Renal Disorders with Oral Tyrosine Kinase Inhibitors in Metastatic Colorectal Cancer: An Analysis from the FDA Adverse Event Reporting System Database

Round 1

Reviewer 1 Report

This study is an important study.

But there are some areas that need improvement.

1.You mention regorafenib as a BRAF inhibitor, but regorafenib is not used as a BRAF inhibitor. It is used as a multi-tyrosine kinase inhibitor against angiogenesis regardless of the presence or absence of BRAF inhibitory mutation.I think your title may mislead the reader and should be changed.

2. Encorafenib is not used alone for BRAF-mutant colorectal cancer. Were all cases co-administered with cetuximab? Cetuximab is another drug that can cause kidney damage. Please add any concomitant medications.

3.Renal disorders include "urinary tract obstruction" and "hydronephrosis", but these are considered complications or tumor exacerbation, not adverse events. Care must be taken when handling.

If possible, it is desirable to add information such as the number of metastatic organs and treatment lines to the patient background table.

Author Response

This study is an important study.

But there are some areas that need improvement.

1. You mention regorafenib as a BRAF inhibitor, but regorafenib is not used as a BRAF inhibitor. It is used as a multi-tyrosine kinase inhibitor against angiogenesis regardless of the presence or absence of BRAF inhibitory mutation.I think your title may mislead the reader and should be changed.

Thank you for this suggestion. The title has been changed in order to not mislead the reader. Furthermore, a clarification has been added for regorafenib in lines 48-55, and modifications have been applied throughout the text to emphasize oral tyrosine kinase inhibitors in colorectal cancer, rather than solely focusing on BRAF inhibitors.

2. Encorafenib is not used alone for BRAF-mutant colorectal cancer. Were all cases co-administered with cetuximab? Cetuximab is another drug that can cause kidney damage. Please add any concomitant medications.

We apologize for the lack of clarity. As previously stated in the Materials and Methods section, we considered reports with a unique Case ID related to regorafenib and encorafenib reported in the FAERS database as primary suspect drug and having CRC as the indication were considered for the analysis. Encorafenib (ENC), a pure BRAF inhibitor (BRAFi) is approved in combination with cetuximab (CET) for the treatment of mCRC in 2020 (as mentioned in the Introduction section, lines 53-54). Furthermore, our study's discussion section (lines 241-245) already addresses “….., the potential involvement of ENC in association with CET cannot exclude the role of CET itself in the development of renal disorders. This can be explained by the role of EGFR in cell regeneration following ATN. The use of anti-EGFR therapies, such as CET, may potentially hinder the re-epithelialization of tubules and impede the recovery process…”. Nonetheless, among the reports where encorafenib was the primary suspect, 150 cases indicated cetuximab as a secondary suspected drug (30.7%). We incorporated this concern into the results section, lines 133-134. Additionally, as we highlighted in our limitations, lines 307-310 “Details such as a patient's past medical history, concomitant treatments, and precise dosing and frequency of drug administration may not always be available, which limits the ability to fully assess the impact of these factors on kidney toxicity.”

3. Renal disorders include "urinary tract obstruction" and "hydronephrosis", but these are considered complications or tumor exacerbation, not adverse events. Care must be taken when handling.

Thank you for this valuable suggestion. We know the possibility that "urinary tract obstruction" and "hydronephrosis," as reported adverse drug reactions in the FAERS database, could potentially be related to tumor complications or tumor exacerbation. To ensure clarity, we have included the following statement in the Discussion section (lines 269-272): “Furthermore, it is important to note that urinary tract obstruction and hydronephrosis could potentially be complications or exacerbations of the mCRC condition. Therefore, reports containing these adverse drug reactions should be approached with careful consideration.”

If possible, it is desirable to add information such as the number of metastatic organs and treatment lines to the patient background table.

Thank you for this suggestion. However, it's important to clarify that this study is an observational retrospective pharmacovigilance analysis based on suspected adverse drug reaction reports collected from the FAERS database. Spontaneous reporting doesn't provide the means to access patients directly; rather, it relies on the reporting of adverse drug reactions that may be associated with encorafenib and regorafenib. Details such as the number of metastatic organs and treatment lines are not provided in the FAERS reports, and therefore, we were unable to include this information in the analysis. As we highlighted in our limitations, lines 307-310 “Details such as a patient's past medical history, concomitant treatments, and precise dosing and frequency of drug administration may not always be available, which limits the ability to fully assess the impact of these factors on kidney toxicity.”

Reviewer 2 Report

It is an interesting study showing the renal disorders with oral BRAF inhibitors in metastatic CRC. The authors concluded renal ADRs that required further investigations to better characterize the safety profile of BRAFi in patients with mCRC.

The authors highlighted the positives and limitations of the study in the discussion section.

The study is well designed and had a good flow.

language is fine

Author Response

It is an interesting study showing the renal disorders with oral BRAF inhibitors in metastatic CRC. The authors concluded renal ADRs that required further investigations to better characterize the safety profile of BRAFi in patients with mCRC.

The authors highlighted the positives and limitations of the study in the discussion section.

The study is well designed and had a good flow.

We express our gratitude to the reviewer for their favorable comments and appreciation of our manuscript.

Reviewer 3 Report

The manuscript of Giulia Russo reports a descriptive and disproportional analyses regarding patients treated with oral BRAF inhibitors (BRAFi), regorafenib 12 (REG) and encorafenib (ENC) on patients with mCRC, drugs that can cause nephrotoxicity effects. These results highlighted some unreported renal ADRs associated with the use of some of  oral BRAFi, which require further investigation.

In my opinion, the manuscript is interesting, although a few points need to be clarified.

• In the abstract, the meaning of ADR abbreviation is not reported

• In the tables, some figures are in bold. In  tables notes an explanation must be indicated

Author Response

The manuscript of Giulia Russo reports a descriptive and disproportional analyses regarding patients treated with oral BRAF inhibitors (BRAFi), regorafenib 12 (REG) and encorafenib (ENC) on patients with mCRC, drugs that can cause nephrotoxicity effects. These results highlighted some unreported renal ADRs associated with the use of some of oral BRAFi, which require further investigation.

In my opinion, the manuscript is interesting, although a few points need to be clarified.

1. In the abstract, the meaning of ADR abbreviation is not reported:

Thank you for this suggestion. We added the meaning of ADR in the abstract, accordingly (see abstract, line 17).

2. In the tables, some figures are in bold. In tables notes an explanation must be indicated

Thank you for this comment. Bold types have been clarified in Table note.