Rationale Efficacy and Safety Evidence of Lenvatinib and Pembrolizumab Association in Anaplastic Thyroid Carcinoma

Round 1

Reviewer 1 Report

The manuscript by Boudin and collaborators describes the use of lenvatinib and pembrolizumab in the therapy of anaplastic thyroid cancer. Unfortunately, the manuscript cannot be accepted in the current form. The suggested changes are listed below.

1.       The manuscript requires substantial improvement in English and thorough proofreading. Examples of suggested changes:

  a.       Lines 224-225: The sentence “Adam et al. looked…” should be removed.

  b.       Lines 136, 212, 271, 295, etc.: “et al” should be changed for “et al.”.

  c.       Lines 156-157: “V600EBRAF mutation” should be corrected.

  d.       Line 179: “Adam et colleagues” should be changed for “Adam and colleagues”.

  e.       Lines 46, 175, 223, 225: “FGFR 1-4” should be changed for “FGFR1-4”.

  f.        Line 190: “targetgenes” should be corrected.

  g.       Line 191: “pathways These” should be corrected.

  h.       Lines 249-251 are unclear. Please write in other words this part of the manuscript.

  i.         Lines 312-315: This part should be rewritten.

  j.         Line 316: I would suggest writing “Tahara and colaborators published” in place of “Tahara published”.

  k.       Lines 358, 401, etc.: “Lenvatinib” should be changed for “lenvatinib”.

  l.         Line 283: “ipilimumab: (DTC with radioiodine resistance) and” should be rephrased.

  m.     Line 378: It seem to me that “BRAF V600E mutations” should be changed for “BRAF V600E mutation”.

2.       Line 95: PD-L1 is not the proper name of the gene. It should be changed for CD274.

3.       Line 299: I would suggest explaining molecular targets of dabrafenib/trametinib-based therapy.

4.       Please check if the clinical trials listed in lines 306-309 are really “ongoing” as stated in the line 309. It seems to me that, for example, NCT03211117 (mentioned in the line 309) has been already completed.

5.       Lines 246-252: It is unclear if this part of manuscript belongs to the caption for Figure 1. Please explain it.

6.       Figure 1 caption: Please explain all abbreviation used in Figure 1, e.g., MDCS, ROS, etc. Please change “T-cell” and “B-cell” for “T cell” and “B cell”. Then the way these names are written throughout the manuscript will be unified.

7.       The quality of Figure 1 must be improved. Currently, it has low resolution and is blurred.

8.       Abbreviations used in tables should be explained only once, on first use.

9.       References:

  a.       Line 161: Please add more recent article describing dysregulation of signaling pathways in thyroid cancer, e.g., Int J Mol Sci. 2021;22(21):11829.

  b.       Please add references in lines 375, 260 and 274.

  c.       Please change “Derk et al” for “Derks et al.” or “Derks and collaborators”.

  d.       Table 2: “Yamazaki 2021 [62]” should be changed for “Yamazaki 2020 [62]”.

  e. Please correct Ref. [93]. Now it is “93. Meeting Program and Abstracts. Thyroid 2021, 31, P-1, doi:10.1089/thy.2021.29115.abstracts.”. Some details such as author(s), title, etc. are missing.

Author Response

We thank your Editorial Board and the two Reviewers for the positive and helpful comments that have been taken into account as described below.

The manuscript by Boudin and collaborators describes the use of lenvatinib and pembrolizumab in the therapy of anaplastic thyroid cancer. Unfortunately, the manuscript cannot be accepted in the current form. The suggested changes are listed below.

1. The manuscript requires substantial improvement in English and thorough proofreading. Examples of suggested changes:
2. Lines 224-225: The sentence “Adam et al. looked…” should be removed.

We deleted that sentence.

1. Lines 136, 212, 271, 295, etc.: “et al” should be changed for “et al.”.

We changed all “et al” for “et al.”

1. Lines 156-157: “V600EBRAF mutation” should be corrected.

As request V600EBRAF was changed for BRAF V600E

1. Line 179: “Adam et colleagues” should be changed for “Adam and colleagues”.

We changed Adam et colleagues for Adam and colleagues.

1. Lines 46, 175, 223, 225: “FGFR 1-4” should be changed for “FGFR1-4”.

We changed FGFR 1-4 for FGFR1-4.

