Current Evidence for Immune Checkpoint Inhibition in Advanced Hepatocellular Carcinoma

Round 1

Reviewer 1 Report

The review entitled “Current evidence for immune checkpoint inhibition in advanced hepatocellular carcinoma” by Foy et al. summarizes the current state of knowledge about global systemic therapy options for advanced hepatocellular carcinoma (aHCC). The work outlines recent insights regarding varying management strategies including single immune checkpoint inhibition (ICI), dual ICI, and ICI in combination with anti-angiogenic drugs. Finally, the authors give an evaluation of molecular biomarkers for the treatment of aHCC.

This work is of immense significance for the field of HCC research. It highlights the need for further investigation of biomarkers that would predict the outcome of individual treatment options and for further clinical studies testing immune therapies in combination with established therapies, and also local-regional therapies all based on adequate biomarkers.

The review is perfectly structured and well comprehensible. Adequate references/studies were selected. Only minor flaws were detected (see specific comments below). Besides that, table 1 needs to be revised since some values are not correct (refer to point 3 below).

Specific comments:

1.    Misspelling: p. 1, line 30: „Whist“; p. 7, line 278: “enrolment” should be “enrollment”

2.    Space errors: Please delete the following blanks: p. 3, line 97: “…tremelimumab. _Twenty patients…”; p. 11, line 388/9: “..prevalent. _ Several…”; p. 15, line 593: “…toxicity from ICI _(35,106). _ Further…”; p. 15, line 631/2: “…investigating _ ICI/VEGF…”; p. line 16, line 667: “…Astra Zeneca. _She has…”

3.    Please revise table 1 as follows:

- The studies summarized here should be given in a chronological order as mentioned in the main text. The current order is a bit unsettling.

- Please explain the abbreviations “ORR”, “CR”, “mPFS”, “mOS”, “CI”, “HR”, and “TRAE” in a footnote below the table.

- Please add the reference number after each year according to the reference list. This will help to identify the study for the reader, e.g. (“Yau et al., 2022; 38)

- Please correct the following values:

row 3: (14.0 - 18.5) instead of (4.0 - 18.5) (p. 5, line 148)

row 7: 27.3 (8) instead of 30 (8) (p. 7, line 267)

row 10 and 11: here, 581 patients are reported; however, in the main text, the authors speak of 595 patients (p. 7, line 287). Please double-check.

Row 13: 0.78 instead of 0.76 (p. 7, line 241)

row 31: (11.6 – 16.0) instead of (1.6 – 16.0) (p. 5, line 162)

row 34: 12.7 instead of 18 (p. 5, line 178)

row 35: 1.3 instead of 4 (p. 5, line 178)

- Is there a reason why the studies CheckMate 040 and KEYNOTE-224 (p. 3) were not added to table 1? If no, please add.

Overall, it is recommended to use values rounded to the same decimal place, e.g. 18.5, throughout the whole text in order to report identical values in the main text and in the tables in order to avoid confusion.

4.    Table 2 and 3: Also here, please add the reference number after each year according to the reference list and the explanation of abbreviations in a footnote below the table.

5.    Comment on Table 2: Why were these studies not described in detail in the main text? “…Varying rates of response and toxicity.” Is a bit too brief. Please expand this passage.

6.    Wrong line separation: p. 6, line 232: “mon-oclonal” should be “mono-clonal”

7.    Please remove the excessive figure caption in Figure 1 on page 16

8.    Please remove the excessive periods: p. 16, line 669: “… (UK and Ireland) Ltd..”; p. 17, line 682: “…Julien Edeline. has received…”

Author Response

Please see attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

This is a comprehesive review on HCC epidemiology and pharmaceutical therapy.It does however repeat "old" concepts about the possible mechanism(s) of action of the different drugs like TKIs and ICI.

I would suggest:

a) mention form the beginning the word cirrhosis as a "second" disease besids HCC

b) differentiate HCC in the wetsern world and in the asiatic regions as in CHINA diabetes type II and overweight are much less widspread.

c)it should be mentioned that the reduction of the viral etiology is also due to the elimination of visus-contaminated blood products and therefore excess of alocoholic beverages is the majr cause of cirrhosis and of HCC.

d) efficacy of TKI in HCC treatment was published before 2008 although the first approval was that of sorafenib

e)data on efficacy-mechanism(s) of both TKIs and ICI is based on in vitro data (especially for ICI).However the numberand the quality of side effect should allow to suppose an indirect mechanism such as reduction of systemic growth factor deprivation.There is no data showing binding of the administered antibodies to tumor cells or to other cells of the tumor microenviroment.This should be mentioned and further studies on antigen expression in tumor tissues should be now avoided as there is no correlation between expression of those antigens and clinical efficacy.We do not have any quality standards for pathology studies.

f) the fact that the liver has a "special" immunsystem is based on old statments to justify the fact that for kidney tranplantation not only AB0-compatibility but also HLA-compatibility are needed,while the second is not necessary in cases of liver transplantation.However HLA-non-compatible kidney-transplantation have been successfully performed.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

To the authors: The specific reviewer comments have been addressed accordingly. Overall, the manuscript has been optimized in a laudable way. Congratulations!

Specifically:

1.    Misspelling: p. 1, line 30: „Whist“; p. 7, line 278: “enrolment” should be “enrollment”

Corrected (now line p. 1, line 32 and p 7, line 263).

