Title: Evaluation of pembrolizumab plus cisplatin and fluorouracil in radical treatment for
patients with T4b esophageal squamous cell carcinoma
Version: 1 Date: 03 Feb 2024
Reviewer's report:
In this article, the authors performed a retrospective study in a small cohort of patients treated
with first palliative regimen based on the results of KEYNOTE-590 trial, a doublet of platinum
plus fluoropyrimidine and pembrolizumab, for patients with cT4b with or without distant
metastasis squamous esophageal carcinomas. They wanted to illustrate cases in which this new
combination of chemotherapy plus immune-checkpoint inhibitor can increase the response rate
in terms of shrinkage of the primary cT4b tumor, leading to a subsequent radical approach, such
as radical surgery or radiotherapy.
In my opinion, I think this is an interesting original article, as it provides with some real-
world data of a subset of patients with dismal prognosis in which better therapeutic options are
obviously warranted. However, in its current version I have detected some incongruencies and
I think it does need major review to addressing some points:
• In the TITLE, I might suggest a change of the phrasing, as “induction therapy” can lead to a
misunderstanding of the scope here presented. The KEYNOTE-590 trial was a pivotal trial in
the first line palliative setting, hence only patients with metastatic disease or locally advanced
irresectable patients were deemed eligible. The word “induction” could be interpretated as
“neoadjuvant” setting, and the results here presented should be interpretated with caution as
readers should not interpret that the aim of starting CHT plus pembrolizumab is to get a
final surgery. Maybe something like “radical management of patients with unresectable T4b
esophageal squamous cell carcinomas responding to pembrolizumab plus cisplatin and 5-
fluorouracil”. It will give a more broaden insight into the retrospective review of this single
center experience, not only for resected tumors but also for those treated with radiotherapy.
• In the ABSTRACT, there is an apparent error (line 39) stating that only 1 patient underwent
conversion surgery, but table 2 highlights that 2 patients underwent surgery. Please clarify if 1
or 2 patients and correct accordingly.
• In the INTRODUCTION, after the third paragraph introducing the ORR of KEYNOTE-590
trial of 40% (lines 85-86), the authors should include a paragraph explaining the relevant results
observed in this pivotal trial, such as the benefit seen in the whole cohort of patients, but
remarkably, increased efficacy in the ESCC population that consisted on the 75% of the total of
included patients (OS HR 0.72), a higher benefit in the PD-L1 CPS >= 10 patients (OS HR 0.62),
and the highest benefit seen in the ESCC PD-L1 CPS>= 10 patients (OS HR 0.57). This could
serve to highlight the differences seen in approval indications (e.g. FDA approval for both adeno/
ESCC independently of PD-L1 expression whilst EMA approval for both histologies BUT only
PD-L1 CPS>= 10 # this introductory paragraph is relevant to later on include in the discussion
a paragraph about the differences in efficacy seen between responders and non-responders and
their PD-L1 expression, which is currently missing in this version of the article.
• In MATERIAL AND METHODS, I think the authors should reference the evaluation of
clinical response (lines 130-133), as the formula has not been previously referenced in this
article, and justify why they have used it (e.g. are they using it in their clinical practice?)
• In RESULTS, there is contradictory information regarding the cases: (lines 145-146) they
report 2 patients with distant organ metastasis (1 in the liver, the other in pleura), whilst in
material and methods/patients (lines 109-110) they describe 3 patients with distant metastasis
(1 in the liver, 1 in the lung and the third in the pleura). Please clarify and correct accordingly.
In this sense, TABLE 1 PATIENT’S CHARACTERISTICS could be more detailed: I would
suggest adding between T and M, the N to give full details of cTNM of these 8 presented cases.
