Effect of concurrent beta-blocker use in patients receiving immune checkpoint inhibitors for advanced solid tumors.

e15068 Background: Stress-induced adrenergic signaling suppresses the immune system. In animal model systems, pharmacological beta-blockade stimulated CD8+ T-cell activity, and further, it improved clinical activity of immune checkpoint inhibitors (ICI) in inhibiting tumor growth. Herein, we investigate the effect of beta blockers (BB) on clinical outcomes of patients receiving ICI in advanced solid tumors. Methods: We retrospectively evaluated patients with solid tumors treated with at least 2 doses of ICI at our institution from December 2010 to April 2017. The primary outcome was disease control rate (DCR), as defined by radiographic complete response, partial response, or stable disease, by RECIST 1.1 criteria. The primary predictor was use of BB (β1-selective BB vs. no BB; non-selective BB vs no BB). The primary predictive variable was analyzed using multivariate logistic regression model controlling for several parameters including patient demographics, co-morbidities, ECOG performance status, and tumor type and location of metastases. All tests were two-sided at the significant level of 0.05. Results: We identified 298 evaluable patients with median age of 66.5 (31-95). Of these patients, 200 (67%) did not use BB, 75 (25%) used β1-selective BB, and 23 (8%) used non-selective BB. In multivariate analysis, use of β1-selective BB was significantly associated with improved DCR compared to no BB (ORR 2.43, 95% CI 1.31-4.51, P = 0.005), while use of non-selective BB was not associated with improved DCR (ORR 1.71, 95% CI 0.65-1.47, P = 0.27). Conclusions: The concurrent use of BB may enhance the clinical activity of ICI, particularly β1-selective BB. Our findings warrant further investigation to understand the interaction of β1- and β2-adrenergic signaling and antitumor immune activity, and potentially explore a combination strategy of ICI and BB.

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Preliminary safety, efficacy, and pharmacokinetics (PK) results of KN046 (bispecific anti-PD-L1/CTLA4) from a first-in-human study in subjects with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.2554 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 2554-2554 ◽

Cited By ~ 1

Author(s):

Jermaine Coward ◽

Vinod Ganju ◽

Ramin Behzadigohar ◽

Kenneth Kwong ◽

June Xu ◽

...

Keyword(s):

Solid Tumors ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Single Agent ◽

Human Study ◽

Safety Data ◽

Advanced Solid Tumors ◽

Duration Of Treatment ◽

Efficacy Evaluation

2554 Background: KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD1 and CTLA-4 interaction with CD80/CD86. KN046 has a wild type IgG1 Fc portion that preserves intact effector functions, such as depletion of Tregs in tumor microenvironments. This first-in-human study evaluated the safety, tolerability, PK and preliminary efficacy of KN046 in subjects with advanced solid tumors. Methods: This traditional “3+3” dose-escalation design study enrolled patients (pts) with advanced unresectable or metastatic solid tumors refractory or intolerant to standard therapies. Previous treatment from PD1 or PD-L1 immune checkpoint inhibitors was allowed. KN046 was administered intravenously Q2W. Dose limit toxicity (DLT) evaluation period is 28 days. The planned dose levels (DL) were 0.3, 1, 3, 5 and 10 mg/kg. Efficacy evaluation was performed by RECIST 1.1 every 8 weeks. Results: As of Dec 13, 2018, 10 pts had been enrolled (0.3 mg/kg, n = 1; 1 mg/kg, n = 3; 3 mg/kg, n = 3; and 5 mg/kg, n = 3). Median duration of treatment was 8 (range: 2-24) weeks. 1 DLT was observed at 5 mg/kg dose (a grade 3 immune-related hepatitis without elevation in total bilirubin; reversible in two weeks). The most common (≥30%) treatment-emergent AEs (TEAE) were Fatigue, Diarrhea, Nausea, Vomiting. Six immune-related TEAEs (Abdominal pain lower, Arthralgia, Hepatic function abnormal, Hyperthyroidism, Nausea and Transaminitis) were observed in 3 pts. One pt with NSCLC from 3 mg/kg cohort had confirmed completed response. Two pts (TNBC and nivolumab refractory RCC) from 1 mg/kg cohort had shown long-term stable disease ( > 12 weeks). Faster clearance of KN046 was observed at lower dose might be due to target-mediated clearance. T1/2 is approximately 7~9 days at doses of 3 mg/kg and above when saturation occurs. Conclusions: Single agent KN046 has an acceptable safety profile and is in line with previously reported safety data from other immune checkpoint inhibitors. Preliminary efficacy results are promising. PK data from initial 4 cohorts support Q2W schedule. The study is currently ongoing at dose level of 5 mg/kg Q2W. Clinical trial information: NCT03529526.

