(UroToday.com) The 2024 American Urological Association (AUA) annual meeting held in San Antonio, TX between May 3 and May 6, 2024, was host to the Society of Urologic Oncology (SUO) session Dr. Tian Zhang discussed risk stratification for identifying suitable candidates with high-risk renal cell carcinoma for adjuvant therapy.
Dr. Zhang initiated her presentation by delving into the chronological evolution of prognostic indicators and prognostic nomograms for renal cell carcinoma (RCC), as illustrated in Figure 1. She underscored a significant advancement since 2003 in risk stratification for RCC patients, enabling more precise selection for adjuvant therapies.
Continuing her presentation, Dr. Zhang delved into the UCLA integrated staging score, which uses TNM staging, Fuhrman grade, and ECOG PS. This scoring system underwent validation in a cohort of 661 patients who underwent nephrectomy at UCLA. Analysis of four distinct risk groups revealed significant disparities in overall survival among these risk categories.
Additionally, Dr. Zhang covered the Mayo Clinic/Leibovich score, validated in 1,671 patients at the Mayo Clinic, demonstrating excellent discrimination between risk groups for metastasis-free survival using a point-based system. Transitioning to the ASSSURE nomogram, the latest tool for risk-stratifying RCC patients, she highlighted its validation in patients from the ECOG-ASSURE trial. Initially validated in a training set of 1,139 patients and subsequently in a validation set of 596 patients, this nomogram predicts disease-free survival and OS from 1 to 10 years post-surgery, with an AUC of 0.68 (as shown in the figure below).
Dr. Zhang proceeded to outline the timeline of US FDA-approved therapies for advanced or locally advanced RCC. She emphasized significant progress over the past decade, resulting in numerous available treatment options. However, controversy remains regarding whether these therapies offer benefits in the adjuvant RCC setting. Dr. Zhang then delved into clinical trials assessing adjuvant systemic therapy post-nephrectomy for high-risk localized or locally advanced RCC during the era of immune checkpoint inhibitors (IO). She discussed five trials: IMmotion 10, Keynote 564, CheckMate 914, PROSPER, and Rampart.1-4 Each trial investigated different molecules, and inclusion criteria varied considerably among them, as illustrated in the figure below:
The inclusion criteria for each of these trials varied. Keynote 564, IMmotion 010, and PROSPER included patients with the highest-risk disease and allowed enrollment of those with M1 NED (non-evidence of disease) status. In contrast, CheckMate 914 also included patients with the lowest-risk disease (T2a G3). Understanding these differences in inclusion criteria could provide insights into the variations observed in clinical outcomes across these trials and aid in the selection of high-risk candidates who would derive the most benefit from adjuvant therapy.
Dr. Zhang moved up to discuss the CheckMate 914 trial, this is a phase 3, randomized, double-blind, multicenter, two-part trial evaluating adjuvant nivolumab + ipilimumab vs placebo (Part A) or adjuvant nivolumab monotherapy vs placebo (and nivolumab monotherapy vs nivolumab + ipilimumab to assess the contribution of components; Part B). Patients eligible for CheckMate 914 included those undergoing radical or partial nephrectomy between 4 and 12 weeks before randomization with negative surgical margins with predominantly clear cell histology (with or without sarcomatoid features), pathological TNM stage T2a (grade 3/4) N0M0, T2b-T4 (any grade) N0M0, or any T (any grade) N1M0, and no evidence of residual disease or distant metastases (M0). 
Dr. Zhang provided an overview of the Keynote 564 trial study design and outcomes. Notably, she emphasized that around 12-13% of the patients enrolled had high-risk disease. Within the Pembrolizumab arm, 5.8% of patients had M1 NED (non-evidence of disease) status, a proportion that was mirrored in the placebo arm, where 5.6% of patients had the same status.
The Keynote 564 trial was the first trial in the adjuvant RCC space to show some benefit in OS (HR 0.62 95% CI 0.44-0.87, p=0.002). Most importantly the proportion of patients who received subsequent therapies in the intention to treat population after relapse was phenomenal with an overall subsequent therapy given to 79.5% in the Pembrolizumab arm and 81.4% in the placebo arm. (Figure below)
Additionally, the Keynote 564 trial confirmed a disease-free survival (DFS) benefit in patients with sarcomatoid features. This finding expands treatment options for individuals with sarcomatoid features in the adjuvant treatment space. Dr. Zhang emphasized the importance of striking a balance between the benefits and risks associated with administering adjuvant therapy after nephrectomy. She underscored that the decision must be tailored to each patient's preferences, priorities, tolerance for toxicity, and treatment goals. Dr. Zhang stressed the significance of engaging in shared decision-making when considering adjuvant therapy for RCC.
As she concluded her presentation, Dr. Zhang highlighted two trials in the perioperative space. The first is an investigator-initiated trial evaluating Lenvatinib + Pembrolizumab for RCC with IVC thrombus (NCT05319015), this trial included patients with histologically confirmed ccRCC and cT3/T4 disease, level 2-4 IVC tumor thrombus, with no pre-existing metastatic lesions. Its primary endpoint is disease control rate. While the second is the Litespark-022 trial, which investigates Belzutifan + Pembrolizumab versus Placebo + Pembrolizumab for adjuvant RCC, this trial included patients with Intermediate-high risk disease: pT2, Grade 4 or sarcomatoid, N0, M0; pT3, any Grade, N0, M0; High risk: pT4, any Grade, N0, M0; any pT, any Grade, N+, M0, and M1 no evidence of disease (NED) after surgery (≤ 2 years from nephrectomy). The primary endpoint of the LITESPARK trial is disease-free survival by investigator.
The key takeaways from Dr Zhang’s presentation were:
- Risk factors for recurrence can be calculated through clinical and pathologic features.
- Trial populations differ by risk and exposure to subsequent treatment, impacting outcomes.
- For adjuvant therapy, choose patients at the highest risk, and most likely to benefit from treatment.
- Shared decision-making is critical to help patients feel comfortable with their treatment vs surveillance decision.
Presented by: Tian Zhang, MD, Medical Oncologist, UT Southwestern Medical Center, Dallas, TX
Written by: Julian Chavarriaga, MD - Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @chavarriagaj on Twitter during the 2024 American Urological Association (AUA) annual meeting held in San Antonio, TX between May 3rd and May 6th, 2024
References:
- Motzer, R. J., et al. LBA4 Adjuvant nivolumab plus ipilimumab (NIVO+ IPI) vs placebo (PBO) for localized renal cell carcinoma (RCC) at high risk of relapse after nephrectomy: Results from the randomized, phase III CheckMate 914 trial. Annals of Oncology33 (2022): S1430.
- Powles, Thomas, et al. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Oncology 23.9 (2022): 1133-1144.
- Allaf, M., et al. LBA67 Phase III randomized study comparing perioperative nivolumab (nivo) versus observation in patients (Pts) with renal cell carcinoma (RCC) undergoing nephrectomy (PROSPER, ECOG-ACRIN EA8143), a National Clinical Trials Network trial. Annals of Oncology 33 (2022): S1432-S1433.
- Oza, Bhavna, et al. RAMPART: A phase III multi-arm multi-stage trial of adjuvant checkpoint inhibitors in patients with resected primary renal cell carcinoma (RCC) at high or intermediate risk of relapse. Contemporary Clinical Trials 108 (2021): 106482.