Reviewer response: Agreed.

2. Space errors: Please delete the following blanks: p. 3, line 97: “…tremelimumab. _Twenty patients…”; p. 11, line 388/9: “..prevalent. _ Several…”; p. 15, line 593: “…toxicity from ICI _(35,106). _ Further…”; p. 15, line 631/2: “…investigating _ ICI/VEGF…”; p. line 16, line 667: “…Astra Zeneca. _She has…”

Blanks deleted p.2, line 96 (tremelimumab. Twenty); p.11, line 375 (prevalent. Several); p.14 line 577 (toxicity from ICI [35,106]. Further); p.15, Line 613/614 (investigating ICI/VEGF); p.17 line 656 (Astra Zeneca. She has). 

Reviewer response: Agreed.

3. Please revise table 1 as follows:

- The studies summarized here should be given in a chronological order as mentioned in the main text. The current order is a bit unsettling.

Thank you, the table has been updated to reflect the order presented in the text.

Reviewer response: Agreed.

- Please explain the abbreviations “ORR”, “CR”, “mPFS”, “mOS”, “CI”, “HR”, and “TRAE” in a footnote below the table.

Thank you, abbreviations have been clarified in a footnote.

Reviewer response: Agreed.

- Please add the reference number after each year according to the reference list. This will help to identify the study for the reader, e.g. (“Yau et al., 2022; 38)

Thank you, reference number has been added.

Reviewer response: Agreed

- Please correct the following values:

row 3: (14.0 - 18.5) instead of (4.0 - 18.5) (p. 5, line 148)

row 7: 27.3 (8) instead of 30 (8) (p. 7, line 267)

Thank you – values corrected

Reviewer response: Agreed.

- row 10 and 11: here, 581 patients are reported; however, in the main text, the authors speak of 595 patients (p. 7, line 287). Please double-check.

Thank you for your comment. In ORIENT 32, 595 patients were enrolled: 24 were enrolled directly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab-bevacizumab biosimilar (n=380) or sorafenib (n=191) in the phase III. The outcomes quoted in the table is the survival analysis from the phase III study. We have updated the text accordingly to reflect the number of patient randomised p7. Line 272.

‘In this study, 571 patients with HCV-HCC were randomised to receive sintilimab (a PD-1 inhibitor) plus IBI305 (a bevacizumab biosimilar), or sorafenib in the first line setting.

Reviewer response: Thank you for double-checking. Agreed.

- Row 13: 0.78 instead of 0.76 (p. 7, line 241)

- row 31: (11.6 – 16.0) instead of (1.6 – 16.0) (p. 5, line 162)

- row 34: 12.7 instead of 18 (p. 5, line 178)

- row 35: 1.3 instead of 4 (p. 5, line 178)

Thank you- these values have been corrected 

Reviewer response: Agreed.

Is there a reason why the studies CheckMate 040 and KEYNOTE-224 (p. 3) were not added to table 1? If no, please add.

Thank you for your comment. The intention of table 1 is to provide a summary of results of phase III RCT involving ICI in aHCC. CheckMate 040 and KEYNOTE-224 were not included as they were phase II studies. We have amended the title of the table to ‘Results of phase III randomised controlled trials involving ICI in aHCC’ to make the intention clear to the reader. p3. Line 137

Reviewer response: Thank you for the explanation. Now, the aim of table 1 is clear. 

Overall, it is recommended to use values rounded to the same decimal place, e.g. 18.5, throughout the whole text in order to report identical values in the main text and in the tables in order to avoid confusion.

Thank you for this comment. We have amended the table and the text so values are consistently reported throughout. 

Reviewer response: Agreed. 

4. Table 2 and 3: Also here, please add the reference number after each year according to the reference list and the explanation of abbreviations in a footnote below the table.

Thank you. The tables have been amended accordingly.

Reviewer response: Agreed.

5. Comment on Table 2: Why were these studies not described in detail in the main text? “…Varying rates of response and toxicity.” Is a bit too brief. Please expand this passage.

Thank you. The aim of the table was to provide a summary and minimize text for the reader. We have expanded with introductory passage (p8 line 329-333) within the text to read

‘Table 2 summarises a selection of other early phase studies investigating ICI with targeted therapies. These phase I and II studies investigated PD-1 directed therapy in combination with antiangiogenics +/- immune modulating therapy in the first line and second line setting, demonstrating signals of activity with varying response rates and potentially manageable toxicity profiles.

Reviewer response: Agreed.

6. Wrong line separation: p. 6, line 232: “mon-oclonal” should be “mono-clonal”

Thank you- this was an auto-formatting issue, now corrected

7. Please remove the excessive figure caption in Figure 1 on page 16

Thank you. A figure has been provided without caption to allow substitution into the manuscript.

Reviewer response: I supposed it was a technical/auto-formatting error. Thank you for correcting.

8. Please remove the excessive periods: p. 16, line 669: “… (UK and Ireland) Ltd..”; p. 17, line 682: “…Julien Edeline. has received…”

Thank you. This has been corrected. 

Reviewer response: Agreed.

Reviewer 2 Report

Thank you for the additional chnages.

Imatinib has been shown to be effective in some patients with HCC in the years 2003-2005 (just for your information)