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80P Blood tumor mutational burden (bTMB) and efficacy of immune checkpoint inhibitors (ICIs) in advanced solid tumors: SCRUM-Japan MONSTAR-SCREEN

Annals of Oncology ◽

10.1016/j.annonc.2021.08.360 ◽

2021 ◽

Vol 32 ◽

pp. S390-S391

Author(s):

M. Saori ◽

Y. Nakamura ◽

K. Sawada ◽

S. Horasawa ◽

S. Kadowaki ◽

...

Keyword(s):

Solid Tumors ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Advanced Solid Tumors ◽

Mutational Burden ◽

Tumor Mutational Burden

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Clinical outcomes of patients with stage IV cancer receiving immune checkpoint inhibitors in the inpatient setting.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.6634 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 6634-6634

Author(s):

Sienna Durbin ◽

Leyre Zubiri ◽

Andrzej Niemierko ◽

Laura A Petrillo ◽

Aditya Bardia ◽

...

Keyword(s):

Solid Tumors ◽

Immune Checkpoint ◽

Readmission Rate ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Stage Iv ◽

Tumor Type ◽

Single Institution ◽

Post Discharge ◽

Tumor Types

6634 Background: Immune checkpoint inhibitors (ICI) represent a major leap in the treatment of many cancers. Use has rapidly expanded in recent years, yet it is unknown whether hospitalized patients, who are often sicker than those who were studied in clinical trials, derive benefit from ICI. The primary objectives of this study were to characterize the clinical features and outcomes of inpatients receiving ICI at a single institution, and to identify predictors of survival. Methods: After IRB approval, we conducted a retrospective chart review of inpatients with Stage IV solid tumors receiving ICI between 2015 – 2018 at a tertiary care referral hospital. Patients receiving ICI on clinical trial were excluded. We examined the clinical characteristics, readmission rate, and post-discharge survival. We then conducted a Cox multivariable regression analysis to identify predictors of post-discharge survival. Results: A total of 103 patients with Stage IV solid tumors were treated with ICI as inpatients between 2015 – 2018. Average age was 57 years (range = 26 to 85); 57% were male; 27% had ECOG performance status (PS) 3-4; average Charlson Comorbidity Index score was 8.3. Most common tumor types were melanoma (35%) and lung (22%). Seventy-six percent began ICI as an inpatient and 24% received ICI as continuation of outpatient therapy. Seventeen percent experienced an immunotherapy related adverse event, most commonly colitis and pneumonitis. The 30 day readmission rate was 41%. The median post-discharge survival was 31 days; 47% of patients died during admission or within 30 days of discharge; 14% survived more than 6 months. Factors predictive of shorter post-discharge survival were PS of 3-4 relative to PS 0-2 (HR 2.0, p < 0.004), and lung cancer (HR 2.0, p < 0.024) and other tumor types (HR 2.1, p < 0.004) relative to melanoma. Conclusions: While the majority of inpatients receiving ICI died during admission or within 30 days of discharge, a subset of patients with stage IV disease were alive at 6 months. Tumor type and ECOG PS predict post-discharge survival and may be used to identify inpatients more likely to benefit from ICI. These novel findings, which are unique to a single institution, require additional validation.

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