(UroToday.com) The 2025 American Society of Clinical Oncology (ASCO) Genitourinary (GU) Annual Symposium held in San Francisco, CA was host to a session on the current state and future directions of biomarkers and adjuvant therapy for renal cell carcinoma (RCC). Dr. Laurence Albiges discussed a practical guide to implementing adjuvant therapy in RCC in contemporary practice.
She noted that since ASCO 2021, pembrolizumab was established as the standard of care therapy in the post-nephrectomy adjuvant setting, demonstrating a disease-free survival benefit over placebo.1 A year ago, at GU ASCO 2024, this adjuvant strategy was demonstrated to have an overall survival benefit for the 1st time in RCC.2 In this presentation, Dr. Albiges reviewed:
- Who benefits from adjuvant therapy?
- How to discuss risk of relapse and risks associated with treatment itself
- Identify the gaps and next steps in the adjuvant setting
She began with a case presentation of a 54-year-old man with an incidental finding of a 6.5 cm right renal mass, with negative metastatic workup. He underwent upfront surgery with the following findings:
- Clear cell RCC measuring 5.2 cm
- ISUP 4
- 20% necrosis, 10% rhabdoid component, no sarcomatoid component
- Clear surgical margins, no lymphovascular invasion, no invasion of the pyelocaliceal system (pT3aN0R0)
What do the guidelines recommend in this setting? Such a patient, with pT3a disease, should be counseled on the benefits/risks of adjuvant pembrolizumab in this setting.
Who are these patients? The key eligibility criteria from the KEYNOTE-564 trial are summarized below:
In the initial publication in 2021, the KETYNOTE-564 trial demonstrated that adjuvant pembrolizumab was associated with significantly longer disease-free survival than placebo (24 months: 77% vs. 68%; HR: 0.68; 95% CI: 0.53–0.87; p=0.002).1
Subsequently, in 2024, a significant improvement in overall survival was observed with pembrolizumab, as compared with placebo (HR: 0.62; 95% CI: 0.44–0.87; p=0.005). The estimated overall survival at 48 months was 91.2% in the pembrolizumab group, as compared with 86% in the placebo group.3
How does this patient fit within the context of the KEYNOTE-564 trial? This patient falls within the pT2/G4 or pT3/Gx subgroup that accounted for ~80% of the trial cohort. In this subgroup, a ~10% DFS benefit (72% 81%) is observed at 24 months with the addition of adjuvant pembrolizumab. However, it is worth noting that 72% of patients in the placebo arm did not have disease recurrence, highlighting that many patients do not require adjuvant therapy.
How should patients be counseled about the risk of relapse? There are many nomograms available, such as the Fox Chase ASSURE RCC prognostic nomogram, MSKCC nomogram, and the Leibovich Mayo nomogram, that all rely on readily available clinicopathologic variables:
However, one of the limitations of these nomograms is the wide variability in the recurrence estimates – for the same patient. For example, for the patient discussed earlier, his metastasis-free survival probability would range from 31% in the Leibovich nomogram to as high as 89% in the MSKCC nomogram, highlighting the limitations of these nomograms in practice.
She highlighted the merging UroPredict nomogram, which employed a machine learning model on real-world data of 3,372 patients who underwent nephrectomy for TanyNanyM0 disease for predicting kidney cancer recurrences.4
How do we inform patients about the potential risks associated with treatment? First, we must recognize the patients’ perspectives on this subject matter. Presented at ASCO 2023, in work led by patient advocate, Dena Battle, patients with high-risk localized disease estimate their recurrence risk to be higher than their doctors. This highlights the presence of a knowledge gap in educating our patients, which may have important implications for treatment selection. From a preference standpoint, it is clear that patients rank risk of dying from cancer over risks related to toxicity when weighing decisions about adjuvant therapy. From an expectations standpoint, an overestimation of the benefits of adjuvant therapy is noted with one quarter of patients believing that adjuvant therapy will reduce their risk of recurrence by ≥50%.
So, how should we inform patients? The EAU provides guidance in this setting. If adjuvant therapy is discussed:
- Discuss the contradictory results available from adjuvant ICI trials with the patient to facilitate shared decision-making
- Inform the patient about the potential risk of overtreatment and immune-related side effects, if adjuvant therapy is considered
In pooled data of all trials of pembrolizumab in the adjuvant setting, including breast, melanoma, non-small cell lung cancer, it was observed that 16% of patients had Grade 3–5 adverse events, with almost all these patients discontinuing therapy.5
While immune-mediated high-grade toxicities are rare, occurring in <1–2%, some are life threatening and lifelong lasting. They require prompt diagnosis and management by a trained team.
What about adjuvant pembrolizumab use in the real world? At this meeting, three abstracts addressing real-world use of adjuvant pembrolizumab in RCC patients were presented. In the UK-based one presented by McCarty et al., it was notable that almost a third of patients did not complete the full course of adjuvant pembrolizumab either due to toxicity (24%) or recurrence (8%). Almost 20% of patients required high-dose steroids, and 14% were hospitalized for management of toxicity.
In the US-based one from the US Oncology Network, almost two-thirds of eligible patients received adjuvant pembrolizumab, of whom 91% had ccRCC (i.e., 9% who received therapy were non-ccRCC). Importantly, early referral to medical oncology was key, as those with a 1st oncologist visit ≥2 months post-nephrectomy had 61% lower odds (OR: 0.39, p=0.035) of receiving adjuvant pembrolizumab treatment.