On the other hand, I find difficult to follow the whole evaluation of efficacy section, as it is
described. May I suggest to re-write this section only in two major points, first describe the
responders=patients who then underwent radical approaches (cases 1, 3, 4, 5, 6) and their main
characteristics in terms of cTNM and PD-L1 CPS expression, compared to the non-responders=
patients who had to continue systemic treatment (cases 2, 7, 8). Alongside, maybe I would re-
structure TABLE 2 in these two subgroups with different subheadings (RESPONDERS VS
NON-RESPONDERS), adding anatomo-pathology information in the resected specimen (e.g.
pCR and R0?) together with radiological details of downgrading of the cTNM – yTNM if
available to get more details of the real “induction” results of CHT+ICI. I think, the review
would have more value if figures of responders were added (1, 3, 4, 5, 6), with timelines of their
diseases (duration of treatment in number of cycles, time of surgery or radiotherapy, with photos
comparing RECIST 1.1. of initial tumor and re-evaluation that prompted to the radical therapy).
In the adverse events section, I miss information regarding potential irAEs presented, are there
any potential immune related AEs? Please clarify and develop the G2 prolonged renal damage
(platinum-related? Immune nephritis? did this patient required steroids?). Depending on these,
please re-structure TABLE 3 according with AEs / irAEs
• In DISCUSSION, I think the statement in lines 202-203 is too strong as it currently reads “there
was no apparent relationship between efficacy and the PD-L1 CPS”. Authors should be very
cautious as this is a RWD review but with several limitations that are not disclosed: small n,
heterogeneous populations -mixed metastatic patients and locally advanced, no data regarding
pCR or downstaging of cTNM/yTNM…hence if lack of complete correlation between data is a
limitation, they should elaborate a bit more the hypothesis behind the results here presented.
Line 210-211 should be rephrased as it currently states “depending on these results, this
regimen…PD-L1 CPS is low”. In fact, FDA has approved the combination of CHT+pembro
independently of PD-L1 expression in both ESCC and adenocarcinomas.
In my opinion, the last 2 paragraphs from lines 220-241 do not offer relevant information for
this kind of article, as hyperprogressors are still not well characterized and airway fistulas in
rapidly growing patients harboring cT4b can occur without pembrolizumab, as it is commonly
seen and reported in trials with only chemotherapy. On top of this, I do not feel appropriate
adding a figure in the discussion of an article. Instead, as mentioned before, the article would
much improve reinforcing the information about the responders that could underwent radical
approaches (surgery or radiotherapy), adding a composed figure with more details of the
responders in the efficacy section.
Instead, in this final part of the discussion the authors should mention that recent updates of the
5-year outcomes of the KEYNOTE-590 trial presented in ASCO GI 2024 meeting this January
by Shah M. demonstrated that 11.8% of ESCC patients that received CHT+pembro are alive
compared to only 3.4% with CHT alone, and interestingly when asked during the discussion,
it was noted that in this 11.8% of long-term survivors were included patients that underwent
salvage surgery or radiotherapy. cT4b responders might have fallen in this subgroup of patients
reported in the tail of the OS Kaplan-Meier curves, and it should be further developed here in
this discussion to wrap up the review.
Title: Evaluation of pembrolizumab plus cisplatin and fluorouracil in radical treatment for
patients with T4b esophageal squamous cell carcinoma
Version: 1 Date: 03 Feb 2024
Reviewer's report:
In this article, the authors performed a retrospective study in a small cohort of patients treated
with first palliative regimen based on the results of KEYNOTE-590 trial, a doublet of platinum
plus fluoropyrimidine and pembrolizumab, for patients with cT4b with or without distant
metastasis squamous esophageal carcinomas. They wanted to illustrate cases in which this new
combination of chemotherapy plus immune-checkpoint inhibitor can increase the response rate
in terms of shrinkage of the primary cT4b tumor, leading to a subsequent radical approach, such
as radical surgery or radiotherapy.
In my opinion, I think this is an interesting original article, as it provides with some real-
world data of a subset of patients with dismal prognosis in which better therapeutic options are
obviously warranted. However, in its current version I have detected some incongruencies and
I think it does need major review to addressing some points:
• In the TITLE, I might suggest a change of the phrasing, as “induction therapy” can lead to a
misunderstanding of the scope here presented. The KEYNOTE-590 trial was a pivotal trial in
the first line palliative setting, hence only patients with metastatic disease or locally advanced
irresectable patients were deemed eligible. The word “induction” could be interpretated as
“neoadjuvant” setting, and the results here presented should be interpretated with caution as
readers should not interpret that the aim of starting CHT plus pembrolizumab is to get a
final surgery. Maybe something like “radical management of patients with unresectable T4b
esophageal squamous cell carcinomas responding to pembrolizumab plus cisplatin and 5-
fluorouracil”. It will give a more broaden insight into the retrospective review of this single
center experience, not only for resected tumors but also for those treated with radiotherapy.
