Treatment with a retinoic acid-inducible gene I (RIG-I) agonist as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors: results from two phase 1 studies.

BACKGROUND: We evaluated MK-4621, an oligonucleotide that binds and activates retinoic acid-inducible gene I (RIG-I), as monotherapy (NCT03065023) and in combination with the anti-programmed death 1 antibody pembrolizumab (NCT03739138). PATIENTS AND METHODS: Patients were ≥ 18 years with histologically/cytologically confirmed advanced/metastatic solid tumors with injectable lesions. MK-4621 (0.2‒0.8 mg) was administered intratumorally as a stable formulation with jetPEI™ twice weekly over a 4-week cycle as monotherapy and weekly in 3-week cycles for up to 6 cycles in combination with 200 mg pembrolizumab every 3 weeks for up to 35 cycles. Primary endpoints were dose-limiting toxicities (DLTs), treatment-related adverse events (AEs), and treatment discontinuation due to AEs. RESULTS: Fifteen patients received MK-4621 monotherapy and 30 received MK-4621 plus pembrolizumab. The only DLT, grade 3 pleural effusion that subsequently resolved, occurred in a patient who received MK-4621/jetPEI™ 0.8 mg plus pembrolizumab. 93% of patients experienced ≥ 1 treatment-related AE with both monotherapy and combination therapy. No patients experienced an objective response per RECIST v1.1 with MK-4621 monotherapy; 4 (27%) had stable disease. Three (10%) patients who received combination therapy had a partial response. Serum and tumor biomarker analyses provided evidence that MK-4621 treatment induced an increase in gene expression of interferon signaling pathway members and associated chemokines and cytokines. CONCLUSIONS: Patients treated with MK-4621 monotherapy or in combination with pembrolizumab experienced tolerable safety and modest antitumor activity, and there was evidence that MK-4621 activated the RIG-I pathway. At the doses tested, MK-4621 did not confer meaningful clinical benefit. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03065023 and NCT03739138.

First-in-human phase 1 study of the anti-TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non-small-cell lung cancer☆.

BACKGROUND: In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy or in combination with pembrolizumab. PATIENTS AND METHODS: Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1. RESULTS: Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs-the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs-the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy. CONCLUSIONS: Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC.

Adalimumab plus methotrexate or standard therapy is more effective than methotrexate or standard therapies alone in the treatment of fatigue in patients with active, inadequately treated rheumatoid arthritis.

OBJECTIVES: Fatigue is an important systemic symptom of rheumatoid arthritis (RA) but has rarely been evaluated consistently after initiation of treatment in RA patients. This study examined the effects of adalimumab (HUMIRA, Abbott Laboratories, Abbott Park, IL, USA), a fully human, anti-tumor necrosis factor (anti-TNF) monoclonal antibody, on reducing fatigue in patients with RA. METHODS: A total of 1526 patients with RA were enrolled in 3 randomized, placebo-controlled clinical trials of adalimumab versus placebo plus methotrexate (MTX) or placebo plus standard antirheumatic therapies. Fatigue was assessed with the Functional Assessment of Chronic Illness Therapy (FACIT) fatigue scale questionnaire (which has been validated in RA) at baseline, mid-study, and at the end of the study. Logistic regression models were constructed using baseline demographic variables to test for treatment effect. In addition, sensitivity analyses were performed to determine the robustness of the data. RESULTS: At baseline in the 3 trials, patients' fatigue ranged from 27.9-29.7, representing considerable fatigue on the FACIT fatigue scale. Fatigue was significantly and consistently reduced in adalimumab-treated patients in the 3 clinical trials. Relative to placebo plus MTX, the adalimumab 40-mg-every-other-week dosage group reported statistically significantly less fatigue at all time points post-baseline. Improvements between adalimumab and placebo ranged from 3-7 points across all 3 trials, with a 3-4-point change representing a minimum clinically important difference. CONCLUSION: Adalimumab treatment was shown to significantly reduce fatigue in patients with moderate to severe RA. Changes in fatigue in all 3 trials were found to be clinically important.