1. Line 190: “targetgenes” should be corrected.

We corrected targetgenes for target genes

1. Line 191: “pathways These” should be corrected.

We corrected this mistake.

1. Lines 249-251 are unclear. Please write in other words this part of the manuscript.

We agree that it was unclear. We corrected these sentences: Lenvatinib also inhibits tumour angiogenesis and abnormalities by inhibiting the secretion of angiogenic factors, such as VEGF, FGF, and PDGF. Finally immune checkpoint inhibitors restore the exhausted T cell activity to kill the cancer cell.

1. Lines 312-315: This part should be rewritten.

We agree. We rewrote this part: Thirteen studies evaluated efficacy and safety of lenvatinib alone in ATC : 4 single-arm phase II studies [70–73], 8 retrospective studies [58,74–80] and a meta-analysis [81]. All these studies are reported in Table 2.

1. Line 316: I would suggest writing “Tahara and colaborators published” in place of “Tahara published”.

As request we changed “Tahara published” for “Tahara and collaborators published”.

1. Lines 358, 401, etc.: “Lenvatinib” should be changed for “lenvatinib”.

We changed Lenvatinib for lenvatinib.

1. Line 283: “ipilimumab: (DTC with radioiodine resistance) and” should be rephrased.

We agree and we rephrased this sentence: Only one study explored the effectiveness of immune checkpoint inhibitors combination. This phase II trial analyzed the association of nivolumab and ipilimumab in three distinct cohorts: DTC with radioiodine resistance, locally advanced or metastatic ATC and metastatic MTC. Response rate was 30% for the 7 patients of the ATC cohort.

1. Line 378: It seem to me that “BRAF V600E mutations” should be changed for “BRAF V600E mutation”.

It’s true. BRAF V600E mutations was changed for BRAF V600E mutation.

2. Line 95: PD-L1 is not the proper name of the gene. It should be changed for CD274.

We agree. We changed it.

3. Line 299: I would suggest explaining molecular targets of dabrafenib/trametinib-based therapy.

As request we explained molecular targets of dabrafenib/trametinib-based therapy: A case of a patient with ATC for whom pembrolizumab was used after chemotherapy and dabrafenib/trametinib (selective BRAF and MEK inhibitors) has also been reported.

4. Please check if the clinical trials listed in lines 306-309 are really “ongoing” as stated in the line 309. It seems to me that, for example, NCT03211117 (mentioned in the line 309) has been already completed.

We agree. In order to refer only to ongoing clinical trials, we have modified this sentence and clinical trials numbers: “In addition to current clinical trials in ATC testing pembrolizumab (NCT05119296) and atezolizumab (NCT03181100) a study evaluating a dual PD-1 and CTLA-4 inhibitor is ongoing (NCT05453799).”

5. Lines 246-252: It is unclear if this part of manuscript belongs to the caption for Figure 1. Please explain it.

This part of manuscript belongs to the cation of Figure 1. As request we explained it: This figure details mechanisms of immunological check point inhibitors combined with lenvatinib. Lenvatinib increased the CD8+T cells function and the cytotoxicity of NK cells, decreased the expression of PD-1, CTLA-4, and TIM3 in T cells, and inhibited T cell exhaustion. Lenvatinib also inhibits tumor angiogenesis and abnormalities by inhibiting the secretion of angiogenic factors, such as VEGF, FGF, and PDGF. Finally immune checkpoint inhibitors restores the exhausted T cell activity to kill the cancer cell.

6. Figure 1 caption: Please explain all abbreviation used in Figure 1, e.g., MDCS, ROS, etc. Please change “T-cell” and “B-cell” for “T cell” and “B cell”. Then the way these names are written throughout the manuscript will be unified.

As request we explained all abbreviations and changed T-cell and B-cell for T cell and B cell.

7. The quality of Figure 1 must be improved. Currently, it has low resolution and is blurred.

As request we improved Figure 1 resolution.

8. Abbreviations used in tables should be explained only once, on first use.

We corrected that.

9. References:
10. Line 161: Please add more recent article describing dysregulation of signaling pathways in thyroid cancer, e.g., Int J Mol Sci. 2021;22(21):11829.

As request we added this reference.

274. Please add references in lines 375, 260 and 274.

We added these references.

1. Please change “Derk et al” for “Derks et al.” or “Derks and collaborators”.

We changed Derk et al for Derk et al.

