Durable responses to immune checkpoint inhibitor-based regimens for metastatic clear cell renal cell carcinoma stratified by IMDC risk groups: A pooled analysis of four randomized phase 3 trials

Abstract

Background

An immune checkpoint inhibitor (ICI) backbone is a standard of care for frontline metastatic clear cell renal cell carcinoma, involving either ICI doublet or tyrosine kinase inhibitor (TKI) with ICI. These phase 3 trials used a sunitinib control arm. The optimal regimen is uncertain.

Objective

To compare long-term responders of these trials using extended follow-up data stratified by International Metastatic RCC Database Consortium risk group.

Methods

Phase 3 trial data (CheckMate 214, KEYNOTE-426, CheckMate 9ER, and CLEAR) with a minimum follow-up of four years was used. Pseudo individual patient data (IPD) was obtained from Kaplan-Meier curves using the graph digitizer software IPDfromKM R package to extract coordinates of points on the curves and to apply a numerical algorithm to reconstruct progression-free survival (PFS) and overall survival (OS) results. Durable response (DR) was defined as PFS ≥ 24 months, extreme durable response (EDR) as PFS ≥ 36 months, and long-term OS as OS ≥ 48 months.

Results

For the favorable risk group, lenvatinib-pembrolizumab had the highest DR and EDR, while ipilimumab-nivolumab had the lowest DR, and cabozantinib-nivolumab had the lowest EDR; there was no difference in long-term OS among the regimens (p = 0.11). For the intermediate/poor risk group, lenvatinib-pembrolizumab also had the highest DR and EDR compared to other regimens with similar DR and EDR; there was also no difference in long-term OS among the regimens (p = 0.22).

Conclusion

TKI-ICI was overall associated with higher DR and EDR regardless of risk status compared to ICI doublet. Yet, OS at 48 months were similar when stratified by favorable versus intermediate/poor risk.

Keywords

renal cell carcinoma immune checkpoint inhibitor tyrosine kinase inhibitor

Introduction

The treatment landscape for previously untreated metastatic clear cell renal cell carcinoma (mccRCC) has dramatically shifted over the past ten years with immune checkpoint inhibitors (ICIs) as the backbone. In the decade preceding this shift, the standard of care had been vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), notably sunitinib or pazopanib, over interferon-alpha.^1–3

Four phase 3 trials successfully demonstrated a survival benefit for the experimental ICI arm over a sunitinib monotherapy control arm for patients with previously untreated mccRCC. This includes the ICI doublet ipilimumab and nivolumab (ipi-nivo) from CheckMate 214⁴ and three ICI and VEGFR TKI combinations: axitinib and pembrolizumab (axi-pembro) from KEYNOTE-426,⁵ lenvatinib and pembrolizumab (len-pembro) from CLEAR,⁶ and cabozantinib and nivolumab (cabo-nivo) from CheckMate 9ER.⁷ All four combinations now have regulatory approval. All these trials evaluated ICI regimens for patients with previously untreated mccRCC. Despite similarities in study design, there were several key differences such as patient representation from International Metastatic RCC Database Consortium (IMDC) risk groups, varying proportions of patients with sarcomatoid features, different years of enrollment, and thus different salvage systemic therapy options. Moreover, CheckMate 214 was the only study allowing PD-1 inhibitor to be given for longer than two years, while the ICIs for the ICI-TKI regimens were given for two years maximum duration. CheckMate 9ER was the only trial to use the TKI (cabozantinib) at a lower dose (40 mg) compared to the approved dose for use as a single agent (60 mg). In contrast, CLEAR evaluated a higher dose of TKI (lenvatinib, 20 mg) with pembrolizumab compared to the approved dose in combination with everolimus (18 mg).

With several treatment options, there is much interest in identifying which regimen could be the most efficacious at providing durable long-term responses. However, these ICI regimens have not been compared directly. In this analysis, we stratify the outcomes of PFS and OS based on the IMDC risk model for patients with a minimum follow-up of four years (48 months) for the four different combination regimens.^8–11

Methods

A search of clinicaltrials.gov was performed for phase 3/4 trials using search term “renal cell carcinoma” which yielded four frontline ICI-based trials (CheckMate 214, CheckMate 9ER, KEYNOTE-426, and CLEAR) with OS benefit for the experimental arm over the control arm as a primary endpoint (Supplementary Figure 1). For these four ICI-based trials that led to regulatory approval as frontline regimens for mccRCC, pseudo individual patient data (IPD) was obtained from published favorable risk and intermediate/poor risk PFS and OS Kaplan-Meier (KM) curves using the graph digitizer ‘IPDfromKM’ R package to extract coordinates of points on curves and to apply the numerical algorithm.¹²

