Brief Report: Safety and Antitumor Activity of Durvalumab Plus Tremelimumab in Programmed Cell Death-(Ligand)1-Monotherapy Pretreated, Advanced NSCLC: Results From a Phase 1b Clinical Trial.

INTRODUCTION: Although first-line immunotherapy approaches are standard, in patients with non-small cell lung cancer (NSCLC) previously treated with programmed cell death protein-1 or programmed death-(ligand)1 (PD-[L]1) inhibitors, the activity of combined CTLA-4 plus PD-(L)1 inhibition is unknown. This phase 1b study evaluated the safety and efficacy of durvalumab plus tremelimumab in adults with advanced NSCLC who received anti-PD-(L)1 monotherapy as their most recent line of therapy. METHODS: Patients with PD-(L)1-relapsed or refractory NSCLC were enrolled between October 25, 2013, and September 17, 2019. Durvalumab 20 mg/kg plus tremelimumab 1 mg/kg was administered intravenously every 4 weeks for four doses, followed by up to nine doses of durvalumab monotherapy every 4 weeks for up to 12 months of treatment or disease progression. Primary end points included safety and objective response rate (ORR) on the basis of Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) per blinded independent central review; secondary end points were ORR on the basis of RECIST v1.1 per investigator; duration of response, disease control, and progression-free survival on the basis of RECIST v1.1 per blinded independent central review and investigator; and overall survival. CLINICALTRIALS: gov identifier: NCT02000947. RESULTS: PD-(L)1-refractory (n = 38) and PD-(L)1-relapsed (n = 40) patients were treated. The most common treatment-related adverse events were fatigue (26.3%, PD-(L)1-refractory patients) and diarrhea (27.5%, PD-(L)1-relapsed patients). Grade 3 to 4 treatment-related adverse events occurred in 22 patients. Median follow-up duration was 43.6 months for PD-(L)1-refractory patients and 41.2 months for PD-(L)1-relapsed patients. The ORR was 5.3% for PD-(L)1-refractory patients (one complete response, one partial response) and 0% for PD-(L)1-relapsed patients. CONCLUSIONS: Durvalumab plus tremelimumab had a manageable safety profile, but the combination did not have efficacy after PD-(L)1 treatment failure.

First-in-human study of oleclumab, a potent, selective anti-CD73 monoclonal antibody, alone or in combination with durvalumab in patients with advanced solid tumors.

BACKGROUND: CD73 upregulation in tumors leads to local immunosuppression. This phase I, first-in-human study evaluated oleclumab (MEDI9447), an anti-CD73 human IgG1λ monoclonal antibody, alone or with durvalumab in patients with advanced colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), or epidermal growth factor receptor-mutant non-small-cell lung cancer (NSCLC). METHODS: Patients received oleclumab 5-40 mg/kg (dose-escalation) or 40 mg/kg (dose-expansion) intravenously every 2 weeks (Q2W), alone (escalation only) or with durvalumab 10 mg/kg intravenously Q2W. RESULTS: 192 patients were enrolled, 66 during escalation and 126 (42 CRC, 42 PDAC, 42 NSCLC) during expansion. No dose-limiting toxicities occurred during escalation. In the monotherapy and combination therapy escalation cohorts, treatment-related adverse events (TRAEs) occurred in 55 and 54%, respectively, the most common being fatigue (17 and 25%). In the CRC, PDAC, and NSCLC expansion cohorts, 60, 57, and 45% of patients had TRAEs, respectively; the most common were fatigue (15%), diarrhea (9%), and rash (7%). Free soluble CD73 and CD73 expression on peripheral T cells and tumor cells showed sustained decreases, accompanied by reduced CD73 enzymatic activity in tumor cells. Objective response rate during escalation was 0%. Response rates in the CRC, PDAC, and NSCLC expansion cohorts were 2.4% (1 complete response [CR]), 4.8% (1 CR, 1 partial response [PR]), and 9.5% (4 PRs), respectively; 6-month progression-free survival rates were 5.4, 13.2, and 16.0%. CONCLUSIONS: Oleclumab ± durvalumab had a manageable safety profile, with pharmacodynamic activity reflecting oleclumab's mechanism of action. Evidence of antitumor activity was observed in tumor types that are generally immunotherapy resistant. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT02503774; date of registration, July 17, 2015.

Pharmacokinetics and pharmacodynamics of MEDI0680, a fully human anti-PD-1 monoclonal antibody, in patients with advanced malignancies.

MEDI0680 is a humanized immunoglobulin monoclonal antibody that targets human programmed cell death protein 1 (PD-1) for the treatment of cancer. A population two-compartmental pharmacokinetic (PK) model and a sequential direct maximal effective drug concentration receptor occupancy (RO) model with baseline parameters were developed to quantify PK variability, identify significant covariates, and characterize the relationship between the PK and the RO of MEDI0680. A total of 58 patients with advanced malignancies received MEDI0680 by intravenous infusion at a dose of 0.1-20 mg/kg in a phase 1 study. The clearance was 0.27 L per day and the central volume of distribution (V1) was 3.14 L, with a modest between-subject variability of 30 and 19%, respectively. None of the evaluated covariates showed any impact on PK parameters except for a nonclinically meaningful relevant impact of body weight on V1. The estimated half-maximal effective concentration for MEDI0680 binding to the PD-1 antigen was approximately 1.88 µg/mL. Visual predictive check results demonstrated good predictability of the final population PK-RO model. PK-RO simulations demonstrated that > 90% RO could be maintained in all subjects after a 20-mg/kg dose every 2 weeks (Q2W). Therefore, 20 mg/kg Q2W and an equivalently fixed dose of 1500 mg was recommended for phase 2 studies.

