Title: Efficacy and Safety of PD-1 and PD-L1 Inhibitors in Advanced Colorectal Cancer: A
Meta-Analysis of Randomized Controlled Trials
Version: 2 Date: 07 Oct 2024
Reviewer's report:
In this systematic review and meta analysis by Wang et al., the efficacy and safety of PD-1/
PD-L1 inhibitors in advanced colorectal cancer is examined. The subject is highly relevant
and is of importance as the paradigm in treated advanced colorectal cancer is slowly changing,
especially in dMMR or MSI-H colorectal cancer.  Furthermore, the manuscript is well-written.
There are some grammatical error here and there and it should be thoroughly checked.  I have
some questions and suggestions for improvement of the manuscript.
1. Use the abbreviation CRC consistently. You introduce the abbreviation but rarely use it in-
text.
2. Was the protocol submitted to PROSPERO prior to conducting the study?
3. Who were the two independent reviewers doing the reviews of articles?
4. Who was the third reviewer in cases of discrepancy between the first two reviewers?
5. Why was standard deviation extracted for analysis? Werea HR values not available??
6. Please define the outcomes of interest and elaborate on where you have the definition from
e.g., NCI.
7. This reviewer is interesting it whether the patients included in the meta-analysis from trials on
PD-L1 inhibitors included other add-on treatment regimens (e.g., consequently radiotherapy or
chemotherapy) or combinations with other ICIs or other factors that could also explain a higher
rate of > 3 grade AEs in this group.
8. Please make it clear during the beginning of the results section how many of the included
studies involved patients with pMMR and dMMR CRC.
9. Including a GRADE approach of the cumulative evidence could further strengthen the results
of this meta analysis.
10. I miss the references to the results of the NICHE trials.
11. Including some sentences about some major obstacles in establishing which patients may
benefit from PD-1/PD-L1 inhibitors in CRC could improve the manuscript. For instance
discussing the composition of the tumor microenvironment, presence of neoantigens, dMMR
vs. pMMR CRC as well as the density and subtypes of TILs.  You already discuss the potential
mechanism for why PD-1 may be better than PD-L1 referring to T cells, but we all know that the
tumor microenvironment and MMR proteins play a major role in response to ICIs and patients
selection for ICI treatment.
12. Can you specify if any of the included trials included patients receiving other treatment
modalities than immunotherapy.
13. Please discuss the role of timing of immunotherapy. Should we be giving it in a neoadjuvant,
metastatic setting or adjuvantly for instance?  You could easily refer to the work from Chalabi.
14. The number of studies included in the analyses conducted is also a limitation.
15. Future perspectives also involve the applicability of immunotherapy as early as possible to
limit disease progression but also to enhance organ preserving treatments in the future. If you
follow the abovementioned considerations/suggestions you can also add some sentences about
the future perspectives regarding organ preservation.
Title: Efficacy and Safety of PD-1 and PD-L1 Inhibitors in Advanced Colorectal Cancer: A
Meta-Analysis of Randomized Controlled Trials
Version: 2 Date: 07 Oct 2024
Reviewer's report:
In this systematic review and meta analysis by Wang et al., the efficacy and safety of PD-1/
PD-L1 inhibitors in advanced colorectal cancer is examined. The subject is highly relevant
and is of importance as the paradigm in treated advanced colorectal cancer is slowly changing,
especially in dMMR or MSI-H colorectal cancer.  Furthermore, the manuscript is well-written.
There are some grammatical error here and there and it should be thoroughly checked.  I have
some questions and suggestions for improvement of the manuscript.
1. Use the abbreviation CRC consistently. You introduce the abbreviation but rarely use it in-
text.
2. Was the protocol submitted to PROSPERO prior to conducting the study?
3. Who were the two independent reviewers doing the reviews of articles?
4. Who was the third reviewer in cases of discrepancy between the first two reviewers?
5. Why was standard deviation extracted for analysis? Werea HR values not available??
6. Please define the outcomes of interest and elaborate on where you have the definition from
e.g., NCI.
7. This reviewer is interesting it whether the patients included in the meta-analysis from trials on
PD-L1 inhibitors included other add-on treatment regimens (e.g., consequently radiotherapy or
chemotherapy) or combinations with other ICIs or other factors that could also explain a higher
rate of > 3 grade AEs in this group.
