The efficacy and safety of anti-PD-1/PD-L1 antibodies for treatment of advanced or refractory cancers: A meta-analysis.

Zhang, Tengfei; Fan, Ruitai; Shi, Ning; Ma, Wei

doi:10.1200/jco.2017.35.15_suppl.e23075

Cited by 19 publications

(29 citation statements)

References 26 publications

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“…28 The incidence of TRAEs associated with ICIs ranged from 9% to 31%, with a pooled rate of 16% (95% confidence interval, 12%-21%). 30 Treatment with ICIs was associated with a higher incidence of any-grade and grade 3 to 4 irAEs (ie, rash, aspartate aminotransferase increase, hypothyroidism, colitis, and pneumonitis) compared with non-ICI regimens. 31 The incidence of IRRs and hypersensitivity reactions occurring with avelumab and other ICIs was similar to or less than the incidence reported with other systemic and targeted treatments, including commonly used taxane-based chemotherapy.…”

Section: Discussionmentioning

confidence: 94%

“…Meta-analyses of the safety and tolerability of anti-PD-L1/PD-1 agents corroborate findings of improved safety profiles of ICIs compared with chemotherapy regimens used to treat patients with advanced cancers. [28][29][30][31] In a meta-analysis of 3450 patients from 7 randomized controlled trials, treatment with ICIs was associated with a lower incidence of any-grade AEs compared with chemotherapy (67.6% vs 82.9%) and grade 3 to 4 AEs (11.4% vs 35.7%), and treatment discontinuation occurred less frequently with anti-PD-L1/PD-1 agents compared with chemotherapy (4.5% vs 11.1%). 28 The incidence of TRAEs associated with ICIs ranged from 9% to 31%, with a pooled rate of 16% (95% confidence interval, 12%-21%).…”

Section: Discussionmentioning

confidence: 99%

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Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials

Kelly

Infante

Taylor

et al. 2018

Cancer

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BACKGROUNDAntibodies targeting the programmed death‐ligand 1 (PD‐L1)/programmed cell death protein 1 (PD‐1) checkpoint may cause adverse events (AEs) that are linked to the mechanism of action of this therapeutic class and unique from those observed with conventional chemotherapy.METHODSPatients with advanced solid tumors who were enrolled in the phase 1 JAVELIN Solid Tumor (1650 patients) and phase 2 JAVELIN Merkel 200 (88 patients) trials received avelumab, a human anti–PD‐L1 IgG1 antibody at a dose of 10 mg/kg every 2 weeks. Treatment‐related AEs (TRAEs) were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). In post hoc analyses, immune‐related AEs (irAEs) were identified via an expanded AE list and medical review, and infusion‐related reactions (IRRs) occurring ≤2 days after infusion and symptoms occurring ≤1 day after infusion and resolving ≤2 days after onset were identified based on prespecified Medical Dictionary for Regulatory Activities (MedDRA) terms.RESULTSOf the 1738 patients analyzed, grade ≥3 TRAEs occurred in 177 (10.2%); the most common were fatigue (17 patients; 1.0%) and IRR (10 patients; 0.6%). TRAEs led to discontinuation in 107 patients (6.2%) and death in 4 patients (0.2%). Grade ≥3 irAEs occurred in 39 patients (2.2%) and led to discontinuation in 34 patients (2.0%). IRRs or related symptoms occurred in 439 patients (25.3%; grade 3 in 0.5% [9 patients] and grade 4 in 0.2% [3 patients]). An IRR occurred at the time of first infusion in 79.5% of 439 patients who had an IRR, within the first 4 doses in 98.6% of 439 patients who had an IRR, and led to discontinuation in 35 patients (2.0%).CONCLUSIONSAvelumab generally was found to be well tolerated and to have a manageable safety profile. A minority of patients experienced grade ≥3 TRAEs or irAEs, and discontinuation was uncommon. IRRs occurred mainly at the time of first infusion, and repeated events were infrequent. Cancer 2018;124:2010‐7. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials

Kelly

Infante

Taylor

et al. 2018

Cancer

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“…[30][31][32][33][34][35][36][37][38] Some concluded that combination immunotherapy could result in better antitumor efficacy, but were based on only one or two studies. 31,38 One network meta-analysis compared ICIs with targeted therapies for metastatic melanoma, suggesting that a combination of BRAF and MEK inhibitors was superior to anti-CTLA-4 agents and anti-PD-1 agents. As far as we know, no other meta-analysis assessed the added benefits against the toxicity of each drug in the combination.…”

Section: Agreement/disagreement With Previous Meta-analysesmentioning

confidence: 99%

The clinical value of combination of immune checkpoint inhibitors in cancer patients: A meta‐analysis of efficacy and safety

Shi

Jiang

et al. 2017

Intl Journal of Cancer

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The use of immune checkpoint inhibitors (ICIs) in combination therapy is an emerging trend in tumor immunology. However, the value of combination immunotherapy remains controversial, because of the toxic effects induced by combination. The added benefit of each additional drug has not been assessed against the added toxicity. We searched for clinical trials that evaluated ICI monotherapies and combination therapies in lung cancer and melanoma patients. The overall response rate (ORR), grade 3/4 treatment-related adverse event rate, overall survival (OS), and progression-free survival (PFS) were extracted from the most recently published studies to determine the relative risk (RR), hazard ratios (HRs), and 95% confidence intervals (CIs). Seven randomized controlled trials and one open-label study were identified (n = 3,097). Treatments included combinations of several ICIs, a combination of an ICI and dacarbazine, two combinations of an ICI, paclitaxel and carboplatin, and a combination of an ICI and gp100 vaccine. Higher ORR (RR: 1.51, 95% CI: 1.03-2.20, p = 0.034), OS (HR: 0.86, 95% CI: 0.78-0.95, p = 0.000), and PFS (HR: 0.93, 95% CI: 0.72-1.14, p = 0.000) values were observed in combination therapy than in monotherapy. In addition, the toxicity of combination ICI immunotherapy was higher (RR: 1.50, 95% CI: 1.03-2.19, p = 0.036) than that of monotherapy. This meta-analysis showed that the addition of nivolumab to ipilimumab better benefits PFS and ORR. Adding sargramostim was associated with better OS and safety. The efficacy and safety of a nivolumab-ipilimumab-sargramostim combination should be investigated further.

