Current Advances in Immune Checkpoint Inhibition and Clinical Genomics in Upper Tract Urothelial Carcinoma: State of the Art

Round 1

Reviewer 1 Report

The review by Califano et al discusses the challenges in treating UTUC with current therapy modalities and how introduction of immune checkpoint inhibitors have revolutionized the treatment standards for UTUC. The authors also discuss deeply about the genomic landscape with mutational and gene expression profile as well as implications of modulating tumor microenvironment in UTUC. The review is overall well-written, detailed and a value addition to the field.
Minor point-
Authors have described activated FGFR3 signaling in certain subtype of UC. A detailed overview of the current ongoing clinical trials with molecules targeting FGFR3 would be a good addition to the review.

Author Response

We thank the Reviewer for the kind and appropriate comment. As suggested by the Reviewer, we added an overview of the clinical trials with molecules targeting FGFR3 in the Clinical genomics in UTUC section (3.3. Implications for systemic therapy), which now reads as follow:

(p. 9, line 296):” Erdafitinib is a pan-FGF tyrosine kinase inhibitor approved as second-line treatment for locally advanced or metastatic UC with FGFR mutations [12]. In a recent phase II study the use of erdafitinib was associated with a 40% response rate in 99 patients with disease progression following chemotherapy [47]. This study included 23 patients with UTUC and visceral metastases showing a 43% response rate. Additional FGFR-directed agents also continue to be investigated across multiple disease stage in mutated UC in-cluding infigratinib and rogaratinib among others [12]. Furthermore, ongoing trials are combining these agents wit ICI and chemotherapy regimens.”

We hope that the Reviewer will find this reply satisfactory.

Reviewer 2 Report

This manuscript by Califano et al. provided an extensive review on the underlying mechanism of immune therapies and conclude the modern regimens and their clinical trials.  In my personal viewpoints, I would like to see authors add content regarding the following: 

1. In assessing response of the immune therapies in UC, Tumor Proportion Score (TPS), Combined Positive Score (CPS), Tumor Cells (TC), and Immune Cells (IC) are 4 primary tools. Based on the current literature, how accuracy they are in UTUC ?
2. In the manuscript, the authors provided some genetic mutation of UTUC and linked them with the alteration of the immune microenviroments. If possible, please also add some reviews or opinions regarding the the circulating tumor cells and liquid biopsy in detecting mutations. 
3. Are there ongoing trials based on different checkpoints ? such as CTLA-4 
4. Based on current clinical trials, there are some obvious limitation on pathological response rates in all available immune checkpoints inhibitors. Are there any pathological features predicting the failure of immune therapies even with qualification of TPS, CPS, TC and IC ?

Author Response

We thank the Reviewer for the pertinent comments.

Point 1 and 4): The Reviewer highlighted important tools useful for stratifying patients undergoing immunotherapy. However, to date, the available literature has not yet unequivocally clarified their clinical implications. Furthermore, in the context of patients with urothelial carcinoma, there are no available specific data for UTUC patients. Consequently, we thank the Reviewer for this important starting point, which will be surely address in our future researches.

Point 2): According to the Reviewer suggestion, we implemented the new version of the manuscript in the Clinical genomics in UTUC section (3.3. Implications for systemic therapy), which now reads as follow:

(p. 9, line 309): ”In UCs, proof-of-concepts data documented that ctDNA is detectable in plasma and urine, and could be a prognostic factor [48–51]. Liquid biopsy could represent a cost-effective and minimally invasive method for biomarker identification and patient stratification.”

Point 3): Regarding the CTLA-4 immune checkpoint, we included this point in the Immune checkpoint inhibition section, which now reads as follow:

(p. 2, line 65): ” Furthermore, the inhibition of IC CTLA-4 in different stages of the disease is being investigated [11,12].”

 We hope that the Reviewer will find this reply satisfactory.