Efficacy and Safety of Nivolumab and Ipilimumab for Advanced or Metastatic Renal Cell Carcinoma: A Multicenter Retrospective Cohort Study

Round 1

Reviewer 1 Report

In this manuscript by Koji et al., the authors have investigated the safety and efficacy of nivolumab (NIVO) and ipilimumab (IPI) for advanced or metastatic renal cell carcinoma. They found that the Patients treated with NIVO+IPI had a better outcome. The manuscript is not acceptable in its current form. It may be reconsidered for publication after addressing the below comments and subsequent reviews.

1. NIVO and IPI were well studied in metastatic renal cell carcinoma. The authors should justify the novelty of their study.
2. The authors should provide limitations to the study.
3. The level of PD-1, CTLA-4 and other related signalling molecules should be analyzed on the patient tissues to confirm the specific effect of drugs.
4. The data on the level of inflammation would also support the findings.

Author Response

Responses to the reviewer's comments

We would like to thank the Reviewers for taking the time and effort necessary to review the manuscript. We sincerely appreciate all the valuable comments and suggestions, which helped us to improve the quality of the manuscript.

 

Response to Reviewer 1

The authors appreciate the reviewer’s comments. The authors’ point-by-point responses to the comments are given below.

 

1. NIVO and IPI were well studied in metastatic renal cell carcinoma. The authors should justify the novelty of their study.

Response:

We have added the following sentence on line 27:

In addition, we evaluated the role of inflammatory cell ratios, namely, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as predictive biomarkers in patients with mRCC.

 

We have added the following sentence on line 31:

According to NLR stratification, the 1-year PFS rates were 82.6% and 23.7% when the NLR was ≤4.6 and >4.6, respectively (p = 0.04). Based on PLR stratification, the 1-year PFS rates were 81.7% and 34.3% when the PLR was ≤188.1 and >188.1, respectively (p = 0.033).

 

We have added the following sentence on line 100:

the data on the level of inflammation, including neutrophil count, lymphocyte count, platelet count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR),

 

We have added the following sentence on line 122:

NLR and PLR were calculated as the absolute neutrophil count and absolute platelet count divided by the absolute lymphocyte count within the peripheral blood, respectively. The cutoff values for NLR and PLR were defined as the minimal value for (1 − sensitivity)² + (1 − specificity)² according to the area under the receiver operating characteristic (ROC) curve [17].

 

We have added the following sentence on line 131:

In addition, PFS was evaluated according to NLR and PLR.

 

We have added the following sentence on line 147:

The median NLR and PLR were 3.5 and 215.6, respectively. Based on ROC analysis, the NLR cutoff was estimated to be 4.6 (sensitivity, 72.7%; specificity, 79.2%) and the PLR cutoff was estimated to be 188.1% (sensitivity, 90.9%; specificity, 54.2%).

 

We have added the following sentence on line 163 and Figure 2:

According to NLR stratification, the 1-year PFS rates were 82.6% and 23.7% when the NLR was ≤4.6 and >4.6, respectively (p = 0.04; Fig. 2A). Based on PLR stratification, the 1-year PFS rates were 81.7% and 34.3% when the PLR was ≤188.1 and >188.1, respectively (p = 0.033; Fig. 2B).

 

We have added the following sentence on line 181 and Table 3:

In multivariate analysis, IMDC poor risk and PLR >188.1 were associated with poor PFS (Table 3).