• In the ABSTRACT, there is an apparent error (line 39) stating that only 1 patient underwent
conversion surgery, but table 2 highlights that 2 patients underwent surgery. Please clarify if 1
or 2 patients and correct accordingly.
• In the INTRODUCTION, after the third paragraph introducing the ORR of KEYNOTE-590
trial of 40% (lines 85-86), the authors should include a paragraph explaining the relevant results
observed in this pivotal trial, such as the benefit seen in the whole cohort of patients, but
remarkably, increased efficacy in the ESCC population that consisted on the 75% of the total of
included patients (OS HR 0.72), a higher benefit in the PD-L1 CPS >= 10 patients (OS HR 0.62),
and the highest benefit seen in the ESCC PD-L1 CPS>= 10 patients (OS HR 0.57). This could
serve to highlight the differences seen in approval indications (e.g. FDA approval for both adeno/
ESCC independently of PD-L1 expression whilst EMA approval for both histologies BUT only
PD-L1 CPS>= 10 # this introductory paragraph is relevant to later on include in the discussion
a paragraph about the differences in efficacy seen between responders and non-responders and
their PD-L1 expression, which is currently missing in this version of the article.
• In MATERIAL AND METHODS, I think the authors should reference the evaluation of
clinical response (lines 130-133), as the formula has not been previously referenced in this
article, and justify why they have used it (e.g. are they using it in their clinical practice?)
• In RESULTS, there is contradictory information regarding the cases: (lines 145-146) they
report 2 patients with distant organ metastasis (1 in the liver, the other in pleura), whilst in
material and methods/patients (lines 109-110) they describe 3 patients with distant metastasis
(1 in the liver, 1 in the lung and the third in the pleura). Please clarify and correct accordingly.
In this sense, TABLE 1 PATIENT’S CHARACTERISTICS could be more detailed: I would
suggest adding between T and M, the N to give full details of cTNM of these 8 presented cases.
On the other hand, I find difficult to follow the whole evaluation of efficacy section, as it is
described. May I suggest to re-write this section only in two major points, first describe the
responders=patients who then underwent radical approaches (cases 1, 3, 4, 5, 6) and their main
characteristics in terms of cTNM and PD-L1 CPS expression, compared to the non-responders=
patients who had to continue systemic treatment (cases 2, 7, 8). Alongside, maybe I would re-
structure TABLE 2 in these two subgroups with different subheadings (RESPONDERS VS
NON-RESPONDERS), adding anatomo-pathology information in the resected specimen (e.g.
pCR and R0?) together with radiological details of downgrading of the cTNM – yTNM if
available to get more details of the real “induction” results of CHT+ICI. I think, the review
would have more value if figures of responders were added (1, 3, 4, 5, 6), with timelines of their
diseases (duration of treatment in number of cycles, time of surgery or radiotherapy, with photos
comparing RECIST 1.1. of initial tumor and re-evaluation that prompted to the radical therapy).
In the adverse events section, I miss information regarding potential irAEs presented, are there
any potential immune related AEs? Please clarify and develop the G2 prolonged renal damage
(platinum-related? Immune nephritis? did this patient required steroids?). Depending on these,
please re-structure TABLE 3 according with AEs / irAEs
• In DISCUSSION, I think the statement in lines 202-203 is too strong as it currently reads “there
was no apparent relationship between efficacy and the PD-L1 CPS”. Authors should be very
cautious as this is a RWD review but with several limitations that are not disclosed: small n,
heterogeneous populations -mixed metastatic patients and locally advanced, no data regarding
pCR or downstaging of cTNM/yTNM…hence if lack of complete correlation between data is a
limitation, they should elaborate a bit more the hypothesis behind the results here presented.
