Predicting Outcomes of Atezolizumab and Bevacizumab Treatment in Patients with Hepatocellular Carcinoma

Round 1

Reviewer 1 Report

I have read with great interest the review paper by Ji Won Han and Colleague. It tackles the very hot-topic of personalized medicine in the field of advanced HCC trying to summarize the present evidence on the predictive and prognostic role of reported clnical, tissutal and circulating factors across different research experiences. Overall, the topic is very interesting, the article quite well organized and the literature sufficiently widely revised.

However, I believe the following points need to be addressed before considering the article for publication.

Major revisions:

1. Some of the paragraphs relative to the discussed biomarkers do not report any findings specific to atezolizumab-bevacizumab (AB) combination, but only to ICI monotherapy, therefore these biomarkers should be removed and maybe moved to a seprate dedicated paragraph.

2. The paragraph 3.1.1. Etiology shoudl also comprise some evidence from the meta-analyses conducted on the topic in the last years, to expand the discussion of such a relevant topic of discussion among experts of the field.

3. In each biomarker-dedicated paragraph, more details should be given on the type of cited studies, such as concise information of numerosity and design (even though more details are given in the table). 

Minor revisions:

1. I would consider to shorten the introduction, merging the first 2 paragraphs (introduction + mechanism of action), since the second one is not the main focus of the review.

2. For the sake of clarity, I would add a table (or a column to table 2) indicating which of the discussed biomarkers are -to present knowledge- predictive and which are prognostic.

 

Author Response

Reviewer 1

I have read with great interest the review paper by Ji Won Han and Colleague. It tackles the very hot-topic of personalized medicine in the field of advanced HCC trying to summarize the present evidence on the predictive and prognostic role of reported clinical, tissue and circulating factors across different research experiences. Overall, the topic is very interesting, the article quite well organized and the literature sufficiently widely revised.

However, I believe the following points need to be addressed before considering the article for publication.

Major revisions:

1. Some of the paragraphs relative to the discussed biomarkers do not report any findings specific to atezolizumab-bevacizumab (AB) combination, but only to ICI monotherapy, therefore these biomarkers should be removed and maybe moved to a separate dedicated paragraph.

Authors’ response) Thank you for the helpful comment. As the pointed out, we have created the additional section named as ‘Potential but unproven markers’, and sections regarding biomarkers that do not report any findings specific to AB combination, such as ‘Sarcopenia and obesity’, ‘Tumor mutational burden’, ‘Gene mutations’, and ‘Gut microbiome’, were moved to the newly created section 6. (highlighted in revised manuscript line 554-612)

2. The paragraph 3.1.1. Etiology should also comprise some evidence from the meta-analyses conducted on the topic in the last years, to expand the discussion of such a relevant topic of discussion among experts of the field.

Authors’ response) Thank you for the important comment. A recent meta-analysis which included 3 large randomized phase III trials of nivolumab, AB, and pembrolizumab, suggested that the ICI regimen might be superior to the sorafenib in terms of OS in the HBV- and HCV-related HCC (PMID: 33762733). In addition, a recent network meta-analysis showed that patients with viral etiology showed significant survival benefit of the AB regimen compared to the TKIs (PMID: 34239810). (highlighted revised manuscript line 119-125).

3. In each biomarker-dedicated paragraph, more details should be given on the type of cited studies, such as concise information of numerosity and design (even though more details are given in the table). 

Authors’ response) As the reviewer recommended, we described the type of cited studies such as concise information of numerosity and design. (highlighted in the yellow throughout the manuscript).

Minor revisions:

1. I would consider to shorten the introduction, merging the first 2 paragraphs (introduction + mechanism of action), since the second one is not the main focus of the review.

Authors’ response) We totally agree with the reviewer’s opinion. We have shortened the introduction, and merged 2 paragraphs (introduction + mechanism of action), since the second one is not the main focus of the review.

2. For the sake of clarity, I would add a table (or a column to table 2) indicating which of the discussed biomarkers are -to present knowledge- predictive and which are prognostic.

Authors’ response) As the reviewer recommended, we added a column to table 2, which indicates whether the discussed markers are predictive or prognostic, for the clarity. Of note, we indicated the markers regarding treatment responses as ‘predictive’, and the markers regarding the patients’ survival as ‘prognostic’. 

 

Author Response File: Author Response.docx

Reviewer 2 Report

The literature review, voluminous in text and chapters, is completely devoid of illustrations and tables. Most sections of the review contain superficial information, which, therefore, is known to most experts in this field. And for a wide range of readers, this article is of no interest due to the lack of illustrations. I do not recommend this review for publication.

1) The median overall survival (OS) was 16.4 months for the 46 nivolumab group and 14.7 months for the sorafenib group, with a hazard ratio of 0.85 (p = 0.0 8). This statement should be supported by reference to the literature.

2) The abbreviation for bevacizumab (AB) is introduced in the abstract, while atezolizumab is spelled in full throughout the text of the manuscript.