 

We have added the following paragraph on line 227:

Zhang et al. [19] reported that systemic inflammation plays a crucial role in the development and progression of cancer. NLR and PLR can be easily determined from the peripheral blood count. Several studies have evaluated the role of such inflammatory cell ratios as predictive biomarkers in patients with various solid tumors treated with NIVO [19–21]. While high baseline NLR and PLR were found to be associated with treatment failure and increased risk of death, low NLR following NIVO treatment was associated with improved oncological outcomes [19,20]. However, the relationship between NLR and PLR and their predictive effects in mRCC patients treated with NIVO + IPI remain unclear. Recently, several meta-analyses have evaluated the utility of PLR as a prognostic factor in cancer patients treated with ICIs [22]. To our knowledge, this is the first study to evaluate the utility of PLR as a prognostic marker in mRCC patients who received ICI therapy, particularly NIVO + IPI. Our study suggests that a high pretreatment PLR may be associated with poor PFS in mRCC patients administered NIVO + IPI. Previous studies have revealed the utility of NLR as an inflammatory biomarker in mRCC patients [23–25]. Although NLR was not significantly associated with PFS in the multivariate analysis in our study, mRCC patients with NLR <4.6 reported a significantly longer PFS than their counterparts. Therefore, NLR may be considered a prognostic marker in mRCC patients treated with NIVO + IPI. Further long-term studies are required to verify the effectiveness of PLR and NLR as prognostic biomarkers in mRCC patients treated with NIVO + IPI.

 

2. The authors should provide limitations to the study.
3. The level of PD-1, CTLA-4 and other related signalling molecules should be analyzed on the patient tissues to confirm the specific effect of drugs.

Response:

We have added the following paragraph on line 255:

 Fourth, we could not evaluate the expression levels of PDL-1 and CTLA-4 because this was a multicenter retrospective study. Indeed, lack of PD-L1 expression correlates with worse outcomes with ICI treatment [29,30]. However, several randomized studies have demonstrated that patients with PD-L1- positive tumors did not show improved OS and ORR [7,8,13].

 

4. The data on the level of inflammation would also support the findings.

Response:

We have revised Table 2, including inflammatory parameters.

 

 

 

Reviewer 2 Report

Iinuma et al report on a retrospective cohort study investigating the efficacy of Nivolumab and Ipilimumab in the treatment of patients with metastatic renal cell carcinoma. The study investigates the effect of immunotherapy in a real-world setting in a Japanese population which was represented only in small numbers in the pivotal Checkmate 214 trial.

The authors should be congratulated for their work. It is important to investigate whether results from large randomized trials hold true in a real world setting outside the artificial environment of multi-centre randomized controlled trials.

We have significant concerns regarding the small sample size and the short follow-up which did not allow for median PFS (or OS) and thus make it difficult to draw comparisons with the results from randomized trials. Iinuma et al. concllude that this cohort study may provide evidence that IO has potential advantages compared to targeted therapy. This conclusion is too strong and cannot be justified from this small, retrospective study. The study is of some merit for describing the real-world, population-specific results.

Major comments:

The endpoint of most interest and importance is OS. Choosing ORR allows early submission of results of course but limits their interpretation.

This is a retrospective cohort study only investigating the combination of Nivolumab plus Ipilimumab, comparisons regarding a higher efficacy compared to targeted therapy is not within the scope of such a study.

A direct, descriptive comparison of the study results with the Checkmate 214 trial would be of more interest. It is relevant and of interest to investigate whether the study results hold true in a real-world setting.

Minor comments:

The written English is largely very good but requires some attention in a few places.

Abstract:

1. Please add the number of patients included.

Introduction:

1. Line 45: The NCCN guidelines also include combination immunotherapy or combination of immunotherapy and targeted therapy as first line treatment. Please describe that as well. Also the list presented as options in first line includes options only approved in other lines of therapy, beyond first line and thus is unclear. Will need to be better described.

2. Line 70f: Actually, the results show, that the effect of Ipilimumab plus Nivolumab vs. Sunitnib is similar in the Japanese population. The HR of 0.56 for the Japanese population is align with the HR for the overall population 0.66. The wider CIs and the p value of 0.267 are explained by the small size of this subgroup. Please discuss that accordingly.

Material Methods:

1. Please use a reporting guideline for this study (e.g. STROBE and add the corresponding checklist)

2. Please briefly explain how you calculated the follow-up time.

3. Please quantify missing data and report how you handled it.

 

Discussion:

1. Line 155f: Those differences are not substantial. Overall, the results confirm the results from the CM-214 trial.

2. Please discuss also characteristics of your patient population and compare it with the population from the CM-214 in more detail.