Safety and Clinical Activity of MEDI1873, a Novel GITR Agonist, in Advanced Solid Tumors.

PURPOSE: The safety and preliminary efficacy of MEDI1873, an agonistic IgG1 fusion protein targeting glucocorticoid-induced TNF receptor-related protein (GITR), were evaluated in an open-label, first-in-human, phase I, dose escalation study in previously treated patients with advanced solid tumors. PATIENTS AND METHODS: Two single-patient cohorts at 1.5 and 3 mg i.v. were followed by 3+3 dose escalation in six cohorts at 7.5, 25, 75, 250, 500, and 750 mg, all every 2 weeks, for up to 52 weeks. Primary endpoints were safety and tolerability, dose-limiting toxicities (DLT), and MTD. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics. RESULTS: Forty patients received MEDI1873. Three experienced DLTs: grade 3 worsening tumor pain (250 mg); grade 3 nausea, vomiting, and headache (500 mg); and grade 3 non-ST segment elevation myocardial infarction (750 mg). An MTD was not reached and treatment was well tolerated up to 500 mg. Most common treatment-related adverse events were headache (25%), infusion-related reaction (17.5%), and decreased appetite (17.5%). MEDI1873 exposure was dose proportional. Antidrug-antibody incidence was low. MEDI1873 increased peripheral CD4+ effector memory T-cell proliferation as well as cytokines associated with effector T-cell activation at dose levels ≥75 mg. The best response was stable disease (SD) in 17 patients (42.5%), including 1 unconfirmed partial response. Eight patients (20.0%) had SD ≥24 weeks. CONCLUSIONS: MEDI1873 showed acceptable safety up to 500 mg i.v. every 2 weeks with pharmacodynamics activity, and prolonged SD in some patients. However, further development is not planned because of lack of demonstrated tumor response.

Anti-PD-1 monoclonal antibody MEDI0680 in a phase I study of patients with advanced solid malignancies.

BACKGROUND: The safety, efficacy, pharmacokinetics, and pharmacodynamics of the anti-programmed cell death-1 antibody MEDI0680 were evaluated in a phase I, multicenter, dose-escalation study in advanced solid malignancies. METHODS: MEDI0680 was administered intravenously once every 2 weeks (Q2W) or once every 3 weeks at 0.1, 0.5, 2.5, 10 or 20 mg/kg. Two cohorts received 20 mg/kg once a week for 2 or 4 weeks, then 20 mg/kg Q2W. All were treated for 12 months or until progression. The primary endpoint was safety. Secondary endpoints were efficacy and pharmacokinetics. Exploratory endpoints included pharmacodynamics. RESULTS: Fifty-eight patients were treated. Median age was 62.5 years and 81% were male. Most had kidney cancer (n = 36) or melanoma (n = 9). There were no dose-limiting toxicities. Treatment-related adverse events occurred in 83% and were grade ≥ 3 in 21%. Objective clinical responses occurred in 8/58 patients (14%): 5 with kidney cancer, including 1 with a complete response, and 3 with melanoma. The relationship between dose and serum levels was predictable and linear, with apparent receptor saturation at 10 mg/kg Q2W and all 20 mg/kg cohorts. CONCLUSIONS: MEDI0680 induced peripheral T-cell proliferation and increased plasma IFNγ and associated chemokines regardless of clinical response. CD8+ T-cell tumor infiltration and tumoral gene expression of IFNG, CD8A, CXCL9, and granzyme K (GZMK) were also increased following MEDI0680 administration. TRIAL REGISTRATION: NCT02013804 ; date of registration December 12, 2013.

Dose-escalation of human anti-interferon-α receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study.

INTRODUCTION: Type I interferons (IFNs) are implicated in the pathogenesis of systemic sclerosis (SSc). MEDI-546 is an investigational human monoclonal antibody directed against the type I IFN receptor. This Phase 1 study evaluated the safety/tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) of single and multiple intravenous doses of MEDI-546 in adults with SSc. METHODS: Subjects (≥18 years) with SSc were enrolled in an open-label, dose-escalation study to receive single (0.1, 0.3, 1.0, 3.0, 10.0, or 20.0 mg/kg), or 4 weekly intravenous doses (0.3, 1.0, or 5.0 mg/kg/week) of MEDI-546. Subjects were followed for 12 weeks. Safety assessments included adverse events (AEs), laboratory results, and viral monitoring. Blood samples were collected from all subjects for determination of PK, presence of anti-drug antibodies (ADAs), and expression of type I IFN-inducible genes. RESULTS: Of 34 subjects (mean age 47.4 years), 32 completed treatment and 33 completed the study. Overall, 148 treatment-emergent AEs (TEAEs) were reported (68.9% mild, 27.7% moderate). TEAEs included one grade 1 infusion reaction (5.0 mg/kg/week multiple dose). Of 4 treatment-emergent serious AEs (skin ulcer, osteomyelitis, vertigo, and chronic myelogenous leukemia (CML)), only CML (1.0 mg/kg/week multiple dose) was considered possibly treatment-related. MEDI-546 exhibited non-linear PK at lower doses. ADAs were detected in 5 subjects; no apparent impact on PK was observed. Peak inhibition of the type I IFN signature in whole blood was achieved within 1 day and in skin after 7 days. CONCLUSION: The safety/tolerability, PK, and PD profiles observed in this study support further clinical development of MEDI-546. TRIAL REGISTRATION: ClinicalTrials.gov NCT00930683.