Regression of Intracranial Meningiomas Following Treatment with Cabozantinib

Round 1

Reviewer 1 Report

This excellent case report presents a patient with 2 meningeomas. This patient was treated with the oral multikinase inhibitor cabozantinib for thyroid carcinoma. Under this therapy, both meningeomas shrinked considerably. This effect has to be ascribed to a specific effect of cabozantinib. The linguistic style of the manuscript is very good, making the manuscript easy to read and understand. All results presented are sound and the conclusions drawn are comprehensible. The results presented are of high relevance and interest to your readers. The pharmacologic treatment options for meningeomas are very limited. This is escpecially a problem for patients suffering from grade II-III meningeomas after several relapses, when often further surgery is not possible. The results presented in this case report are the basis for further prospective research for the use of cabazantinib in meningeoma. Therefore I strongly recommend publication without further changes needed.

Author Response

We highly appreciate the encouraging remarks by the reviewer and thank them for their comprehensive review.

Reviewer 2 Report

1.  The Introduction and Discussion sections describe prior trials of systemic therapies directed towards recurrent WHO Grade II and III meningiomas.  There should be a little more discussion regarding prior studies targeting recurrent Grade I meningiomas, as presumably this is what this patient in the case report had.

2.  It would be helpful to describe in slightly more detail the possibility of a prospective evaluation of Cabozantinib in meningiomas as stated in the Conclusion.  Based on this case, what would the potential trial patient population be, and what biomarkers would ideally be evaluated?

Author Response

We appreciate the reviewer’s comments and acknowledge the lack of discussion regarding prior studies targeting recurrent Grade I meningiomas. In the manuscript we did provide discussion about limitations with extrapolation across WHO grades:

Lines 182-188: An additional limitation to note is that this particular patient was presumed to have low-grade meningiomas based on their lack of growth trajectory and imaging appearance and responded to single agent Cabozantinib. Therefore, although similar VEGFR-directed agents have been utilized in those with higher grade recurrent or progressive disease, the responses may differ across different grades of meningioma and evaluation of the molec-ular underpinnings are key to better understanding response assessments.

In addition, we have now provided additional detail to the introduction section to specifically address this with more detail:

Reports focused on recurrent WHO grade I meningiomas are limited. A phase II study evaluated the combination of bevacizumab and everolimus, an mTOR inhibitor, in patients with recurrent or progressive meningioma (n=5 WHO grade I, 17 total) [11]. Interestingly, the median PFS was greater for WHO grade II and III tumors (22 months) as compared to grade I tumors (17 months). Similarly, another phase II study investigated the efficacy of Vatalanib, a small molecule protein kinase inhibitor with activity against VEGF receptors, PDGFR-beta, and c-kit in refractory meningiomas (n=2 WHO grade I, 25 total), with overall modest activity [12].

2. It would be helpful to describe in slightly more detail the possibility of a prospective evaluation of Cabozantinib in meningiomas as stated in the Conclusion.  Based on this case, what would the potential trial patient population be, and what biomarkers would ideally be evaluated?

We appreciate the reviewer’s comments to describe in more detail the possibility of a prospective evaluation of Cabozantinib in meningiomas, what would the potential trial patient population be, and what biomarkers would ideally be evaluated, which we have now included in the conclusion. This is a study which has recently gone into protocol activation as a multi-institutional status.

Given the preclinical understanding of the molecular underpinnings of meningioma and the lack of effective systemic therapeutic options, a prospective evaluation of Cabozantinib is encouraged and warranted in patients with relapsed or refractory disease. This study is currently in development with the objectives of evaluating the PFS, overall response rate, overall survival, safety and tolerability, and quality of life for patients treated for recurrent meningioma, WHO Grades I-III. Correlation of MET expression, angiogenesis receptor status, and inflammatory signatures by gene expression profiling with response to cabozantinib on pre-treatment tissue samples will lead to a better understanding of this potential therapeutic modality. Similar initiatives are encouraged in this space to help provide alternatives for this challenging disease.