BackgroundQuantification of circulating tumor DNA (ctDNA) levels is a reliable prognostic tool in several malignancies. Dynamic changes in ctDNA levels in response to treatment may also provide prognostic information. Here, we explore the value of changes in ctDNA levels in response to immune checkpoint inhibitors (ICIs).MethodsWe searched MEDLINE (host: PubMed) for trials of ICIs in advanced solid tumors in which outcomes were reported based on change in ctDNA levels. ctDNA reduction was defined as reported in individual trials. Typically, this was either >50% reduction or a reduction to undetectable levels. We extracted HRs and related 95% CIs and/or p values comparing ctDNA reduction versus no reduction for progression-free survival (PFS) and/or overall survival (OS). Data were then pooled in a meta-analysis. Variation in effect size was examined using subgroup analyses.ResultsEighteen trials were included in the meta-analysis. ctDNA levels were detectable in all participants in all studies prior to initiation of ICIs. A reduction in ctDNA measured 6–16 weeks after starting treatment was associated with significantly better PFS (HR 0.20; 95% CI, 0.14 to 0.28; p<0.001). Similarly, OS was superior in patients with reduced ctDNA levels (HR 0.18; 95% CI, 0.12 to 0.26; p<0.001). The results were consistent across all disease sites, lines of treatment, magnitude of change (to undetectable vs >50% reduction) and whether treatment exposure comprised single or combination ICIs.ConclusionsIn advanced solid tumors, a reduction in ctDNA levels in response to ICIs is associated with substantial improvements in outcome. ctDNA change is an early response biomarker which may allow for de-escalation of cross-sectional imaging in patients receiving ICIs or support treatment de-escalation strategies.
Background: Multiple anti-PD-1/PD-L1 antibodies have been approved, and in some diseases, there is a choice of more than one. Comparative efficacy, safety and tolerability are unknown. Methods: Randomized trials (RCTs) supporting the registration of single agent anti-PD1 or anti-PDL1 inhibitors between 2015-2019 were identified. We extracted the hazard ratio (HR) for overall survival (OS) and calculated the odds ratio (OR) for commonly reported safety and tolerability outcomes. We then performed a network meta-analysis, reporting multiple pair-wise comparisons between different anti-PD-1/PD-L1 antibodies. Results: Sixteen RCTs comprising 10673 patients were included; 10 in non-small-cell lung cancer, 2 in melanoma, 2 in head and neck squamous cell carcinoma and 2 in urothelial cancer. Compared to pembrolizumab, efficacy was similar for nivolumab (HR: 1.02 95% CI: 0.91-1.14) and for atezolizumab (HR: 0.97 95% CI: 0.85-1.10), however, avelumab appeared inferior (HR: 1.30, 95% CI: 1.06-1.56). Pembrolizumab showed similar odds of serious adverse events (SAEs) as nivolumab (OR: 1.12, 95% CI: 0.56-2.27) and atezolizumab (OR: 1.05, 95%
Disease-free survival (DFS) comprises both breast cancer and non-breast cancer events. DFS has not been validated as a surrogate endpoint for overall survival (OS) in most breast cancer subtypes. We assessed changes to the type of events contributing to DFS over time. We identified adjuvant studies in breast cancer (BC) from 2000 to 2020 where the endpoint was DFS. We examined change in distant DFS events and the BC-related DFS using univariable and multivariable linear regression. Data were reported quantitatively using the Burnand criteria irrespective of statistical significance. We included 84 studies (88 cohorts), comprising 212,191 participants, 41,604 DFS events and 23,205 distant DFS events. The DFS event rate/100 participants/year has declined modestly over time (ß − 0.34, p = 0.001). Start year was negatively associated with distant DFS events (ß − 0.58, p < 0.0001); however, the effect was lost after adjusting for follow-up time (ß − 0.18, p = 0.096). The average number of BC-related events/100 participants/year also declined over time (ß − 0.28, p = 0.009). In multivariable analysis, start year and ER expression were quantitatively associated with distant DFS events and BC-related DFS events. DFS events have declined over time driven by a reduction in BC related events. As DFS events are increasingly defined by non-BC events, there will be limited surrogacy between DFS and OS.
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