3) Atezolizumab, Bevacizumab. Even the structural formulas for these key molecules in this review are not given.

4) Rationale for combination treatment. This section is not covered enough. These data do not fully convince the reader of the need for combination therapy. Limitations and concentration ranges for each molecule are not indicated.

5) 3.1.3. Liver function. This section is completely unexplored. The title doesn't match the content. Liver function in normal and carcinogenic conditions should be discussed in detail. This section strictly needs illustrative material.

6) 3.2. imaging studies. I'm not sure if this section correlates with the purpose of this review.

7) The Discussion section should be presented.

I am not a native English speaker, but the quality of the language is poor and needs serious improvement

Author Response

Reviewer 2

The literature review, voluminous in text and chapters, is completely devoid of illustrations and tables. Most sections of the review contain superficial information, which, therefore, is known to most experts in this field. And for a wide range of readers, this article is of no interest due to the lack of illustrations. I do not recommend this review for publication.

1) The median overall survival (OS) was 16.4 months for the 46 nivolumab group and 14.7 months for the sorafenib group, with a hazard ratio of 0.85 (p = 0.0 8). This statement should be supported by reference to the literature.

Authors’ response) The CheckMate-459 phase III trial compared nivolumab with sorafenib as a first-line treatment in unresectable HCC, but it did not achieve its primary endpoint, whereas it has been proved to be effective in the second-line systemic treatment after sorafenib (PMID: 34914889). The median overall survival (OS) was 16.4 months for the nivolumab group and 14.7 months for the sorafenib group, with a hazard ratio of 0.85 (p = 0.08). (PMID: 34914889). According to reviewer 1’s recommendation, we have removed those sentences in the revised manuscript for the shortening of the introduction section, but the limited efficacy of the ICI monotherapy in HCC patients is briefly presented in the revised manuscript line 39-41.

2) The abbreviation for bevacizumab (AB) is introduced in the abstract, while atezolizumab is spelled in full throughout the text of the manuscript.

Authors’ response) To avoid misunderstanding, we revised the words `A combination of atezolizumab and bevacizumab (AB)’ to `A combination of atezolizumab plus bevacizumab (AB)’ in the abstract. (highlighted in revised manuscript line 12). The abbreviation for this combination regimen can be presented as various words, and we used `AB’, as previously described (PMID: 35289074).

3) Atezolizumab, Bevacizumab. Even the structural formulas for these key molecules in this review are not given.

Authors’ response) To complement the issue pointed out by the reviewer, we have revised the sentences and added the reference providing the structural information of the agents in the introduction section.

‘Atezolizumab is a monoclonal antibody of IgG1 isotype which acts on PD-L1 (PMID: 36305812) which is present in immune cells or tumor cells within the tumor, blocking its interaction with receptors programmed cell death protein 1 (PD-1) and B7-1 (CD80).’ (highlighted in revised manuscript line 61-64).

‘Bevacizumab a monoclonal antibody of IgG1 isotype which targets VEGF, which is a key factor in angiogenesis (PMID: 36305812).’ (highlighted in revised manuscript line 68-69).

The detailed structural formulas of these two agents can be found in the previous report (PMID: 36305812).

4) Rationale for combination treatment. This section is not covered enough. These data do not fully convince the reader of the need for combination therapy. Limitations and concentration ranges for each molecule are not indicated.

Authors’ response) Thank you for the recommendation.

Although the exhaustion of T cells with immune-checkpoint molecules is well known in the HCC, the use of ICIs as monotherapy has demonstrated limited efficacy with a response rate between 15% and 20%, which benefits only a small sub-group of HCC patients in a second-line setting (highlighted revised manuscript line 39-40). On the other hand, there is no randomized trial showing the clinical benefit of bevacizumab monotherapy in HCC (highlighted in revised manuscript line 79-80). There are several suggested mechanisms related to the resistance to ICI treatment in HCC, including tumor-intrinsic and extrinsic factors (PMID: 36230538). Thus, numerous efforts to overcome this resistance and improve the clinical outcome of HCC patients have been tried, and combinations of other regimens to the ICI have also been tried. (highlighted in revised manuscript line 43-46)

Potential synergistic effect of these two agents has been discussed in this manuscript, as follows ‘VEGF not only fosters angiogenesis in tumors but also establish-es an immunosuppressive TME by attracting and inducing immunosuppressive cells, such as regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs). Moreover, VEGF hampers dendritic cell (DC) differentiation and maturation, as well as effector T-cell proliferation, ultimately weakening T-cell priming and targeting cell elimination. In addition, VEGF drives the T-cell exhaustion-specific program, which upregulates transcription fac-tor TOX in the TME. Thus, blocking VEGF signaling not only inhibits intra-tumoral angiogenesis and normalizes tumor vasculature but also transforms the TME from immunosuppressive to immune-active, which might enhance the efficacy of ICIs. However, potential synergisms might improve AB efficacy in HCC compared to monotherapy-based ICIs such as nivolumab and pembrolizumab.’ (highlighted in revised manuscript line 635-649).