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“…We built upon the ordinary differential equation model explored in the original sycnhrionized lysis circuit system (19). The following set of ordinary differential equations were derived to describe the bacterial population number (N, equation [1]), total extracellular AHL (H, equation [2]), intracellular concentrations of the lysis protein E (L, equation [3]), intracellular concentrations of the LuxI protein (I, equation [4]), and intracellular concentrations of the PD-L1 Nb protein (P, equation [5]). In this system, bacteria grow logistically at a rate of µ N to a maximum capacity, N 0 and lyse once at quorum.…”

Section: Mathematical Modelmentioning

confidence: 99%

“…These inhibitory checkpoint blockade mechanisms have prompted the exploration of blocking monoclonal antibodies (mAbs) as therapeutics against these molecules. While anti-PD-L1 mAbs have achieved some level of tumor regression in ~30% of cancers like melanoma (4,5), they can also result in immune-related adverse effects (iRAEs), with up to 70% of patients experiencing a range of toxicity grades resulting in fatigue, skin rashes, endocrine disorders, or hepatic toxicities (6)(7)(8)(9). Furthermore, combination therapies of anti-PD-L1/PD-1 mAbs and anti-cytotoxic T-lymphocyte associated protein-4 (CTLA-4) mAbs are more efficacious than monotherapies, but cause higher grade toxicities that lead to favoring of less efficacious monotherapies or eventual drug discontinuation (10,11).…”

Section: Introductionmentioning

confidence: 99%

Engineered probiotics for local tumor delivery of checkpoint blockade nanobodies

Gurbatri

Coker

Hinchliffe

et al. 2019

Preprint

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Immunotherapies such as checkpoint inhibitors have revolutionized cancer therapy yet lead to a multitude of immune-related adverse events, suggesting the need for more targeted delivery systems. Due to their preferential colonization of tumors and advances in engineering capabilities from synthetic biology, microbes are a natural platform for the local delivery of cancer therapeutics. Here, we present an engineered probiotic bacteria system for the controlled production and release of novel immune checkpoint targeting nanobodies from within tumors. Specifically, we engineered genetic lysis circuit variants to effectively release nanobodies and safely control bacteria populations. To maximize therapeutic efficacy of the system, we used computational modeling coupled with experimental validation of circuit dynamics and found that lower copy number variants provide optimal nanobody release. Thus, we subsequently integrated the lysis circuit operon into the genome of a probiotic E. coli Nissle 1917, and confirmed lysis dynamics in a syngeneic mouse model using in vivo bioluminescent imaging. Expressing a nanobody against PD-L1 in this strain demonstrated enhanced efficacy compared to a plasmid-based lysing variant, and similar efficacy to a clinically relevant monoclonal antibody against PD-L1. Expanding upon this therapeutic platform, we produced a nanobody against cytotoxic T-lymphocyte associated protein -4 (CTLA-4), which reduced growth rate or completely cleared tumors when combined with a probiotically-expressed PD-L1 nanobody in multiple syngeneic mouse models. Together, these results demonstrate that our engineered probiotic system combines innovations in synthetic biology and immunotherapy to improve upon the delivery of checkpoint inhibitors. bacteria to grow within the hypoxic and necrotic tumor core (24)(25)(26)(27). At the same time, microbiome research efforts have revealed the widespread prevalence of microbes within malignant tissue that do not cause infections or other long-term detrimental health effects (28, 29). Since bacteria are both inherently present and selectively grow in tumors, they provide a natural platform for the development of programmable therapeutic delivery vehicles.Harnessing the converging advancements in both immunotherapy and synthetic biology, we engineered probiotic bacteria to locally and controllably release PD-L1 and CTLA-4 antagonists in the form of blocking nanobodies. Specifically, we coupled immunotherapeutic expression with an optimized lysing circuit mechanism, such that probiotic bacteria carrying the anti-PD-L1 nanobody homes to the necrotic tumor core, grow to a critical density, and lyse effectively releasing the anti-PD-L1 nanobody to block the PD-1/PD-L1 interaction between tumor and T cells (Fig. 1a). RESULTS Construction and characterization of a probiotically-expressed PD-L1 NbA single-domain antibody, or nanobody (Nb), blocking PD-L1 was chosen from the RCSB Protein Data Bank as therapeutic cargo. Unlike antibodies with a molecular size of approximately 150...

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The efficacy and safety of anti-PD-1/PD-L1 antibodies for treatment of advanced or refractory cancers: A meta-analysis.

Cited by 19 publications

References 26 publications

Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials

Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials

The clinical value of combination of immune checkpoint inhibitors in cancer patients: A meta‐analysis of efficacy and safety

Engineered probiotics for local tumor delivery of checkpoint blockade nanobodies

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