Treatment of RET-Positive Advanced Medullary Thyroid Cancer with Multi-Tyrosine Kinase Inhibitors—A Retrospective Multi-Center Registry Analysis

Round 1

Reviewer 1 Report

Viktoria Florentine Koehler et al reported the efficacy of multi-tyrosine kinase inhibitors in patients with RET positive advanced medullary thyroid cancer.

They extracted patients’ data from the German Study Group for a rare malignant tumor of the thyroid and parathyroid glands.

They revealed that vandetanib and cabozantinib are more effective to patients with RET positive than those without RET variants.

 

Figure 1. is a little bit complicated to understand. Isn’t an arrow from the box of “25 patients with second-line MKI treatment” to the box of “47 patients treated with Vandetanib” needed?

 

Why did the authors analyze with both backward model selection and stepwise model selection of P-value and AIC-based in multiple cox regression analyses?

 

In consequence, which is the favorable MKI therapy as the first-line and the second-line therapy according to the multiple Cox regression?

 

Author Response

Response to reviewers:

We would like to thank the reviewers for their insightful comments and suggestions that have helped to improve our manuscript. Detailed responses to each of the reviewers’ comments are provided below. The manuscript has been modified accordingly. Changes are highlighted in the text. Page and line specifications refer to the revised, highlighted version of the manuscript.

Response to Reviewer 1:

We would like to thank the reviewer very much for the positive evaluation of our study and the very useful comments.

 

Ad 1: Figure 1. is a little bit complicated to understand. Isn’t an arrow from the box of “25 patients with second-line MKI treatment” to the box of “47 patients treated with Vandetanib” needed?

We thank the reviewer for raising this valid point. We have revised Figure 1 and included an additional arrow (page 4, Figure 1).

 

Ad 2: Why did the authors analyze with both backward model selection and stepwise model selection of P-value and AIC-based in multiple cox regression analyses?

We thank the reviewer for raising this question. We used different model selection methods, including backward elimination, stepwise selection, and penalized regression, to select a more robust and reliable set of predictive factors. We have now included this information in the Methods section (page 5, lines 200-202).

 

Ad 3: In consequence, which is the favorable MKI therapy as the first-line and the second-line therapy according to the multiple Cox regression?

According to Multiple Cox regression analysis there was no favorable type of MKI treatment in first line setting in regard of overall survival (OS). Patients with second line vandetanib treatment showed a longer OS compared to patients receiving cabozantinib. Nevertheless, these data need to be interpreted with caution due to the limited number of patients receiving first line treatment with cabozantinib and the limited number of patients receiving second line treatment with vandetanib after first line treatment with cabozantinib (8/10 patients received vandetanib after first line treatment with sorafenib or imatinib). We have now included the information about number of patients in second line setting (page 7, lines 285-287) and added this information in the Discussion section (page 11, lines 450-457).

Reviewer 2 Report

This manuscript is well-written and presents an interesting and carefully designed retrospective multi-center registry analysis.  

Author Response

Response to reviewers:

We would like to thank the reviewers for their insightful comments and suggestions that have helped to improve our manuscript. Detailed responses to each of the reviewers’ comments are provided below. The manuscript has been modified accordingly. Changes are highlighted in the text. Page and line specifications refer to the revised, highlighted version of the manuscript.

 

Response to Reviewer 2:

We would like to thank the reviewer very much for the positive evaluation of our study.

Reviewer 3 Report

 

This is a well written article regarding the outcome of RET positive medullary thyroid cancer patients receiving vandetanib or cabozantinib as first or second line treatment. The topic is of interest since in this population, RET specific inhibitors have recently shown major efficacy and the best treatment sequence is yet to be determined.

 

Major comments

The authors analyzed the outcome of patients receiving cabozantinib and vandetanib irrespective of the setting in which the treatment was prescribed (first or second line). This analysis must be analyzed with caution since the efficacy of a MKI treatment is expected to be different after previous MKI. These results should be removed from the abstract but may be kept in the article since the poor efficacy of cabozantinib frequently given in second line in this study, suggest modest inhibition of RET as compared to specific RET inhibitors. If these results are kept in the abstract, it must be specified that there are given as first or second line otherwise the message is very confusing.

On the contrary, the results concerning the efficacy of the first and second line are more interesting since they could help decide between a MKI and a RET inhibitor in this setting. I propose to present these results in the abstract.

In the Methods section the authors write “Due to the limited sample size, no statistical tests comparing the characteristics or outcomes of patients with and without germline/somatic RET variants were performed.” which is appropriate but they compare the outcome of the 2 populations in Figure 2 and 3. I suggest removing those figures and avoiding such comparisons.