Line 210-211 should be rephrased as it currently states “depending on these results, this
regimen…PD-L1 CPS is low”. In fact, FDA has approved the combination of CHT+pembro
independently of PD-L1 expression in both ESCC and adenocarcinomas.
In my opinion, the last 2 paragraphs from lines 220-241 do not offer relevant information for
this kind of article, as hyperprogressors are still not well characterized and airway fistulas in
rapidly growing patients harboring cT4b can occur without pembrolizumab, as it is commonly
seen and reported in trials with only chemotherapy. On top of this, I do not feel appropriate
adding a figure in the discussion of an article. Instead, as mentioned before, the article would
much improve reinforcing the information about the responders that could underwent radical
approaches (surgery or radiotherapy), adding a composed figure with more details of the
responders in the efficacy section.
Instead, in this final part of the discussion the authors should mention that recent updates of the
5-year outcomes of the KEYNOTE-590 trial presented in ASCO GI 2024 meeting this January
by Shah M. demonstrated that 11.8% of ESCC patients that received CHT+pembro are alive
compared to only 3.4% with CHT alone, and interestingly when asked during the discussion,
it was noted that in this 11.8% of long-term survivors were included patients that underwent
salvage surgery or radiotherapy. cT4b responders might have fallen in this subgroup of patients
reported in the tail of the OS Kaplan-Meier curves, and it should be further developed here in
this discussion to wrap up the review.
Please review this paper.
user
Title: Evaluation of pembrolizumab plus cisplatin and fluorouracil in radical treatment for
patients with T4b esophageal squamous cell carcinoma
Version: 1 Date: 03 Feb 2024
Reviewer's report:
In this article, the authors performed a retrospective study in a small cohort of patients treated
with first palliative regimen based on the results of KEYNOTE-590 trial, a doublet of platinum
plus fluoropyrimidine and pembrolizumab, for patients with cT4b with or without distant
metastasis squamous esophageal carcinomas. They wanted to illustrate cases in which this new
combination of chemotherapy plus immune-checkpoint inhibitor can increase the response rate
in terms of shrinkage of the primary cT4b tumor, leading to a subsequent radical approach, such
as radical surgery or radiotherapy.
In my opinion, I think this is an interesting original article, as it provides with some real-
world data of a subset of patients with dismal prognosis in which better therapeutic options are
obviously warranted. However, in its current version I have detected some incongruencies and
I think it does need major review to addressing some points:
• In the TITLE, I might suggest a change of the phrasing, as “induction therapy” can lead to a
misunderstanding of the scope here presented. The KEYNOTE-590 trial was a pivotal trial in
the first line palliative setting, hence only patients with metastatic disease or locally advanced
irresectable patients were deemed eligible. The word “induction” could be interpretated as
“neoadjuvant” setting, and the results here presented should be interpretated with caution as
readers should not interpret that the aim of starting CHT plus pembrolizumab is to get a
final surgery. Maybe something like “radical management of patients with unresectable T4b
esophageal squamous cell carcinomas responding to pembrolizumab plus cisplatin and 5-
fluorouracil”. It will give a more broaden insight into the retrospective review of this single
center experience, not only for resected tumors but also for those treated with radiotherapy.
• In the ABSTRACT, there is an apparent error (line 39) stating that only 1 patient underwent
conversion surgery, but table 2 highlights that 2 patients underwent surgery. Please clarify if 1
or 2 patients and correct accordingly.
• In the INTRODUCTION, after the third paragraph introducing the ORR of KEYNOTE-590
trial of 40% (lines 85-86), the authors should include a paragraph explaining the relevant results
observed in this pivotal trial, such as the benefit seen in the whole cohort of patients, but
remarkably, increased efficacy in the ESCC population that consisted on the 75% of the total of
included patients (OS HR 0.72), a higher benefit in the PD-L1 CPS >= 10 patients (OS HR 0.62),
and the highest benefit seen in the ESCC PD-L1 CPS>= 10 patients (OS HR 0.57). This could
serve to highlight the differences seen in approval indications (e.g. FDA approval for both adeno/
ESCC independently of PD-L1 expression whilst EMA approval for both histologies BUT only
PD-L1 CPS>= 10 # this introductory paragraph is relevant to later on include in the discussion
a paragraph about the differences in efficacy seen between responders and non-responders and
their PD-L1 expression, which is currently missing in this version of the article.
