Analysis of Spatial Heterogeneity of Responses in Metastatic Sites in Renal Cell Carcinoma Patients Treated with Nivolumab

Round 1

Reviewer 1 Report

* Albeit the item (organ response) is very interesting, the major drawback is constituted by the small patients sample size, rendering therefore difficult, if not impossible, to draw general conclusions. In other words I wonder if a real organ related responsiveness to Nivolumab supports the final conclusion or if these results are determined by chance, even if for the liver in other cancer types (as you correctly pointed out) there are indications to a lower response rate.

In the BIONIKK trial (Lancet Oncol. 2022 Apr 4:S1470-2045(22)00128-0. doi: 10.1016/S1470-2045(22)00128-0) the results for nivolumab in the ccrcc4 group show the highest objective response rate ever reported evaluating an anti-PD-1 agent alone. Obviously I agree that is impossible now, to assess the molecular group determination in primary or metastatic site of your patients, but this aspect is worthwhile to be discussed.

 

* row 6,7 Affiliations are incomplete

* row 76. It is not reported in which hospital treatment was performed

* Fig. 5. Lettering of the x axis is very difficult to read

Author Response

Thank you for the comments. 

I have added the Lancet study as proposed by your kind self. Thank you for pointing out such a novel study. 

Affiliations have been corrected as desired by you. 

The hospital name has been added. 

Figure 5 has been replaced which is now legible. 

 

Reviewer 2 Report

This is a retrospective cohort study on metastatic renal cell carcinoma (RCC) undergoing immune checkpoint inhibitor (ICI) treatment with nivolumab. The presented patients had undergone prior tumor nephrectomy or partial nephrectomy, and also a variety of other systemic therapy. Only 21 of the initial 30 patients were eligible for evaluation and statistical analysis.

Although this cohort is small, the authors try to describe the different response rates of metastatic lesions in different organ systems. Under ICI treatment the response rates in lymph nodes and adrenals were found to be the highest, whereas the response rates in other soft tissue organs such as the liver were found to be low.

The limitations of this study are adequately mentioned/ outlined at the end of the Discussion section, which is appreciated by the reviewer.

The following questions or comments are coming up when reading this manuscript:

• The study results should also be reviewed by an experienced statistician in order to confirm the statistical approach and study results.
• In Table 1 under the 4^th line item  -> “Co-morbidity” is listed. The authors should specify which specific co-morbidities were observed in this cohort (for instance the three most common co-morbidities should be listed).
• In the Discussion section the authors should summarize how many similar studies have been reported on this topic (response rates of RCC metastases in different organ systems under ICIs). The readers want to know how the presented study results have to be seen in the context of similar previously reported studies. 
• After adequately addressing these comments I support the publication of this manuscript.

Author Response

Thank you for such valuable feedback and comments. 

Co-morbidities have been now listed as desired by your kind self. 

A recent study has been added in the discussion for viewers interest as correctly pointed by yourself. 

 

Reviewer 3 Report

The authors set out to analyse the response of differently localized metastases to therapy with the CPI nivolumab. This is interesting overall and also shows interesting results despite the relatively small study group.

The manuscript is well written and covers the most important components, especially with a detailed and instructive discussion.

The fact that different RECIST variants are used is not apparent in the abstract. Sometimes only the "normal" RECIST is mentioned, sometimes it is declared as RECIST 1.1. It would be nice if it were consistently referred to as RECIST 1.1.

In addition, a few formal things need to be improved. 

The affiliations are described relatively vaguely

In the abstract on page 1, line 24, it says "(19 percent)", which certainly does not belong there.

Page 2 says iRECIST1819, where 1819 probably means the corresponding references.

The caption for table 2 is missing.

Relatively many acronyms are not explained, e.g. LVNI, ICPD, IUPD, LFU, ...

In the discussion, there is a change from CPI to ICI, even without prior explanation of the acronym.

 

Author Response

Thank you for the feedback. 

The comments as pointed out have now been addressed and corrected throughout the manuscript. 

Round 2

Reviewer 2 Report

I agree to publish the revised manuscript.