Dataset Information

Trends in clinical development of pediatric cancer for PD-1 and PD-L1 inhibitors: an analysis of ClinicalTrials.gov.

ABSTRACT: Compared with cytotoxic chemotherapy, radiotherapy, and surgery, positive findings have been acquired through the approach of blocking the programmed cell death protein 1 (PD-1) pathway with antibodies that exert inhibitory effects on PD-1 or cell death protein ligand 1 (PD-L1). Results from clinical trials showed great potential in adult patients with cancers, such as melanoma, non-small cell carcinoma, and nasopharyngeal carcinoma. However, studies of checkpoint inhibitors specifically targeting PD-1/PD-L1 in pediatric patients are limited. We evaluated ongoing clinical trials using PD-1 or PD-L1 inhibitors alone or in combination with other therapies to treat pediatric cancer. The proportion of PD-1/PD-L1 combination clinical trials has increased since 2018; the three most common trials over the past 2 years used CTLA-4 monoclonal antibodies, chemotherapy, and therapies that target the vascular endothelial growth factor axis. This commentary aimed to provide trends and specific insights into methods for conducting clinical trials of immunotherapy in the pediatric population.

SUBMITTER: Que Y

PROVIDER: S-EPMC8479973 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Trends in clinical development of pediatric cancer for PD-1 and PD-L1 inhibitors: an analysis of ClinicalTrials.gov.

Que Yi Y Hu Yang Y Hong Dongchun D Zhang Yizhuo Y

Journal for immunotherapy of cancer 20210901 9

Compared with cytotoxic chemotherapy, radiotherapy, and surgery, positive findings have been acquired through the approach of blocking the programmed cell death protein 1 (PD-1) pathway with antibodies that exert inhibitory effects on PD-1 or cell death protein ligand 1 (PD-L1). Results from clinical trials showed great potential in adult patients with cancers, such as melanoma, non-small cell carcinoma, and nasopharyngeal carcinoma. However, studies of checkpoint inhibitors specifically targeti ...[more]

PMID: 34583971

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Project description:Anti-PD-1/PD-L1 immunotherapy could offer an alternative to traditional chemo- and/or radiotherapy to treat pediatric cancer patients. To unveil the potential benefit of this new therapeutic approach, the prevalence of PD-L1 and other relevant immune markers using quantitative digital image analysis (DIA) could help to clarify this point. A bridging study was first conducted using commercially available normal formalin-fixed paraffin-embedded (FFPE) tonsils to compare immunostaining patterns and intensities from PD-L1, tumor infiltrating lymphocyte (TIL) markers CD3, CD8, FoxP3, CD45RO, and macrophage marker CD68 in adult (n = 5) and pediatric (n = 10) samples. Then, commercially available pediatric FFPE tumor samples from five prevalent pediatric solid tumor indications: ganglioneuroblastoma (n = 7); neuroblastoma (n = 23); nephroblastoma (n = 30); osteosarcoma (n = 24); and rhabdomyosarcoma (n = 25) were immunostained and their images (n = 654) digitally analyzed using predefined algorithms. The qualitative analysis of staining patterns and intensities in all 15 tonsils for all 6 biomarkers was similar regardless of age category. Quantitative DIA showed that PD-L1 values varied across cancer-types, nephroblastoma having the lowest counts. PD-L1 counts in ganglioneuroblastoma, our pediatric indication with the highest average value, was approximately 12-times lower than in a similar nonsmall cell lung cancer study, an indication approved for anti-PD-1/PD-L1 immunotherapies. Variable values were measured for the TIL markers CD3, CD8, and CD45RO. FoxP3 was scant across all indications. The macrophage marker CD68 showed highest values in ganglioneuroblastoma, with lowest levels in nephroblastoma. In conclusion, the low PD-L1 levels uncorrelated with TIL values from the present biomarker morphological study suggest that a PD-L1 immunohistochemistry patient selection strategy used for anti-PD-1/PD-L1 monotherapy in adult tumors may not succeed in these pediatric indications.

Project description:Whereas time trends in the epidemiologic burden of US pediatric mental health disorders are well described, little is known about trends in how these disorders are studied through clinical research. We identified how funding source, disorders studied, treatments studied, and trial design changed over the past decade in US pediatric mental health clinical trials. We identified all US pediatric interventional mental health trials submitted to ClinicalTrials.gov between October 1, 2007 and April 30, 2018 (n = 1,019) and manually characterized disorders and treatments studied. We assessed trial growth and design characteristics by funding source, treatments, and disorders. US pediatric mental health trials grew over the past decade (compound annual growth rate [CAGR] 4.1%). The number of studies funded by industry and US government remained unchanged, whereas studies funded by other sources (e.g., academic medical centers) grew (CAGR 11.3%). Neurodevelopmental disorders comprised the largest proportion of disorders studied, and Non-DSM-5 (Diagnostic and Statistical Manual-5) conditions was the only disorder category to grow (14.5% to 24.6%; first half to second half of decade). There was significant growth of trials studying non-psycho/pharmacotherapy treatments (33.8% to 49.0%) and a decline in trials studying pharmacotherapies (31.7% to 20.6%), though these trends differed by funding source. There were also notable differences in funding sources and treatments studied within each disorder category. Trials using double blinding declined (26.2% to 18.0%). Limitations include that ClinicalTrials.gov is not an exhaustive list of US clinical trials, and trends identified may in part reflect changes in trial registration rather than changes in clinical research. Nevertheless, ClinicalTrials.gov is among the largest databases available for evaluating trends and patterns in pediatric mental health research that might otherwise remain unassessable. Understanding these trends can guide researchers and funding bodies when considering the trajectory of the field.

