* # Correspondence: Prof. Michael D. Staehler. Ludwig-Maximilians University of Munich, D-80539 München, Germany; Email: Michael.Staehler@med.uni-muenchen.de
ABSTRACT
BACKGROUND AND OBJECTIVE: Despite extensive trials investigating tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) for adjuvant therapy in renal cell carcinoma (RCC), only two have resulted in FDA approvals. At the IKCSEU24 Think Tank, 31 experts convened to define future research priorities. METHODS: The group used an open forum and breakout groups to make key recommendations. RECOMMENDATIONS AND FUTURE DIRECTIONS: Recommendations include to improve patient selection by moving beyond traditional TMN staging and develop tumorbased biomarkers of response; to limit overtreatment by prioritizing the detection of minimal residual disease through novel approaches (e.g., circulating tumor DNA (ctDNA)). The group advocated for the application of novel clinical trial endpoints to speed clinical development, such as time to firstline therapy for metastatic disease (TTFT) and emphasized the importance of patientcentered outcomes like quality of life and functional status. Collaborative efforts across institutions and industry are necessary to share data, streamline protocols, and explore novel therapeutic approaches. CONCLUSIONS: Future advancements in RCC adjuvant therapy should focus on drugs with new mechanisms of action, enhanced patient selection, and minimizing longterm toxicity.
INTRODUCTION
A djuvant therapy for locally advanced renal cell carcinoma (RCC) has been investigated with a plethora of clinical trials based on VEGF ty rosinekinase (TKI) and immunecheckpoint inhib itors (ICI) with only two trials showing diseasefree survival (DFS) benefit and only one trial showing an overall survival (OS) benefit, sparking debate on its routine use.
Out of 17 trials using VEGF TKIs, mTOR inhibi tors and ICIs, only two met their primary endpoint. Sunitinib was approved for adjuvant therapy in high risk patients by the FDA based on significantly pro longed diseasefree survival (DFS). The only trial that has shown an overall survival (OS) benefit was the KEYNOTE564 trial investigating pembrolizumab in a similar setting.1 Pembrolizumab was initially ap proved for adjuvant therapy based on DFS in 2023, with the final OS benefit reported in 2024.2 TKIs can cause fatigue, diarrhea, hypertension, and handfoot syndrome. ICIs can lead to immunerelat ed adverse effects with organ inflammation, which can be severe and longlasting. Given these side ef fects and the commitment required, it's crucial to weigh the qualityoflife impact and financial costs and clinical benefit. Recent trials indicate that in the setting of advanced disease, sequential immunother apy after initial combination treatments is not effec tive, necessitating a reevaluation of future adjuvant therapy research.3,4
Table 1. Risk of Bias Table of Adjuvant Trials in aRCC (Cochrane RoB 2.0 tool)
METHODS
During the European International Kidney Cancer Symposium (IKCSEU24) conference organized by the Kidney Cancer Association (KCA) in April 2024 a panel of 31 international experts convened for the KCA Think Tank. The KCA Think Tank meetings, which occur the day before the start of the IKCS con ference, have become a key forum for thought lead ers to collaboratively address significant challenges in kidney cancer research and clinical care. The group included clinicians, academic researchers and pa tient advocates as well as industry representatives. This year’s discussion centered on defining future re search principles for adjuvant therapy for RCC. The goal was to share ideas, establish collaborations, and advance scientific progress in addressing this clin ically unique situation. Building on feedback from the original recommendations, the panel of experts discussed and later voted on proposals regarding the diagnosis, management, and clinical trial eligibility criteria for adjuvant therapy in RCC in order to agree recommendations. Not all participants could attend for the entire meeting. Some participants, who partic ipated virtually, disconnected from online participa tion, while others couldn’t vote on the endpoint devel opment questions discussed later in this manuscript. The recommendations from the meeting were drafted and circulated electronically among participants, who provided additional input until a final consensus was reached. All coauthors participated in the review and final approval of the manuscript.
Table 2. Key eligibility criteria for inclusion into adjuvant trials. A) trials investigation TKI. B) trials investigating immunotherapy.
Identification of similarities and risk of bias in adjuvant trials
A formal Cochran 2.0 analysis was performed and presented prior to the meeting to identify relevant studies, address the risk of bias and to compare in clusion and exclusion criteria (Table 1-3). Some con cerns about bias arose from missing data on endpoints in Checkmate914 and IMmotion010. In addition, SORCE and PROSPER were deemed to have a high potential for bias of endpoints.5-8 All other trials were perceived to have a lower risk of bias.1,9-11 , Some trials did not provide enough insight to be evaluated com pletely as they only have preliminary data.12,13 Details on trial characteristics and patient selection are given in Tables 1-3. Inclusion criteria varied amongst trials and different risk classifications were used making it difficult to compare placebo arms of adjuvant trials. The only positive trial investigating immunotherapy also included patients who underwent metastasecto my for oligometastatic disease within the first year af ter nephrectomy.2
Enhancing Patient Selection
The focus on improving patient selection in clinical trials aims to address the difficulty in comparing out comes due to diverse trial populations. Enhancing se lection processes to target higher-risk patients can im prove trial results and avoid exposing lowrisk patients to unnecessary and harmful treatments. This approach seeks to better tailor interventions to those who will benefit most, optimizing trial design and therapeutic strategies to reduce unnecessary overtreatment for lowrisk patients.
Table 3A. Inclusion criteria used for stratification in TKI-based adjuvant trials
Currently, no consensus has been reached regarding
the optimal patient populations for adjuvant therapy.