PFS and OS were defined similarly among the four trials. Durable response (DR) was defined as PFS ≥ 24 months, extreme durable response (EDR) as PFS ≥ 36 months, and long-term OS as OS ≥ 48 months. These values were determined from evaluating the median PFS for all these ICI-based regimens in the intention-to-treat (ITT) groups and noting the median PFS ranged from 12 to 24 months, with the ICI arm in the CLEAR trial having the longest PFS at 23.9 months; therefore, we considered DR of PFS ≥ 24 months for all patients meeting this definition to perform better than the median PFS of all the ICI-based regimens. Similarly, the median OS for the ITT groups for the ICI-based regimens ranged from 46 to 53 months, so OS ≥ 48 months were chosen for long-term OS. DR, EDR, and long-term OS rates were estimated using the KM method to estimate the survival rates at 24-month PFS, 36-month PFS, and 48-month OS using the extracted IPD. Then, the survival rates at these four time points were calculated using the generalized linear model for the survival rates at fixed time points obtained from the Kaplan-Meier method. These four time points for each curve were then compared using the statistical method of Klein and colleagues¹³ analyzing survival curves at fixed time points, with CheckMate 214 used as the points of reference for these calculations. Overall PFS and OS KM curves among the four trials between the experimental arms and between the control arms were separately compared using the log-rank test.

Results

From 186 phase 3/4 trials reviewed on clinicaltrials.gov, there were 17 trials evaluating ICIs for mccRCC in the frontline setting. Of these, four trials had an overall survival benefit as a primary endpoint: CheckMate 214, CheckMate 9ER, KEYNOTE-426, and CLEAR.

A breakdown of the intention-to-treat populations for the ICI and sunitinib arms by IMDC risk status (favorable, intermediate, and poor) and sarcomatoid features is shown in Table 1. CLEAR had the lowest percentage of poor risk patients enrolled, while CheckMate 9ER had the highest percentage of poor risk patients enrolled. CLEAR also had the lowest percentage of sarcomatoid patients enrolled, while CheckMate 214 had the highest percentage of sarcomatoid patients enrolled.

Table 1.

Baseline demographics at the time of randomization.

Trial	Arm of therapy	Intention to treat arm	Favorable risk	Intermediate risk	Poor risk	Sarcomatoid (irrespective of risk)
CheckMate 214	Ipilimumab and nivolumab	550	125 (22.7%)	334 (60.7%)	91 (16.5%)	74 (13.4%)
	Sunitinib	546	124 (22.7%)	333 (61.0%)	89 (16.3%)	65 (11.9%)
KEYNOTE-426	Axitinib and pembrolizumab	432	138 (31.9%)	238 (55.1%)	56 (13.0%)	51 (11.8%)
	Sunitinib	429	131 (30.5%)	246 (57.3%)	52 (12.1%)	54 (12.6%)
CLEAR	Lenvatinib and pembrolizumab	355	110 (31.0%)	210 (59.2%)	33 (9.3%)	28 (7.9%)
	Sunitinib	357	124 (34.7%)	192 (53.8%)	37 (10.4%)	21 (5.9%)
CheckMate 9ER	Cabozantinib and nivolumab	323	74 (22.9%)	188 (58.2%)	61 (18.9%)	34 (10.5%)
	Sunitinib	328	72 (22.0%)	188 (57.3%)	68 (20.7%)	41 (12.5%)

Table 2.

Comparison of durable response (24-month PFS), EDR (36-month PFS), and long-term OS (48-month OS) for the immune checkpoint inhibitor arms.

		Durable response		Extreme durable response		Long-term overall survival
Risk	Trial/ Study	Survival rate (95% CI)	p-value	Survival rate (95% CI)	p-value	Survival rate (95% CI)	p-value
Favorable	CheckMate 214	0.360 (0.347, 0.373)		0.300 (0.279, 0.321)		0.657 (0.656, 0.658)
	CheckMate 9ER	0.399 (0.383, 0.414)	0.6223^a	0.188 (0.123, 0.264)	0.1075^a	0.583 (0.579, 0.586)	0.3032^a
	CLEAR	0.572 (0.569, 0.575)	0.0041^b	0.445 (0.436, 0.453)	0.0468^b	0.706 (0.706, 0.707)	0.4517^b
	KEYNOTE-426	0.456 (0.451, 0.461)	0.1475^c	0.337 (0.324, 0.350)	0.5635^c	0.601 (0.600, 0.603)	0.3602^c
Intermediate/Poor	CheckMate 214	0.368 (0.365, 0.372)		0.350 (0.346, 0.354)		0.496 (0.495, 0.497)
	CheckMate 9ER	0.364 (0.358, 0.370)	0.9129^a	0.251 (0.238, 0.264)	0.0132^a	0.470 (0.467, 0.472)	0.5250^a
	CLEAR	0.470 (0.467, 0.473)	0.0220^b	0.351 (0.343, 0.359)	0.9847^b	0.494 (0.491, 0.496)	0.9594^b
	KEYNOTE-426	0.363 (0.358, 0.368)	0.8948^c	0.269 (0.258, 0.279)	0.0354^c	0.444 (0.441, 0.446)	0.1734^c