Project description:OBJECTIVE:To evaluate the relative efficacy of programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors versus conventional drugs in patients with cancer that were PD-L1 positive and PD-L1 negative. DESIGN:Meta-analysis of randomised controlled trials. DATA SOURCES:PubMed, Embase, Cochrane database, and conference abstracts presented at the American Society of Clinical Oncology and European Society of Medical Oncology up to March 2018. REVIEW METHODS:Studies of PD-1 or PD-L1 inhibitors (avelumab, atezolizumab, durvalumab, nivolumab, and pembrolizumab) that had available hazard ratios for death based on PD-L1 positivity or negativity were included. The threshold for PD-L1 positivity or negativity was that PD-L1 stained cell accounted for 1% of tumour cells, or tumour and immune cells, assayed by immunohistochemistry staining methods. RESULTS:4174 patients with advanced or metastatic cancers from eight randomised controlled trials were included in this study. Compared with conventional agents, PD-1 or PD-L1 inhibitors were associated with significantly prolonged overall survival in both patients that were PD-L1 positive (n=2254, hazard ratio 0.66, 95% confidence interval 0.59 to 0.74) and PD-L1 negative (1920, 0.80, 0.71 to 0.90). However, the efficacies of PD-1 or PD-L1 blockade treatment in patients that were PD-L1 positive and PD-L1 negative were significantly different (P=0.02 for interaction). Additionally, in both patients that were PD-L1 positive and PD-L1 negative, the long term clinical benefits from PD-1 or PD-L1 blockade were observed consistently across interventional agent, cancer histotype, method of randomisation stratification, type of immunohistochemical scoring system, drug target, type of control group, and median follow-up time. CONCLUSIONS:PD-1 or PD-L1 blockade therapy is a preferable treatment option over conventional therapy for both patients that are PD-L1 positive and PD-L1 negative. This finding suggests that PD-L1 expression status alone is insufficient in determining which patients should be offered PD-1 or PD-L1 blockade therapy.

Project description:BackgroundImmunotherapy for colorectal cancer has developed rapidly in the past decade. Many high-quality clinical trials examining the application of PD-1/PD-L1 inhibitors in patients with metastatic colorectal cancer (mCRC) have been conducted in recent years. However, the clinical benefits, including the efficacy and safety of these treatments against mCRC, remain controversial. Hence, we conducted this meta-analysis on the clinical benefits of PD-1/PD-L1 inhibitors in patients with mCRC.MethodsWe searched online databases including MEDLINE, Embase, Cochrane Library, and Web of Science, from inception to January 4, 2021. The outcomes related to efficacy and safety were extracted and analyzed. Subgroup analyses were conducted according to the categories of dMMR-MSI-H (tumors with mismatch repair deficiency and high levels of microsatellite instability) ≥ 5% vs. dMMR-MSI-H < 5%, monotherapy vs. combination therapy, PD-1 inhibitors vs. PD-L1 inhibitors, and nivolumab vs. pembrolizumab.ResultsFourteen studies including 1129 subjects were included in our systematic review. The overall complete response (CR), partial response (PR), stable disease (SD), and progression of disease (PD) rates were 0.01 (95% CI 0.00-0.04), 0.04 (95% CI 0.05-0.26), 0.27 (95% CI 0.22-0.32), and 0.44 (95% CI 0.30-0.58), respectively. The overall objective response rate (ORR) and disease control rate (DCR) were 0.16 (95%CI 0.06-0.31) and 0.50 (95%CI 0.35-0.65), respectively. The overall rate of adverse events (AEs) and severe adverse responses (SAEs) were 0.84 (95% CI 0.72-0.92) and 0.30 (95% CI 0.20-0.41), respectively. The ORRs of the dMMR-MSI-H ≥ 5% and dMMR-MSI-H < 5% subgroups were 0.40 (95% CI 0.30-0.51) and 0.04 (95% CI 0.00-0.09), respectively.ConclusionsPD-1/PD-L1 inhibitors produced encouraging clinical benefits including the response rate in the treatment of dMMR-MSI-H mCRC. They actually have been influenced by the present state of mCRC therapy including pMMR-MSI-L mCRC. Nevertheless, additional multi-center prospective studies are still expected.Trial registrationWe have registered this study in the International Prospective Register of Systematic Reviews (PROSPERO), and the registration number is CRD42021249601 .

Dataset Information

Trends in clinical development of pediatric cancer for PD-1 and PD-L1 inhibitors: an analysis of ClinicalTrials.gov.

Publications

Trends in clinical development of pediatric cancer for PD-1 and PD-L1 inhibitors: an analysis of ClinicalTrials.gov.

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