I think the authors should present the data concerning the dose of MKI prescribed, at initiation and the dose adjustment made during treatment. In particular, for cabozantinib since the dose in MTC is different than in other cancer types. If the patients of the study received different or lower doses, this may impact the efficacy.

Table A3 B : for RET negative patients, n=2 but the data concerning 3 patients are reported for responses.

 

Minor comments

Line 269-271 : the sentence is challenging to understand and should be rephrased.

Table 3 : I suggest to remove the lines (the adverse events) that are not represented in both columns/groups.

Author Response

Response to reviewers:

We would like to thank the reviewers for their insightful comments and suggestions that have helped to improve our manuscript. Detailed responses to each of the reviewers’ comments are provided below. The manuscript has been modified accordingly. Changes are highlighted in the text. Page and line specifications refer to the revised, highlighted version of the manuscript.

 

Response to Reviewer 3:

We would like to thank the reviewer very much for the positive evaluation of our study and the very useful comments.

 

Ad 1:     The authors analyzed the outcome of patients receiving cabozantinib and vandetanib irrespective of the setting in which the treatment was prescribed (first or second line). This analysis must be analyzed with caution since the efficacy of a MKI treatment is expected to be different after previous MKI. These results should be removed from the abstract but may be kept in the article since the poor efficacy of cabozantinib frequently given in second line in this study, suggest modest inhibition of RET as compared to specific RET inhibitors. If these results are kept in the abstract, it must be specified that there are given as first or second line otherwise the message is very confusing.

On the contrary, the results concerning the efficacy of the first and second line are more interesting since they could help decide between a MKI and a RET inhibitor in this setting. I propose to present these results in the abstract.

We thank the reviewer for raising this valid point. We have revised this part of the manuscript: we have removed the outcome data of vandetanib and cabozantinib and have now included the treatment outcome of first and second line treatment in the Abstract section (page 2, lines 70-73).

Ad 2: In the Methods section the authors write “Due to the limited sample size, no statistical tests comparing the characteristics or outcomes of patients with and without germline/somatic RET variants were performed.” which is appropriate but they compare the outcome of the 2 populations in Figure 2 and 3. I suggest removing those figures and avoiding such comparisons.

We thank the reviewer for drawing our attention to this ambiguity. We have now removed Figure 2 and Figure 3.

 

Ad 3: I think the authors should present the data concerning the dose of MKI prescribed, at initiation and the dose adjustment made during treatment. In particular, for cabozantinib since the dose in MTC is different than in other cancer types. If the patients of the study received different or lower doses, this may impact the efficacy.

We thank the reviewer for this comment. The median starting doses of vandetanib and cabozantinib were 300 mg/day (range 100-300 mg/day) and 80 mg/day (range 60-140 mg/day), respectively. Twenty-seven (63%) patients started vandetanib treatment with the approved dosage of 300 mg/day, 4 (27%) of patients started cabozantinib with the approved dosage of 140 mg/day. We have now included this information in the paragraph “Results” (page 5, lines 224-228). Furthermore, we now have discussed this aspect in the Discussion section (page 11, lines 447-449). In vandetanib-treated patients, 14 (33%) patients and in cabozantinib-treated patients 10 (67%) required a dose reduction due to treatment emergent adverse events (page 9-10, Table 3). Data about the detailed regimen of dose reductions are unavailable.

 

Ad 4: Table A3 B : for RET negative patients, n=2 but the data concerning 3 patients are reported for responses.

We thank the reviewer for this comment and have corrected the table (page 16-17, Supplementary, Table A3 B).

 

Ad 5: Line 269-271 : the sentence is challenging to understand and should be rephrased.

We agree with the reviewer and have rephrased the respective sentence. The sentence in the Results section (page 8, lines 329-332) now reads: “Patients with RETvariants receiving second line treatment had a longer OS when the time interval between first diagnosis and MKI initiation was longer, a lower number of metastases was present at first diagnosis suggesting less aggressive disease course and when treated in second line with vandetanib.”

 

Ad 6: Table 3 : I suggest to remove the lines (the adverse events) that are not represented in both columns/groups.

We thank the reviewer for this comment and have made changes accordingly (page 9/10, Table 3). We have removed alopecia, chest pain/myocardial infarction, cardiomyopathy, polyneuropathy and posterior reversible encephalopathy syndrome.

Round 2

Reviewer 3 Report

I approve the changes that have been made.