p-values from CheckMate 214 vs. CheckMate 9ER.

p-values from CheckMate214 vs. CLEAR.

p-values from CheckMate 214 vs. KEYNOTE-426.

PFS

In the favorable risk cohort, len-pembro had the highest DR (57.2%) and EDR (44.5%), while ipi-nivo had the lowest DR (36.0%) and cabo-nivo had the lowest EDR (18.8%) (Figure 1A) (Table 2). For the sunitinib arms, CheckMate 214 had the highest DR (58.4%) and EDR (43.7%) (Figure 1C). In the intermediate/poor risk cohort, len-pembro had the highest DR (47.0%) and EDR (35.1%), while axi-pembro and cabo-nivo had the lowest DR (36.3% and 36.4%, respectively) and EDR (26.9% and 25.1%, respectively) (Figure 2A). For the sunitinib arms, CheckMate 214 had the highest DR (27.1%) and EDR (18.6%) compared to the three TKI-ICI trials (Figure 2C).

Figure 1.

(A) Kaplan-Meier curves for progression-free survival of the immune checkpoint inhibitor arms in favorable risk groups. (B) Kaplan-Meier curves for overall survival of the immune checkpoint inhibitor arms in favorable risk groups. (C) Kaplan-Meier curves for progression-free survival of the sunitinib arms in favorable risk groups. (D) Kaplan-Meier curves for overall survival of the sunitinib arms in favorable risk groups.

Figure 2.

(A) Kaplan-Meier curves for progression-free survival of the immune checkpoint inhibitor arms in intermediate/poor risk groups. (B) Kaplan-Meier curves for overall survival of the immune checkpoint inhibitor arms in intermediate/poor risk groups. (C) Kaplan-Meier curves for progression-free survival of the sunitinib arms in intermediate/poor risk groups. (D) Kaplan-Meier curves for overall survival of the sunitinib arms in intermediate/poor risk groups.

OS

In the favorable risk cohort, the long-term OS rate was highest for len-pembro (70.6%) and lowest for cabo-nivo (58.3%), although there was no significant difference for the ICI arms between the four trials (p = 0.11) (Figure 1B) (Table 2). For the sunitinib arms, CheckMate 214 had the highest long-term OS at 68.2% while CheckMate 9ER had the lowest at 56.9%, but there was no significant difference for the sunitinib arms between the four trials (p = 0.55) (Figure 1D). In the intermediate/poor risk cohort, ipi-nivo had the highest long-term OS rate (49.6%) while axi-pembro had the lowest rate (44.4%), without any significant difference between the ICI arms (p = 0.22) (Figure 2B). For the sunitinib arms, CLEAR had the highest long-term OS at 43.7% while CheckMate 9ER had the lowest at 34.7%, but there was also no significant long-term OS difference for the sunitinib arms between the four trials (p = 0.26) (Figure 2D).

Discussion

From these four pivotal phase 3 trials evaluating ICI-based regimens versus sunitinib for patients with previously untreated mccRCC, there is a proportion of patients in both favorable risk and intermediate/poor risk with PFS beyond 36 months and OS beyond 48 months, suggesting the durability of ICI-based regimens for these subsets of patients.

TKI-ICI combinations generally had higher PFS rates at 24 months and 36 months compared to ICI doublet. Although not analyzed in this article, the three TKI-ICI combinations had higher objective response rates compared to ICI doublet, suggesting a “TKI effect.” TKIs can block cancer cell signaling immediately, while it can take time for ICIs to induce upregulation of the immune system to kill cancer cells. This can translate into a higher tumor shrinkage from TKI use, as shown with the higher objective response rates in the TKI-ICI trials and higher PFS rates. However, there was no difference for long-term OS between TKI-ICI and ICI doublet when stratified by risk group. ICIs have the potential to offer long remission in a subset of patients. It has been hypothesized that a dual ICI regimen with a PD-1 and CTLA-4 might have the potential to offer durable remissions to a higher proportion of patients, and we would expect to see differences in long-term OS. With four years of follow-up, our analysis suggests similar landmark analysis, yet this investigation will require longer follow-up, particularly for the favorable risk group.