1. Table 2: “Yamazaki 2021 [62]” should be changed for “Yamazaki 2020 [62]”.

We changed Yamazaki 2021 [62] for Yamazaki 2020 [62].

93. Please correct Ref. [93]. Now it is “93. Meeting Program and Abstracts. Thyroid 2021, 31, P-1, doi:10.1089/thy.2021.29115.abstracts.”. Some details such as author(s), title, etc. are missing.

We changed this reference (new reference: 89.   Dierks, C; Ruf, J; Seufert, J, Kreissl, M, Klein, C; Spitzweg, C; Kroiss, M; Thomusch, O; Lorenz, K; Zielke, A; Miething, C. Phase II ATLEP trial: Final results for lenvatinib/pembrolizumab in metastasized anaplastic and poorly differentiated thyroid carcinoma. Annals Oncol 2022, 33, suppl_7, S750-S757, doi:10.1016/annonc/annonc1077.). Since this reference is more recent, we have updated the results in the manuscript and in Table 3.

Line 383: Final results for 27 ATC patients demonstrated an overall respose rate and clinical benefits rate at 2 years of 51.9% and 96.3% repectively. Median PFS and OS were respectively evaluated at 10 months and 11 months with 26% of patients who survived more than 2 years.

Reviewer 2 Report

The authors present an excellent summary of the current status regarding pembrolizumab and lenvatinib therapy in anaplastic thyroid carcinoma.

The therapy backgrounds are well described as well as the current status of the few clinical studies. As the tumor entity is rare, the number of subjects is small. Nevertheless, a very successful overview is developed in this review. 

Figure 1. What does the green and red color of the arrows mean?

Author Response

The authors present an excellent summary of the current status regarding pembrolizumab and lenvatinib therapy in anaplastic thyroid carcinoma.

The therapy backgrounds are well described as well as the current status of the few clinical studies. As the tumor entity is rare, the number of subjects is small. Nevertheless, a very successful overview is developed in this review. 

We thank the reviewer for her/his positive comments.

Figure 1. What does the green and red color of the arrows mean?

As request we specified that green arrow means activation and red inhibition.

Round 2

Reviewer 1 Report

The manuscript by Boundin et al. has been significantly improved, however, I would still suggest some changes as listed below.

1. Line 46: Please replace “VEGFR 1–3” with “VEGFR1–3”.

2. Line 161: I would still suggest adding a more recent reference on disturbances in the activity of signaling pathways in thyroid cancer. Only Santarpia et al. (2008) reference is given in the manuscript. I would suggest citing here, e.g., Novel Inhibitor-Based Therapies for Thyroid Cancer-An Update. Int J Mol Sci. 2021 Oct 31;22(21):11829.

3. Lines 306-307: Please change “(selective BRAF and MEK inhibitors)” for “(selective BRAF and MEK inhibitors, respectively)”.

4. Line 368: Please replace “Dierk at al” with “Dierks at al.”.

5. Line 378: Please replace “Dierk” with “Dierks”.

6. Line 405: “Pembrolizumab” should be changed for “pembrolizumab”.

Author Response

We thank your Editorial Board and the two Reviewers for the positive and helpful comments that have been taken into account as described below.

1. Line 46: Please replace “VEGFR 1–3” with “VEGFR1–3”.

As request we replaced “VEGFR 1–3” with “VEGFR1–3”.

2. Line 161: I would still suggest adding a more recent reference on disturbances in the activity of signaling pathways in thyroid cancer. Only Santarpia et al. (2008) reference is given in the manuscript. I would suggest citing here, e.g., Novel Inhibitor-Based Therapies for Thyroid Cancer-An Update. Int J Mol Sci. 2021 Oct 31;22(21):11829.

As request we added this citation.

3. Lines 306-307: Please change “(selective BRAF and MEK inhibitors)” for “(selective BRAF and MEK inhibitors, respectively)”.

As request we changed (selective BRAF and MEK inhibitors)” for “(selective BRAF and MEK inhibitors, respectively).

4. Line 368: Please replace “Dierk at al” with “Dierks at al.”.

As request we replaced “Dierk at al” with “Dierks at al.”.

5. Line 378: Please replace “Dierk” with “Dierks”.

As request we did it.

6. Line 405: “Pembrolizumab” should be changed for “pembrolizumab”.

As request we changed Pembrolizumab for pembrolizumab.