It can be administered at a dose of atezolizumab 1,200 mg plus bevacizumab 15 mg/kg IV every 3 weeks with target concentrations of 6 μg/mL for atezolizumab (PMID: 26918260) and 140 μg/mL for bevacizumab (PMID: 15169807). (highlighted in revised manuscript line 52-54).

5) 3.1.3. Liver function. This section is completely unexplored. The title doesn't match the content. Liver function in normal and carcinogenic conditions should be discussed in detail. This section strictly needs illustrative material.

Authors’ response) The management of HCC requires a unique approach that takes into account both the cancer itself and the patient's overall liver function. Liver function plays a critical role in determining the prognosis and treatment options for HCC patients, but this is not considered very important in other types of cancer. Most patients with HCC have underlying chronic liver disease or liver cirrhosis (LC), and there might be insufficient metabolism of chemotherapy agents and tolerance to chemotherapy. Furthermore, liver dysfunction, which can be exacerbated by chemotherapy, and the complications of LC, such as ascites, coagulopathy, or jaundice, can lead to treatment interruptions or discontinuation. Therefore, liver function is considered as an important prognostic factor in patients with HCC in the clinical practice, and most staging systems of HCC which are using the parameters of liver function such as Child-Pugh score, albumin, bilirubin, or ascites as showed in the following table (PMID: 30593649).

Staging systems	Liver functional parameters	Performance status, symptoms	AFP	Tumor status				Other
				Number	Size	Vascular invasion	Metastasis
Okuda (1985)	Ascites, albumin, bilirubin				Yes
CLIP (1998)	Child-Pugh score		Yes	Yes	Yes	Yes
French (1999)	Bilirubin	Karnofsky scale	Yes			Yes		Alk-P, PVT
BCLC (1999)	Child-Pugh score	EGOS PST		Yes	Yes	Yes	Yes
AJCC TNM-7 (2010)				Yes	Yes	Yes	Yes
CUPI (2002)	Ascites, bilirubin	Symptoms	Yes	Yes	Yes	Yes	Yes	Alk-P
JIS (2003)	Child-Pugh score			Yes	Yes	Yes	Yes
m-JIS (2006)	+ICG-R15 (- encepalopathy)			Yes	Yes	Yes	Yes
bm-JIS (2008)	Child-Pugh score		Yes	Yes	Yes	Yes	Yes	AFP-L3, DCP
Tokyo (2005)	Albumin, bilirubin			Yes	Yes
BALAD (2006)	Albumin, bilirubin		Yes					AFP-L3, DCP
ALPCS (2008)	Child-Pugh score	Symptoms	Yes		Yes		Yes	Alk-P, Urea, PVT
TIS (2010)	Child-Pugh score		Yes	Total tumor volume
MESIAH (2012)	MELD, albumin	Age	Yes	Yes	Yes	Yes	Yes
HKLC (2014)	Child-Pugh score	EGOS PST	No	Yes	Yes	Yes	Yes
ITA.LI.CA (2016)	Child-Pugh score	EGOS PST	Yes	Yes	Yes	Yes	Yes

Also, to avoid the misunderstanding, we revised the title ‘liver function’ which can be understood as ‘the physiologic or pathologic role of the liver in carcinogenesis’ to ‘liver functional parameters’ including the level of bilirubin, albumin, INR, or the scoring systems reflecting the liver functional status. (highlighted in revised manuscript line 160).

6) 3.2. imaging studies. I'm not sure if this section correlates with the purpose of this review.

Authors’ response) Radiologic (imaging) studies can be used to predict how a patient might respond to cancer chemotherapy. These biomarkers can be observed through imaging techniques like CT scans, PET scans, or MRI, and in addition to the tumor size or number, radiomic features or metabolic activities can also be analyzed and they can be used as biomarkers for predicting clinical outcomes in HCC patients receiving AB treatment. To avoid misunderstanding, we revised the term ‘imaging studies’, which can mean the imaging studies evaluating the responses following the treatment, to ‘Pre-treatment radiologic examinations’. (highlighted in revised manuscript line 191).

7) The Discussion section should be presented.

Authors’ response) As the reviewer recommended, we presented the discussion section, which includes the importance of biomarker development in AB treatment, and some limitations of this study.

 

 

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

 

The authors have done a serious job on the article. I would also recommend discussing the possibility of nanotechnology to improve therapy.

Comparative Analysis of the Cytotoxic Effect of a Complex of Selenium Nanoparticles Doped with Sorafenib, "Naked" Selenium Nanoparticles, and Sorafenib on Human Hepatocyte Carcinoma HepG2 Cells - PubMed (nih.gov)

Therapeutic Potential and Main Methods of Obtaining Selenium Nanoparticles - PubMed (nih.gov)

the quality of the English language is acceptable