8. Please make it clear during the beginning of the results section how many of the included
studies involved patients with pMMR and dMMR CRC.
9. Including a GRADE approach of the cumulative evidence could further strengthen the results
of this meta analysis.
10. I miss the references to the results of the NICHE trials.
11. Including some sentences about some major obstacles in establishing which patients may
benefit from PD-1/PD-L1 inhibitors in CRC could improve the manuscript. For instance
discussing the composition of the tumor microenvironment, presence of neoantigens, dMMR
vs. pMMR CRC as well as the density and subtypes of TILs.  You already discuss the potential
mechanism for why PD-1 may be better than PD-L1 referring to T cells, but we all know that the
tumor microenvironment and MMR proteins play a major role in response to ICIs and patients
selection for ICI treatment.
12. Can you specify if any of the included trials included patients receiving other treatment
modalities than immunotherapy.
13. Please discuss the role of timing of immunotherapy. Should we be giving it in a neoadjuvant,
metastatic setting or adjuvantly for instance?  You could easily refer to the work from Chalabi.
14. The number of studies included in the analyses conducted is also a limitation.
15. Future perspectives also involve the applicability of immunotherapy as early as possible to
limit disease progression but also to enhance organ preserving treatments in the future. If you
follow the abovementioned considerations/suggestions you can also add some sentences about
the future perspectives regarding organ preservation.
Please review this paper.
user
Title: Efficacy and Safety of PD-1 and PD-L1 Inhibitors in Advanced Colorectal Cancer: A
Meta-Analysis of Randomized Controlled Trials
Version: 2 Date: 07 Oct 2024
Reviewer's report:
In this systematic review and meta analysis by Wang et al., the efficacy and safety of PD-1/
PD-L1 inhibitors in advanced colorectal cancer is examined. The subject is highly relevant
and is of importance as the paradigm in treated advanced colorectal cancer is slowly changing,
especially in dMMR or MSI-H colorectal cancer.  Furthermore, the manuscript is well-written.
There are some grammatical error here and there and it should be thoroughly checked.  I have
some questions and suggestions for improvement of the manuscript.
1. Use the abbreviation CRC consistently. You introduce the abbreviation but rarely use it in-
text.
2. Was the protocol submitted to PROSPERO prior to conducting the study?
3. Who were the two independent reviewers doing the reviews of articles?
4. Who was the third reviewer in cases of discrepancy between the first two reviewers?
5. Why was standard deviation extracted for analysis? Werea HR values not available??
6. Please define the outcomes of interest and elaborate on where you have the definition from
e.g., NCI.
7. This reviewer is interesting it whether the patients included in the meta-analysis from trials on
PD-L1 inhibitors included other add-on treatment regimens (e.g., consequently radiotherapy or
chemotherapy) or combinations with other ICIs or other factors that could also explain a higher
rate of > 3 grade AEs in this group.
8. Please make it clear during the beginning of the results section how many of the included
studies involved patients with pMMR and dMMR CRC.
9. Including a GRADE approach of the cumulative evidence could further strengthen the results
of this meta analysis.
10. I miss the references to the results of the NICHE trials.
11. Including some sentences about some major obstacles in establishing which patients may
benefit from PD-1/PD-L1 inhibitors in CRC could improve the manuscript. For instance
discussing the composition of the tumor microenvironment, presence of neoantigens, dMMR
vs. pMMR CRC as well as the density and subtypes of TILs.  You already discuss the potential
mechanism for why PD-1 may be better than PD-L1 referring to T cells, but we all know that the
tumor microenvironment and MMR proteins play a major role in response to ICIs and patients
selection for ICI treatment.
12. Can you specify if any of the included trials included patients receiving other treatment
modalities than immunotherapy.
13. Please discuss the role of timing of immunotherapy. Should we be giving it in a neoadjuvant,
metastatic setting or adjuvantly for instance?  You could easily refer to the work from Chalabi.
14. The number of studies included in the analyses conducted is also a limitation.
15. Future perspectives also involve the applicability of immunotherapy as early as possible to
limit disease progression but also to enhance organ preserving treatments in the future. If you
follow the abovementioned considerations/suggestions you can also add some sentences about
the future perspectives regarding organ preservation.
assistant