In the German real-world study, it is notable that 42% of included patients had M1NED disease, an over-represented population compared to the KEYNOTE-564 cohort. Overall, key takeaways include:
- A broader spectrum of use than originally approved
- Short follow-up to date
- High rate of discontinuation
- High rate of toxicity
What are the data gaps? The ‘elephant in the room’, as Dr. Albiges noted, is the heterogeneity of results from the adjuvant IO studies. Why was KEYNOTE-564 positive for both DFS and OS, but IMmotion010,6 CheckMate-914,7 and PROSPER8 all negative for both DFS and OS?
Dr. Albiges elaborated on her own personal opinions as to why each of these trials was negative for a DFS/OS benefit:
IMmotion010:
- She argued that the activity of PD-1 inhibitors (pembrolizumab) is not the same as that of PD-L1 inhibitors, such as atezolizumab.
- Dose intensity and treatment duration were underwhelming in this trial
- Toxicity prevented ideal drug exposure
- Distinct patient population compared to KEYNOTE-564
- Challenges of academic neoadjuvant + adjuvant trial
- Patient population at lower risk of recurrence, compared to KEYNOTE-564
Can we use adjuvant pembrolizumab in papillary RCC? A 2021 study of pembrolizumab monotherapy as 1st line therapy in patients with advanced non-ccRCC suggests that this agent has promising activity, with an ORR of 29%, including 6% complete response and long-term duration of response.9
How do we treat patients with disease progression following adjuvant pembrolizumab? Randomized studies of agents with alternate mechanisms of action are needed.
What are the future directions in this space? The LITESPARK-002 is a global, multicenter, double-blind, randomized, phase III trial that is evaluating the combination of belzutifan (HIF-2α inhibitor) + pembrolizumab versus placebo + pembrolizumab in a cohort of patient similar to that in KEYNOTE-564.
A personalized vaccine approach to generate a prolonged anti-tumor response appears to be in the horizon, with early work in 9 patients demonstrating that none of them to date have experienced disease relapse:
Can we adopt a neoadjuvant/adjuvant approach in RCC, similar to what has been observed in melanoma?
The PROSPER trial8 failed to demonstrate a survival benefit with such a combined approach. Despite this being a negative trial, there are key lessons learned from this trial:
Neoadjuvant approaches are being evaluated in this setting with the published NEOAVAX trial of neoadjuvant axitinib10 and the ongoing NESCIO trial.
Finally, can we use biomarkers to help select patients for adjuvant therapy? Promising tools in this field include Kidney Injury Molecule-1 (KIM-1) and ctDNA:
Dr. Albiges concluded as follows:
- Adjuvant therapy for eligible RCC patients post-nephrectomy is standard of care!
- Discussing adjuvant therapy in eligible patients is needed, addressing both the information on the estimated risk of relapse and the potential toxicity related to treatment
- Further developments are ongoing
- To increase the benefit of adjuvant strategy
- To optimize the patient selection
Presented by: Laurence Albiges MD, PhD, Professor, Medical Oncology, Vice chair of the Department of Cancer Medicine at the Gustave Roussy Institute, Villejuif, France
Written by: Rashid K. Sayyid, MD, MSc – Robotic Urologic Oncology Fellow at The University of Southern California, @rksayyid on Twitter during the 2025 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, CA, Thurs, Feb 13 – Sat, Feb 15, 2025.
References:
- Choueiri TK, Tomczak P, Park SH, et al. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. N Engl J Med. 2021; 385(8):683-694.
- Choueiri TK, Tomczak P, Park SH, et al. Overall Survival Results from the Phase 3 KEYNOTE-564 Study of Adjuvant Pembrolizumab vs Placebo for the Treatment of Clear Cell RCC. J Clin Oncol. 2024; 42(4_suppl):LBA359.
- Choueiri TK, Tomczak P, Park SH, et al. Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma. N Engl J Med. 2024; 390:1359-1371.
- Margue G, Ferrer L, Etchepare G, et al. UroPredict: Machine Learning Model on Real-World Data for Prediction of Kidney Cancer Recurrence (UroCCR-120). NPJ Precis Oncol. 2024 ;8(1):45.
- Luke JJ, Ott PA, Powles T, et al. Safety of pembrolizumab as adjuvant therapy in a pooled analysis of phase 3 clinical trials of melanoma, non-small cell lung cancer, and renal cell carcinoma. Eur J Cancer. 2024; 207:114146.
- Pal SK, Uzzo R, Karam JA, et al. Adjuvant atezolizumab versus placebo for patients with renal cell carcinoma at increased risk of recurrence following resection (IMmotion010): a multicentre, randomized, double-blind, phase 3 trial. Lancet. 2022; 400(10359):1103-1116.
- Motzer RJ, Bex A, Rini BI, et al. Adjuvant nivolumab plus ipilimumab versus placebo for localized renal cell carcinoma after nephrectomy (CheckMate 914): a double-blind, randomized, phase 3 trial. Lancet. 2023; 401(10379):821-832.
- Allaf ME, McDermott DF, Haas NB, et al. Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER): a randomized, open-label, phase 3 trial. Lancet. 2024; 403(10370):43-56.
- McDermott DF, Lee JL, Ziobro M, et al. Open-Label, Single-Arm, Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Non-Clear Cell Renal Cell Carcinoma. J Clin Oncol. 2021; 39(7):1029-1039.
- Bex A, van Thienen JV, Schrier M, et al. A phase II, single-arm trial of neoadjuvant axitinib plus avelumab in patients with localized renal cell carcinoma who are at high risk of relapse after nephrectomy (NeoAvAx). Future Oncol. 2019l; 15(19):2203-2209.