3. Figure 1 and Figure2: Please add tick marks for censoring and add the number of censored patients to the x axis.

Author Response

Responses to the reviewer's comments

We would like to thank the Reviewers for taking the time and effort necessary to review the manuscript. We sincerely appreciate all the valuable comments and suggestions, which helped us to improve the quality of the manuscript.

 

 

Response to Reviewer 2

The authors appreciate the reviewer’s comments. The authors’ point-by-point responses to the comments are given below.

 

1. The endpoint of most interest and importance is OS. Choosing ORR allows early submission of results of course but limits their interpretation.

 

Response:

We have revised the following part on line 22:

nivolumab plus ipilimumab (NIVO+IPI) in 35 patients

 

We have revised the following sentence on line 26:

The primary endpoint was overall survival (OS). Secondary endpoints were disease control rate (DCR), best overall response (BOR), objective response rate (ORR), and progression-free survival (PFS).

 

We have revised the following sentence on line 130:

The primary endpoint was OS. Secondary endpoints were DCR, BOR, ORR, and PFS.

 

We have revised the following sentences on line 155 and Figure 1:

The OSs at 6, 12, and 18 months were 100%, 95.8%, and 87.1%, respectively (Fig. 1A). The PFSs at 6, 12, and 18 months were 78.6%, 56.2%, and 56.2%, respectively (Fig. 1B).

 

 

2. This is a retrospective cohort study only investigating the combination of Nivolumab plus Ipilimumab, comparisons regarding a higher efficacy compared to targeted therapy is not within the scope of such a study.

Response:

We have excluded the following sentences on line 160:

Conversely, several studies reported efficacy and safety in Japanese patients with advanced or mRCC using TKIs and VEGF inhibitors [15-17]. Ueda et al. reported the results of subgroup analysis of Japa-nese patients from the AXIS trial [15]. Although the ORR rate was 52.0% for axitinib and 3.4% for so-rafenib (p = 0.0001), none of the patients achieved CR in both groups [15]. Based on the real-world use of SUN in Japanese patients with advanced RCC, the ORR was 22% [16]. In addition, only eight pa-tients (1%) achieved CR, and the majority of the patients who received SUN (40%) achieved SD [16]. In a multicenter randomized trial using SUN or sorafenib as an initial targeted therapy for favorable or intermediate risk mRCC, there were no significant differences of ORR between patients receiving SUN and sorafenib (29.8% vs. 21.7%, respectively; p = 0.390) [17]. According to ORR,

 

3. A direct, descriptive comparison of the study results with the Checkmate 214 trial would be of more interest. It is relevant and of interest to investigate whether the study results hold true in a real-world setting.

Response:

We have added the following sentence on line 195:

The clinical characteristics of the patients in this study were generally similar to those of the population of Checkmate 214 [8]. However, the enrolled patients in this study comprised a relatively higher proportion of patients who were classified as IMDC poor risk than those in Checkmate 214 [8].

 

We have added the following sentence on line 204:

These results were comparable with our results, despite the higher population of IMDC poor risk patients in our study. Based on the results of Japanese patients in Checkmate 214 and our results,

 

4. The written English is largely very good but requires some attention in a few places.

Response:

The manuscript has been checked for language and proofread by an English editing service.

 

5. Abstract: 1. Please add the number of patients included.

Response:

We have added the number of patients on line 22.

combination nivolumab plus ipilimumab (NIVO+IPI) in 35 patients with advanced or metastatic renal cell carcinoma (mRCC).

 

We have revised Tables 1, 2, 3, and 4, and Figure 1.

 

6. Line 45: The NCCN guidelines also include combination immunotherapy or combination of immunotherapy and targeted therapy as first line treatment. Please describe that as well. Also the list presented as options in first line includes options only approved in other lines of therapy, beyond first line and thus is unclear. Will need to be better described.

