The quality of reporting general safety parameters and immune-related adverse events in clinical trials of FDA-approved immune checkpoint inhibitors

Abstract

Background While immune-checkpoint inhibitors (ICIs) have transformed the field of oncology for advanced-stage cancers, they can lead to serious immune toxicities. Several systematic reviews have evaluated the risk of immune-related adverse events (irAEs); however, most have focused on published articles without evaluating trial registries. The objective of this methodological review was to compare the quality of reporting of safety information and in particular, serious irAEs (irSAEs), in both publications and ClinicalTrials.gov for all current FDA-approved ICIs. Methods PubMed was searched to retrieve all published phase III randomized controlled trials (RCTs) evaluating ICIs. For each eligible trial, we searched for corresponding registration on ClinicalTrials.gov and extracted relevant safety data from both the publication and results posted on registry. We then compared the quality of reporting and the value of safety data between both sources. Results Of 42 eligible published trials, 34 had results posted on ClinicalTrials.gov. Considerable variability was noted in the reporting of safety in both sources. SAEs were reported for all trial results in ClinicalTrials.gov compared to 23.5% of publications. An overall incidence for irAEs and irSAEs was reported in 58.8 and 8.8% of publications respectively, compared to 11.8 and 5.9% in registry results. Comparing the value of specific irSAEs was not possible between the two sources in 32/34 trials either due to different reporting formats (61.8%) or data not being reported in one or both sources (32.4%). From the 2 studies with compatible irSAE format, only 1 had matching data in both sources. Conclusions The reporting of irAEs / irSAEs varies considerably in publications and registries, which outlines the importance of standardizing the terminologies and methodologies for reporting safety information relevant to ICIs.

Molecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer

“…Of the 44 patients in the trial treated with eribulin and pembrolizumab, 21 (48%) had irAEs, including 2 patients who experienced both immune-related colitis and grade 5 sepsis 6 . Compared to other trials of ICIs with chemotherapy in metastatic breast cancer, this irAE frequency was similar to ENHANCE-1 (pembrolizumab with eribulin; 43%) 38 and IMpassion130 (atezolizumab with nab-paclitaxel; 57%) 8 but higher than KELLY (pembrolizumab with eribulin; 25%) 39 and KEYNOTE-355 (pembrolizumab with nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin; 26%) 40 , indicating wide heterogeneity that may be attributable to the lack of a standardized definition for irAEs 41 , 42 . In the present trial, patients with vs. without irAEs had no difference in PFS or OS (HR for progression 0.8, 95% CI 0.5–1.4, p = 0.5; HR for death 0.8, 95% CI 0.4–1.4, p = 0.4; Supplementary Data File 1 : Supplementary Table 8 ), which differs from previous studies showing that irAEs correlate with improved ICI responses 43 , 44 , likely because our analysis addressed the possibility of guarantee-time bias 45 .…”

Immune checkpoint inhibitors, endocrine adverse events, and outcomes of melanoma

“…For instance, the classification of thyroid disorders is heterogeneous and has been reported as decreased or increased TSH, or as hypothyroidism, thyrotoxicosis, and thyroiditis. Sometimes studies even report both the abnormal hormonal findings as well as the diagnosed conditions as separate AEs in one patient ( 27 ). In contrast, we classified all thyroid laboratory abnormalities as thyroid endocrine AEs.…”

Supporting study registration to reduce research waste

“…38 ), outcome measures (e.g. 39 ), and result reporting 40,41 . This outcome measure and result reporting bias is often (but not always, e.g.…”