To address this, efforts should be made to pool data
from placebo groups across clinical trials, enabling a
more comprehensive analysis and better patient selec
tion strategies. The group agreed to reach out to phar
maceutical companies to gain access to these data, and
structures for analysis have been established. Industry
representatives expressed a favorable outlook toward
providing these data, although formal commitments
have yet to be made. The group also concurred that
future research should prioritize minimalresidual
disease over TNMbased pathology risk groups. They
highlighted circulating ctDNA as a potential pivotal
marker in this area, recommending it be considered a
primary focus for future investigations.14, 15
Table 3B. Eligibility criteria used for stratification in ICI-based adjuvant trials
Developing New Endpoints
A need to generate new, faster endpoints was dis cussed to shorten the time required for trial readouts. This includes exploring more refined and highreso lution endpoints, which are critical for quicker and more reliable trial outcomes. Among the endpoints discussed, overall survival was still favored by 10 out of 26 (38% participants on the vote), recurrencefree survival (RFS) by 12 (46%), while the majority, 18 out of 26 (69%) participants, prioritized time to firstline therapy (TTFT) for metastatic disease.
Patient Centricity in Endpoints and Trial Design
Patient preferences and the potential side effects of adjuvant therapies, which often have a substantial im pact on daily life, should be central to future trial de signs. A key aspect is how clinical trials can be designed to not only assess the efficacy and safety of treatments but also evaluate their effects on patients' quality of life. This includes considering a broader range of outcomes that are meaningful to patients, such as functional sta tus, symptom burden, and overall wellbeing. Ensuring transparency about the potential benefits and risks of trial participation is essential. Patients need to be thoroughly informed about the nature of the research, the possible outcomes, and how their in volvement could shape future medical practices. Such transparency fosters trust and ensures that patients feel valued, appreciated and respected as research partners. Ethical considerations emphasize the need to prioritize patient participation in trial design, givingthem a voice in the research that directly influences their care.
Statistical Challenges and Solutions
Inclusion of patients with a low risk of recurrence may results in a low signaltonoise ratio and the un derpowered nature of many RCC trials.14This chal lenge may be mitigated with better patient selection as well as refining statistical methodologies. Endpoints that offer highresolution data and faster readouts could also help. The latter can be achieved by utiliz ing informationrich highresolution endpoints. This could include incorporating more sensitive biomarkers or shorterterm clinical endpoints, which may provide quicker and clearer insights than traditional endpoints such as overall survival (OS).
Table 3C. Prognostic models used for stratification in ICI-based adjuvant trials still recruiting.
Prioritizing ordinal over binary longitudinal response
outcomes also can contribute to this effort.15 For ex
ample, instead of the binary RFS outcome of presence
or absence of disease recurrence or death (whichev
er comes first), statistical power can be increased by
having several levels of recurrence with the lowest lev
el representing “none”, followed by recurrence levels
based on the number of recurrent lesions or organ sites
where recurrence occurred. “Death” due to disease re
currence would be the highest (worst) level. Together
with conventional approaches like timetoevent mod
eling, ordinal outcomes can be analyzed using new
er methodologies such as ordinal transition models,
recently popularized to rapidly develop therapeutics
while ensuring safety and efficacy in the context of
COVID-19 clinical trials. From an informationtheo
retic standpoint, papillary and chromophobe RCC are
more rare and less likely to recur than clear cell RCC,
which considerably reduces the effective sample size
making adjuvant randomized clinical trials (RCTs) for
these histologies impractical.14 This may be addressed
by employing informationrich highresolution end
points, developing reliable clinical prediction models
to identify and enrich for papillary and chromophobe
RCC patients at high risk of recurrence, and utilizing
established strategies to increase RCT precision, such
as stratification and covariate adjustment.16
Integration of Molecular and Clinical Data
The integration of molecular data with clinical out comes is a potential way to better predict recurrence and tailor treatments more effectively. If there is access to clinical trial data from either failed trials or control arms, and if it were possible to access tumor tissues, blood or plasma, assays could be run and results inte grated into a multiparametric analysis to identify bet ter predictors of recurrence with the goal of improving patient selection, lower overtreatment and associated toxicities, and build new algorithms. Industry partners signaled that they were willing to contribute the col lected data and specimens from placebo arms of their trials towards this effort.
Regulatory and Ethical Considerations
The discussions also addressed navigating regulato ry frameworks and ensuring that ethical standards are upheld, especially regarding patient consent and data utilization. Overall, the group agreed that no signifi cant ethical or regulatory concerns are anticipated in the pursuit of optimizing adjuvant therapy.
Collaborative Research Efforts
Strengthening collaboration among research cen ters and across disciplines is crucial for breaking down barriers to patient access and ensuring the global stan dardization of treatment. These joint efforts are vital for sharing resources, harmonizing protocols, and effi ciently disseminating findings.
CONCLUSION
Future advancements in adjuvant therapy for RCC must prioritize innovative mechanisms of action. Equally critical is the need for more precise risk strat ification to guide patient selection, especially avoid ing overtreatment through refined inclusion criteria. In addition, the development of improved endpoints must place longterm toxicity, quality of life, and indi vidual patient needs at the forefront, ensuring a truly patientcentered approach with enhanced endpoints in adjuvant therapy.
Acknowledgments
The authors thank Eisai and Pfizer for providing sup port for the IKCSEU24 Think Tank.Keywords
Adjuvant Therapy; Biomarkers; Renal Cell Carcino ma; Minimal Residual Disease; PatientCentered Outcome.
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