There were two phase 2 trials with frontline PD-1 ICI monotherapy for mccRCC: nivolumab in HCRN GU16-260-Cohort A¹⁴ and pembrolizumab in KEYNOTE-427 cohort A.¹⁵ In HCRN GU16-260-Cohort A, the 24-month PFS was approximately 60% for the 35 favorable risk patients, 10% for the 76 intermediate risk patients, and 30% for the 12 poor risk patients.¹⁴ In KEYNOTE-427 cohort A, the 24-month PFS was reported to be 19.1% for 42 patients with favorable risk and 24.4% for 68 patients with intermediate/poor risk.¹⁵ Although long-term follow-up data for the different risk groups in these two trials were not published, the KM curves demonstrated the potential of single agent PD-1 inhibitor to have beneficial long-term outcomes in a subset of patients in all risk cohorts. The 24-month PFS rates overall appear lower than the ICI combination arms of the four phase 3 trials, suggesting the added benefit of a second agent, but patients who cannot tolerate the combination may still benefit long term from single agent PD-1 inhibitor.

The TKI doses selected for the phase 3 trials were noteworthy, particularly for lenvatinib in CLEAR and cabozantinib in CheckMate 9ER. In the Study 205 phase 2 trial, the second-line combination of lenvatinib and everolimus used a lenvatinib dose of 18 mg.¹⁶ The frontline lenvatinib and everolimus arm in the CLEAR trial also used a lenvatinib dose of 18 mg, but the len-pembro arm used a higher lenvatinib dose of 20 mg. In contrast, the CABOSUN phase 2 trial evaluated frontline cabozantinib 60 mg versus sunitinib,¹⁷ while the CheckMate 9ER study used a lower dose of cabozantinib 40 mg when combined with nivolumab. Whether the adjusted TKI dosage led to better DR and EDR for CLEAR over CheckMate 9ER requires further investigation.

As expected, favorable risk patients had a higher DR, EDR, and long-term OS compared to intermediate/poor risk patients for both ICI regimens and sunitinib. The promising eight-year follow-up of the favorable risk cohort in CheckMate 214 helped make ipi-nivo a preferred regimen (category 2A) for favorable risk disease in the recent NCCN guidelines updated in July 2024.¹⁸ However, this indication of ipi-nivo for favorable risk disease has not yet been regulatory approved.

It is noteworthy that the sunitinib control arms in CheckMate 214 had the highest PFS for the favorable risk and intermediate/poor risk groups compared to the sunitinib control arms of the TKI-ICI trials. This emphasizes that despite similar enrollment criteria and the same sunitinib control arm for all trials, there remains heterogeneity among these trials. CheckMate 214 and KEYNOTE-426 had a higher proportion of enrolled patients with prior nephrectomy (80–83%) compared to CheckMate 9ER and CLEAR (70–75%), possibly due to influence of the CARMENA trial suggesting the non-inferiority of sunitinib alone compared to nephrectomy followed by sunitinib.¹⁹ It is also plausible that there may be a higher proportion of patients with a higher angiogenic signature determined by RNA sequencing which corresponded to better outcomes with sunitinib were enrolled in CheckMate 214.²⁰ Biomarker comparison among the different trials derived from RNA sequencing is not available and cannot be balanced between these trials.

We recognize the limitations of using pseudo IPD, which is an approximation of IPD and is thus associated with small inaccuracies, and therefore caution must be used to interpret our findings. However, in the absence of IPD from the phase 3 trials, this method can offer very similar estimates to true IPD analysis.¹² We evaluated the PFS and OS data, combining both intermediate and poor risk groups, as individual data for these groups was not publicly available for most trials. CheckMate 9ER was the only trial to publish Kaplan-Meier curves for PFS and OS for the intermediate and poor risk groups separately, but the other trials did not, so the intermediate and poor risk groups could not be analyzed separately. There were differences in the proportion of the different risk groups in these trials; notably, CheckMate 214 and CheckMate 9ER had the lowest percentage of favorable risk, and CheckMate 9ER had the highest percentage of poor risk. There are no simple methods to balance out these differences between the trials. Similarly, not all trials have reported the outcomes specifically for the subset of patients with sarcomatoid and rhabdoid features, which is a group of patients with poor prognosis and likely impacted overall results. Even if the baseline characteristics were matched or adjusted for, some confounders may remain unaccounted for, leading to residual confounding. Furthermore, we could not evaluate access to subsequent therapies as they are only available for the ITT population and not for the different risk groups, concealing their potential OS implications. The enrollment periods for these trials varied significantly and newer and more effective therapies have been approved since 2015.

