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All issues raised by the reviewers are now resolved. The manuscript is ready for publication.
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meets standards
meets standards
meets standards
Authors addressed all concerns, I think article can publish without further revision.
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Thank you for addressing all my comments. No further comments.
Please address all of the reviewers' issues and comment thoroughly on the third reviewer's assertion that this meta-analysis is necessary.
The manuscript was clearly written and understandable. Few corrections needed as below:
Throughout: inconsistency with TARE and TRAE both being used. Please fix.
Line 73 : add And- “these agents, AND assess the “
Line 65 : Two “ in China “ in a single sentence
Line 60 : “was the firstly approved” to either first drug approved or was first approved
Line 145/146: “Finally, 22 eligible studies (20 trials) involving 1,002 patients for quantitative analysis.” Sentence incomplete.
Line 167: Authors
Zhao et al present a systematic review and Meta analysis, where they are looking at EZH2 inhibitors being used in clinic and show how safe these inhibitors truly are by comparing the incidences of TRAEs across different published studies. They have thoroughly reviewed all the published data and the manuscript is clear in presentation of the analyses.
No comments.
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The article by Zhao et al. is very well-written and interesting in the EZH2 and cancer biology field. Authors have used several clinical trails of EZH2 and identified EZH2 inhibitors in clinical use relatively safe with low TRAE. There are some minor comments to be addressed before acceptance.
1. Authors should expand the discussion section with more focus on comparison between different cancers (Solid cancers vs Hematological cancers), combination therapies and clearly state which cancers or combinations have less treatment-related adverse events and which EZH2 inhibitor authors think safest.
2. Also, authors should discuss about safety versus efficacy of different EZH2 inhibitors.
Basic reporting is to a high standard EXCEPT for the incorrect use of the abbreviation in the first few pages (TARE used instead of TRAE). Data shared in general although raw search data could also be shared.
The research question is well defined and the investigation is performed to an appropriate standard methodologically. The main issues are how relevant these data are, and how this research fills an identified knowledge gap.
The main issues I have with this manuscript:
1. It is not clear how meta-analysing this data is useful. ~2/3 of the weighting in the meta-analysis is irrespectively given to tazemetostat.
2. Inclusion of data for different doses is not relevant (particularly dose escalation cohorts at inactive doses). There is no easy way to necessarily parse this data, but sticking to toxicities observed at recommended phase 2 doses or from phase 2/3 studies is more useful than meta-analysis involving studies at potentially inactive doses. I would suggest some elucidation of the numbers of patients in dose-finding cohorts to mitigate the impact of this.
The data are robust however, it is unclear what the utility of the meta-analysis is. Additionally, the validity of combining toxicities of various drugs is only relevant for on-target toxicities.
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This manuscript performed meta-analysis of safety profile related to EZH2-targeted inhibitors. Overall, the paper is well-written and clearly explains the research question and its interpretation.
The following are some minor comments:
1. For AE related to combination therapies, were they specifically associated with the EZH2 inhibitor alone or with any component of the treatment combination (e.g., NCT04407741 trial involving immunotherapy). Please clarify.
2. In Figure 2, for the subgroup containing only one study, it is unclear why the two confidence intervals (CIs) are different. For example, the CI of GSK2816126 study is (0.77, 0.96) while the CI for subgroup is (0.81, 1.00). In addition, it was unusual that the upper confidence limit for proportion of incidence is above 1 (for example, in Figure S1, the upper limit for combination therapy with endocrine therapy is 1.14). Please explain.
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