Improvement in health utility among patients with rheumatoid arthritis treated with adalimumab (a human anti-TNF monoclonal antibody) plus methotrexate.

OBJECTIVES: To compare health-related quality of life (HRQoL), as measured by health utility, in patients with rheumatoid arthritis (RA) treated with adalimumab (a human anti-tumour necrosis factor (anti-TNF) monoclonal antibody) plus methotrexate or placebo plus methotrexate. METHODS: HRQoL data were obtained in two randomized, double-blind, placebo-controlled, multidose clinical trials conducted in the United States and Canada. The Health Utilities Index Mark 3 (HUI3) was administered in both studies at baseline, at the end of the study and at two time points in between. Patients' HUI3 scores were compared with population norm scores. Change in HUI3 was defined as the end-of-study score minus the baseline score. Utility gained throughout the study was measured by area under the utility curve and expressed as quality-adjusted life years (QALYs). Statistical testing adjusted for confounders and used the Dunnett test to account for multiple comparisons. RESULTS: Patients' utility scores at baseline were low (range of treatment group means 0.38-0.44) compared with population norms (0.88). HUI3 mean changes from baseline scores for adalimumab-treated patients were 0.22 and 0.21 in the two trials, whereas placebo patients' changes were 0.04 and 0.07. The rate of QALYs gained per year in the treatment group compared with the placebo group were 0.145 in the ARMADA trial and 0.104 in the DE019 trial. All gains were clinically important and statistically significant. CONCLUSIONS: Treatment with adalimumab plus methotrexate provides clinically important and statistically significant improvements in HRQoL as measured by health utility in patients with RA. This translates into measurable and important gains in QALYs.

Oligoclonality of V beta 3 TCR chains in the CD8+ T cell population of rheumatoid arthritis patients.

It has been established that oligoclonal expansion is a common feature of the CD8+ T cell population, particularly within the CD8+ CD57+ lymphocyte subset. In addition, clonal malignancies involving CD8+ CD57+ T cells (large granulocytic lymphocytic leukemias) are often accompanied by rheumatoid arthritis, Felty's syndrome, or both. Therefore, to identify disease-related alterations in the CD8+ T cell repertoire, we have compared the patterns of oligoclonality in the CD8+ T cells of rheumatoid arthritis patients (n = 32) with those of age-matched controls (n = 25). By using a multiplex PCR assay for the CDR3 length of TCR beta-chains, we have found a striking increase in the frequency of CD8+ oligoclonality involving V beta 3 TCR: 50% of the rheumatoid arthritis patients had evidence of oligoclonality in this TCR family compared with 4% of controls (p < 0.0002). In addition, two unrelated RA patients had clonally dominant CD8+ T cell beta receptors that were identical in amino acid sequence, suggesting selection by a common Ag. An analysis of a subset of RA patients with mAbs specific for V beta 3 TCR revealed the presence of clonal expansion in a minority of patients usually, but not exclusively, involving the CD57+ subset. These data define a phenotype of the T cell repertoire that is strongly associated with rheumatoid arthritis; the mechanisms and genetic and environmental factors that explain this phenomenon remain to be defined.

Reversible monocular blindness complicating Churg-Strauss syndrome.

A 76-year-old woman hospitalized for treatment of an inferior vena cava thrombus was noted to have eosinophilia as well as asthma, peripheral neuropathy, jaw claudication and visual loss. Pathological review of a temporal artery biopsy revealed vasculitis with eosinophils but no giant cells. Treatment with high dose corticosteroids resulted in improvement of visual acuity from hand motion to 20/60. Whereas at least 6 cases of temporal artery involvement with Churg-Strauss syndrome have been reported, visual loss has occurred in only 3 patients. In each of these cases, visual loss was permanent.