In conclusion, using pseudo IPD, TKI-ICI was overall associated with higher DR and EDR regardless of risk status compared to ipi-nivo, but long-term OS rates were similar between these four regimens when stratified by favorable versus intermediate/poor risks. Longer follow-up is necessary to evaluate the differences in outcomes for these patients, especially regarding OS. Our findings should reassure providers that patients with mccRCC are currently receiving the best care with any ICI-based regimen as frontline therapy. Longer follow-up of these trials is warranted to determine if there are truly any long-term differences in OS.

Supplemental Material

sj-docx-1-kca-10.1177_24684570241311419 - Supplemental material for Durable responses to immune checkpoint inhibitor-based regimens for metastatic clear cell renal cell carcinoma stratified by IMDC risk groups: A pooled analysis of four randomized phase 3 trials

Supplemental material, sj-docx-1-kca-10.1177_24684570241311419 for Durable responses to immune checkpoint inhibitor-based regimens for metastatic clear cell renal cell carcinoma stratified by IMDC risk groups: A pooled analysis of four randomized phase 3 trials by Albert Jang, Jeffrey Y. Zhong, Hamsa L.S. Kumar, Kevin K. Zarrabi, Alec Zhu, Abby L. Grier, Adam Calaway, Jonathan E. Shoag, Laura Bukavina, Angela Y. Jia, Prateek Mendiratta, Iris Y. Sheng, Santosh Rao, Jason R. Brown, Jorge A. Garcia, Seunghee Margevicius, Pingfu Fu and Pedro C. Barata in Kidney Cancer

Footnotes

Acknowledgements

The authors have no acknowledgements.

ORCID iDs

Albert Jang

Jeffrey Y. Zhong

Alec Zhu

Abby L. Grier

Angela Y. Jia

Jason R. Brown

Seunghee Margevicius

Pingfu Fu

Pedro C. Barata

Author contributions

AJ, PCB: performance, interpretation of data, writing, and conception.

JYZ, HLSK, KKZ, AZ, ALG, AC, JES, LB, AYJ, PM, IYS, SR, JRB, JAG: interpretation of data and writing.

SM, PF: performance, statistical analysis, and interpretation of data.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

AJ reports personal fees from RealTimeCase. KKZ reports honoraria from OncLive and Curio; consulting fees from Exelixis, AstraZeneca, and Esai; and grants from Janssen, Exelixis, and Amgen. AC reports a consultant/scientific advisory board role for Fortec Medical, and travel expenses from ASCO. JES reports personal fees from Fortec Medical and grants from BMS Foundation. LB reports consulting fees from Charite and UroGen Pharma, has received funding from Bladder Cancer Advocacy Network, and is an Associate Editor of European Urology and on the Editorial Board Member Urology Times. AYJ reports personal fees from Blue Earth and Myovant. PM has received honoraria from Astellas, Seattle Genetics, and Astra Zeneca, and consulting for Seattle Genetics and Cardinal Health Care. JRB participates in a speaker bureau and advisory board for EMD Serono, Pfizer, and Janssen; has received consulting fees from AstraZeneca; and has received institutional funding from Bicycle Therapeutics, Seattle Genetics, EMD Serono, Jounce Therapeutics, and Novita. JAG is an Editorial Board Member of this journal but was not involved in the peer-review process nor had access to any information regarding its peer-review. JAG reports personal fees from Pfizer, Aptitude Health, and the US Food and Drug Administration. PCB reports honoraria from UroToday; a consulting or advisory role for Bayer, BMS, Pfizer, EMD Serono, Eisai, Caris Life Sciences, Dendreon (institutional), AstraZeneca, Exelixis, AVEO, Merck, and Ipsen; speaker bureau fees from Caris Life Sciences (institutional), Bayer (institutional), Pfizer/Astellas (institutional), AstraZeneca, and Merck; institutional research funding from Blue Earth Diagnostics, Aveo, Pfizer, and Merck; and personal research funding from Exelixis. JYZ, HLSK, AZ, ALG, IYS, SR, SM, and PF report no conflicts of interest.

Supplemental material

Supplemental material for this article is available online.

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