• In MATERIAL AND METHODS, I think the authors should reference the evaluation of
clinical response (lines 130-133), as the formula has not been previously referenced in this
article, and justify why they have used it (e.g. are they using it in their clinical practice?)
• In RESULTS, there is contradictory information regarding the cases: (lines 145-146) they
report 2 patients with distant organ metastasis (1 in the liver, the other in pleura), whilst in
material and methods/patients (lines 109-110) they describe 3 patients with distant metastasis
(1 in the liver, 1 in the lung and the third in the pleura). Please clarify and correct accordingly.
In this sense, TABLE 1 PATIENT’S CHARACTERISTICS could be more detailed: I would
suggest adding between T and M, the N to give full details of cTNM of these 8 presented cases.
On the other hand, I find difficult to follow the whole evaluation of efficacy section, as it is
described. May I suggest to re-write this section only in two major points, first describe the
responders=patients who then underwent radical approaches (cases 1, 3, 4, 5, 6) and their main
characteristics in terms of cTNM and PD-L1 CPS expression, compared to the non-responders=
patients who had to continue systemic treatment (cases 2, 7, 8). Alongside, maybe I would re-
structure TABLE 2 in these two subgroups with different subheadings (RESPONDERS VS
NON-RESPONDERS), adding anatomo-pathology information in the resected specimen (e.g.
pCR and R0?) together with radiological details of downgrading of the cTNM – yTNM if
available to get more details of the real “induction” results of CHT+ICI. I think, the review
would have more value if figures of responders were added (1, 3, 4, 5, 6), with timelines of their
diseases (duration of treatment in number of cycles, time of surgery or radiotherapy, with photos
comparing RECIST 1.1. of initial tumor and re-evaluation that prompted to the radical therapy).
In the adverse events section, I miss information regarding potential irAEs presented, are there
any potential immune related AEs? Please clarify and develop the G2 prolonged renal damage
(platinum-related? Immune nephritis? did this patient required steroids?). Depending on these,
please re-structure TABLE 3 according with AEs / irAEs
• In DISCUSSION, I think the statement in lines 202-203 is too strong as it currently reads “there
was no apparent relationship between efficacy and the PD-L1 CPS”. Authors should be very
cautious as this is a RWD review but with several limitations that are not disclosed: small n,
heterogeneous populations -mixed metastatic patients and locally advanced, no data regarding
pCR or downstaging of cTNM/yTNM…hence if lack of complete correlation between data is a
limitation, they should elaborate a bit more the hypothesis behind the results here presented.
Line 210-211 should be rephrased as it currently states “depending on these results, this
regimen…PD-L1 CPS is low”. In fact, FDA has approved the combination of CHT+pembro
independently of PD-L1 expression in both ESCC and adenocarcinomas.
In my opinion, the last 2 paragraphs from lines 220-241 do not offer relevant information for
this kind of article, as hyperprogressors are still not well characterized and airway fistulas in
rapidly growing patients harboring cT4b can occur without pembrolizumab, as it is commonly
seen and reported in trials with only chemotherapy. On top of this, I do not feel appropriate
adding a figure in the discussion of an article. Instead, as mentioned before, the article would
much improve reinforcing the information about the responders that could underwent radical
approaches (surgery or radiotherapy), adding a composed figure with more details of the
responders in the efficacy section.
Instead, in this final part of the discussion the authors should mention that recent updates of the
5-year outcomes of the KEYNOTE-590 trial presented in ASCO GI 2024 meeting this January
by Shah M. demonstrated that 11.8% of ESCC patients that received CHT+pembro are alive
compared to only 3.4% with CHT alone, and interestingly when asked during the discussion,
it was noted that in this 11.8% of long-term survivors were included patients that underwent
salvage surgery or radiotherapy. cT4b responders might have fallen in this subgroup of patients
reported in the tail of the OS Kaplan-Meier curves, and it should be further developed here in
this discussion to wrap up the review.
assistant