AbbVie, Immutep, Evaxion; leadership or fiduciary role with Society for Immunotherapy of Cancer; stock or stock options with Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, Saros, STipe, Tempest. IM reports support for the current manuscript from Bristol Myers Squibb; grants or contracts from Bristol Myers Squibb, Roche, Genmab, Highlight Therapeutics, AstraZeneca; consulting fees from Bristol Myers Squibb, Roche, Genmab, Merus, Pieris, AstraZeneca, Numab, Highlight Therapeutics; payment or honoraria from Bristol Myers Squibb; support for attending meetings and/or travel from Bristol Myers Squibb and Roche. DL, JN and JH are employees and stock owners of Bristol Myers Squibb. AS is an employee of Boston Scientific. SS, AS, RS and SE report employment with Bristol Myers Squibb. NHS reports consulting fees from ABL Bio, Agenus, AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Numab, Puretech, Regeneron, Revitope, and Roche/Genentech; and research funding from Agenus, AstraZeneca, Bristol Myers Squibb, Immunocore, Merck, Pfizer, Puretech, Regeneron, and Roche/Genentech.
Provenance and peer review Not commissioned; externally peer reviewed.
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