Response:

We have revised the sentence on line 77:

In addition, the treatment for metastatic RCC has dramatically changed. In an open-label phase III trial (KEYNOTE-426), advanced RCC patients who received pembrolizumab plus AXI had a significantly longer OS and PFS and higher objective response rate than those who received SUN only [11]. In the phase 3 JAVELIN Renal 101 trial, PFS was significantly longer with avelumab plus AXI than with SUN among patients who received these agents as first-line treatments for advanced RCC [7]. The results of the IMmotion151 trial for untreated metastatic RCC revealed that in programmed cell death1-ligand 1 (PD-L1)-positive population, the median PFS was 11.2 months in the atezolizumab plus bevacizumab group versus 7.7 months in the SUN group (p = 0.022) [12]. In CheckMate 9ER, nivolumab (NIVO) plus cabozantinib demonstrated superiority over SUN by doubling the PFS time and OS rate and significantly improving OS for advanced RCC [13]. Based on these results, it can be suggested that combination therapy may have several advantages with oncological outcomes in advanced or metastatic RCC compared with NIVO monotherapy.

 

7. Line 70: Actually, the results show, that the effect of Ipilimumab plus Nivolumab vs. Sunitnib is similar in the Japanese population. The HR of 0.56 for the Japanese population is align with the HR for the overall population 0.66. The wider CIs and the p value of 0.267 are explained by the small size of this subgroup. Please discuss that accordingly.

Response:

We have revised the following sentence on line 74:

Although OS was not significantly different between the two groups (HR, 0.56; 95% confidence interval, 0.19-1.59; p = 0.267) because of the small sample size, Japanese patients treated with NIVO+IPI showed a delayed OS benefit compared with those treated with SUN [10].

 

8. Please use a reporting guideline for this study (e.g. STROBE and add the corresponding checklist)

Response:

We have added the STROBE check list and submitted it along with the manuscript.

 

9. Please briefly explain how you calculated the follow-up time.

Response:

We added the following sentences on line 133:

The date of the administration with NIVO+IPI was used as the starting point for estimates of OS and PFS. OS was defined as the time from NIVO+IPI commencement to death from any cause. PFS was defined as the time from NIVO+IPI commencement to the disease progression. The Kaplan-Meier method was used to evaluate OS and PFS, and differences were assessed according to clinical variables using log-rank test. Multivariate analysis was performed using a Cox-proportional hazards model. All p values were two-sided, and p value < 0.05 was considered statistically significant.

 

10. Please quantify missing data and report how you handled it.

Response:

We have revised the following sentence on line 143:

A total of 36 patients were treated with NIVO + IPI between August 2018 and March 2020 at eight institutions. Thirty patients were enrolled in this study because of missing data in one patient.

 

11. Line 155: Those differences are not substantial. Overall, the results confirm the results from the CM-214 trial.

Response:

We have deleted the following sentence:

Although the ORR in the CheckMate 214 trial was higher than that in this study (42% vs. 34.3%), DCR and CR rates in this study were relatively higher than those in the CheckMate 214 trial (80.0% vs. 72.0%, 11.1% vs. 9%, respectively) [8].

Therefore, NIVO+IPI as a first-line therapy for mRCC patients of intermediate or poor risk groups (per the IMDC model) may have potential advantages and lead to a treatment effect compared to those receiving targeted therapies.

 

12. Please discuss also characteristics of your patient population and compare it with the population from the CM-214 in more detail.

Response:

We have added the following sentence on line 196:

The clinical characteristics of the patients in this study were generally similar to those of the population of Checkmate 214 [8]. However, the enrolled patients in this study comprised a relatively higher proportion of patients who were classified as IMDC poor risk than those in Checkmate 214 [8].

 

13. Figure 1 and Figure2: Please add tick marks for censoring and add the number of censored patients to the x axis.

Response:

We have revised Figure 1 and 2.

Round 2

Reviewer 1 Report

The manuscript was improved by revision and may be accepted for publication.

Author Response

The authors appreciate the reviewer’s comments.